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EVERYDAY UROLOGY ONCOLOGY INSIGHTS – A UROTODAY® PUBLICATION TM VOLUME 1, ISSUE 2 Bone Metastases and Mortality in Prostate Cancer: Can We Be Doing More? NEAL SHORE, MD, FACS The Story of the COU-AA-302 Clinical Trial: Highlights from the Journey CHARLES J. RYAN, MD Axumin™ [Fluciclovine F 18]: An Accurate Imaging Approach for Patients with Biochemically Recurrent Prostate Cancer KAREN E. LINDER, MS, PhD Spotlight: Beyond the Abstracts For mCRPC patients with symptomatic bone metastases1 Introduce Xofigo® at the first sign of progression on hormonal therapy1* *In ALSYMPCA, best standard of care (BSOC) was defined as antihormonal agents, local external beam radiation therapy (EBRT), ketoconazole, and treatment with glucocorticoids.2 XOFIGO® IS INDICATED for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease. with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression— notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia—has been reported in patients treated with Xofigo. Important Safety Information Monitor patients with evidence of compromised bone marrow • Contraindications: Xofigo is contraindicated in women who reserve closely and provide supportive care measures when are or may become pregnant. Xofigo can cause fetal harm clinically indicated. Discontinue Xofigo in patients who when administered to a pregnant woman experience life-threatening complications despite supportive • Bone Marrow Suppression: In the randomized trial, 2% of care for bone marrow failure patients in the Xofigo arm experienced bone marrow failure • Hematological Evaluation: Monitor blood counts at baseline or ongoing pancytopenia, compared to no patients treated and prior to every dose of Xofigo. Prior to first administering with placebo. There were two deaths due to bone marrow Xofigo, the absolute neutrophil count (ANC) should be failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should who experienced bone marrow failure, 54% required blood be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue transfusions. Four percent (4%) of patients in the Xofigo Xofigo if hematologic values do not recover within 6 to 8 weeks arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized after the last administration despite receiving supportive care trial, deaths related to vascular hemorrhage in association S I G N I F I C A N T LY E X T E N D OV E R A L L S U R V I VA L ( OS ) 1,2a MME EDDI AI ANNOOSSWI INT HA NO RE XWP ILTOHROAT U TO RC YO NA CNOA M LYIST A I SN1,2b T U S E O F A B I R AT E R O N E 9 a 100 HR=0.695 (95% CI: 0.581-0.832) Probability of survival (%) 90 14.9 MONTHS Planned course of Xofigo treatment is 6 doses 80 70 60 50 40 for Xofigo + BSOC (n=614) (95% CI: 13.9-16.1) 30 % reduction in the risk of death vs placebo (HR=0.695)1,2 11.3 MONTHS 30 for placebo + BSOC (n=307) (95% CI: 10.4-12.8) 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 41 14 18 7 7 4 1 2 0 1 0 0 Time (months) Xofigo 6 1 4 Placebo 3 0 7 578 288 504 228 369 157 277 104 178 67 105 39 60 24 In the prespecified interim analysis.1 An exploratory updated OS analysis was performed before patient crossover, incorporating an additional 214 events, resulting in findings consistent with the interim analysis.1 a b • Prespecified interim analysis: median OS was 14.0 months for Xofigo (95% Conf idence interval [CI]: 12.1-15.8) vs 11.2 months for placebo (95% CI: 9.0-13.2)1 – P=0.00185; Hazard ratio [HR]=0.695 (95% CI: 0.552-0.875) • Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued • Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations • Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and © 2016 Bayer. All rights reserved. BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer. PP-600-US-2253 06/16 Printed in USA peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) References: 1. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; March 2016. 2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223. Please see following pages for brief summary of full Prescribing Information. radium Ra 223 dichloride INJECTION Learn more about Xofigo at hcp.xofigo-us.com XOFIGO (radium Ra 223 dichloride) Injection, for intravenous use Initial U.S. Approval: 2013 BRIEF SUMMARY oF pREScRIBIng InFoRMAtIon conSULt pAcKAgE InSERt FoR FULL pREScRIBIng InFoRMAtIon 1 INDICATIONS AND USAGE Xofigo® is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. 2 DOSAGE AND ADMINISTRATION 2.3 Instructions for Use/Handling General warning Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal Xofigo are subject to the regulations and/or appropriate licenses of the competent official organization. Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations. For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution is recommended to remove contamination. For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly and separately from other clothing. Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. 4 CONTRAINDICATIONS Xofigo is contraindicated in pregnancy. Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Bone Marrow Suppression In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infectionrelated deaths (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate singledose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions (6)]. Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience lifethreatening complications despite supportive care for bone marrow failure. The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label: • BoneMarrowSuppression[see Warnings and Precautions (5.1)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 55 kBq/kg (1.49 microcurie/kg) of Xofigo and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Xofigo exceeds the incidence for placebo. Table 3: Adverse Reactions in the Randomized Trial System/Organ Class Xofigo (n=600) Placebo (n=301) Preferred Term Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 % % % % Blood and lymphatic system disorders Pancytopenia 2 1 0 0 Gastrointestinal disorders Nausea 36 2 35 2 Diarrhea 25 2 15 2 Vomiting 19 2 14 2 General disorders and administration site conditions Peripheral edema 13 2 10 1 Renal and urinary disorders Renal failure and impairment 3 1 1 1 Laboratory Abnormalities Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for Xofigo exceeds the incidence for placebo. Table 4: Hematologic Laboratory Abnormalities Hematologic Xofigo (n=600) Placebo (n=301) Laboratory Grades 1-4 Grades 3-4 Grades 1-4 Grades 3-4 Abnormalities % % % % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle. As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of docetaxel naïve patients and in 3% of patients who have received prior docetaxel. Fluid Status Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia. Injection Site Reactions Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo. Secondary Malignant Neoplasms Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow up for patients on the trial. Subsequent Treatment with Cytotoxic Chemotherapy In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy. 7 DRUG INTERACTIONS No formal clinical drug interaction studies have been performed. Subgroup analyses indicated that the concurrent use of bisphosphonates or calcium channel blockers did not affect the safety and efficacy of Xofigo in the randomized clinical trial. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category X [see Contraindications (4)] Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Xofigo. 8.3 Nursing Mothers Xofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from Xofigo, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of Xofigo in pediatric patients have not been established. In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, disruption/ disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro-osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses beginning in the range of 22 – 88 kBq (0.59 - 2.38 microcurie) per kg body weight. 8.5 Geriatric Use Of the 600 patients treated with Xofigo in the randomized trial, 75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Patients with Hepatic Impairment No dedicated hepatic impairment trial for Xofigo has been conducted. Since radium-223 is neither metabolized by the liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment due to lack of clinical data. 8.7 Patients with Renal Impairment No dedicated renal impairment trial for Xofigo has been conducted. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CrCl less than 30 mL/ min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)]. 8.8 Males of Reproductive Potential Contraception Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with Xofigo. Infertility There are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility [see Nonclinical Toxicology (13.1)]. 10 OVERDOSAGE There have been no reports of inadvertent overdosing of Xofigo during clinical studies. There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate. SingleXofigodosesupto274kBq(7.41microcurie)perkgbodyweightwere evaluated in a phase 1 clinical trial and no dose-limiting toxicities were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted to evaluate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats. Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation. Animal studies have not been conducted to evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action. 17 PATIENT COUNSELING INFORMATION Advise patients: • To be compliant with blood cell count monitoring appointments while receiving Xofigo. Explain the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections. • To stay well hydrated and to monitor oral intake, fluid status, and urine output while being treated with Xofigo. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufficiency. • Therearenorestrictionsregardingcontactwithotherpeopleafterreceiving Xofigo. Follow good hygiene practices while receiving Xofigo and for at least 1 week after the last injection in order to minimize radiation exposure from bodily fluids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily fluids to avoid contamination. When handling bodily fluids, wearing gloves and hand washing will protect caregivers. • Who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective method of birth control during treatment and for 6 months following completion of Xofigo treatment. Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981 Manufactured in Norway Xofigo is a trademark of Bayer Aktiengesellschaft. © 2013, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Revised: March 2016 6708401BS EVERYDAY UROLOGY O NCOLOGY I NSIGHTS – A URO TO DAY® P UBL I CATI ON TM VOLUME 1, ISSUE 2 Contents COVER STORY 10 Bone Metastases and Mortality in Prostate Cancer: Can We Be Doing More? NEAL SHORE, MD, FACS EXPERT PERSPECTIVE 16 The Story of the COU-AA-302 Clinical Trial: Highlights from the Journey CHARLES J. RYAN, MD CLINICAL UPDATE 24 Axumin™ [Fluciclovine F18]: An Accurate Imaging Approach for Patients with Biochemically Recurrent Prostate Cancer KAREN E. LINDER, MS, PHD Everyday Urology™ ONCOLOGY INSIGHTS – A UROTODAY® PUBLICATION Editorial Leadership EDITOR-IN-CHIEF EDITOR-AT-LARGE Neal Shore, MD, FACS Atlantic Urology Clinics Myrtle Beach, South Carolina E.David Crawford, MD University of Colorado Hospital Aurora, Coloradio Editorial Board BTA SPOTLIGHT 28 Spotlight: Beyond the Abstracts Abstracts and original commentary provided by Dr. Bishoy Falstas on current research findings in genitourinary oncology. Bishoy Morris Faltas, MD Weill-Cornell Medical College New York, New York Alicia K. Morgans, MD Vanderbilt-Ingram Cancer Center Nashville, Tennessee Petros Grivas, MD, PhD Cleveland Clinic Cleveland, Ohio Charles J. Ryan, MD University of California San Francisco San Francisco, California Thomas Keane, MBBCh, FRCHI, FACS Medical University of South Carolina Charleston, South Carolina Evan Yu, MD Seattle Cancer Care Alliance Seattle, Washington Phillip Koo, MD Banner MD Anderson Cancer Center Gilbert, Arizona Digital Science Press Inc. About Digital Science Press Digital Science Press, Inc, has been publishing UroToday.com since 2003 and has developed OncToday.com, in 2016. Digital Science Press is committed to providing factually accurate, timely, evidence-based urological and oncology information to healthcare providers around the globe. In 2003 we recognized that there are a significant number of scientific publications and medical conferences and yet there was no single, easy to access platform that accommodates this content. UroToday.com became the reference platform that aggregates the relevant, unbiased urology disease and treatment-based content and is committed to assisting healthcare professionals in staying up-to-date. Founder and CEO Gina B. Carithers President Joseph Palumbo Director of Marketing Courtney Leonard Art Director Lisa Holmes, Yulan Studio DISCLAIMER: The statements and opinions contained in the articles of Everyday Urology™- Oncology Insights are solely those of the authors and contributors. The appearance of the advertisements in the publication is not a warranty, endorsement or approval of the products or services advertised or their effectiveness, quality or safety. The content of the publication may contain discussion of off-label uses of some of the agents mentioned. Please consult the prescribing information for full disclosure of approved uses. 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Subscription Customer Service, 11448 Deerfield Drive, Suite 2, Truckee, CA 96161 CUSTOMER SERVICE: Customer service inquiries should be sent to [email protected] Subscription inquiries should be sent to: [email protected] Access to this journal is online at www.urotoday.com Other correspondence for Digital Science Press, Inc. should be sent to: Attention: Digital Science Press, Inc. 11448 Deerfield Drive, Suite 2 Truckee, CA 96161 COPYRIGHT AND PERMISSIONS: Everyday Urology™- Oncology Insights is published four times a year by Digital Science Press. No portion of the work(s) can be reproduced without written consent from the Publisher. Permission may be requested directly from the Publisher Email: [email protected] ©Copyright, 2016. FROM THE DESK OF THE EDITOR S ince the inaugural publication of Everyday UrologyOncology Insights, we have received wonderful feedback and insights from our readers and colleagues, and I am extremely appreciative for all of the suggestions. We will strive to present ongoing educational content which should enhance your specific practice model, and we will always look forward to receiving your feedback for this in order to ensure that this quarterly publication provides you with actionable and useful information. Changing paradigms in the treatment of metastatic castration-resistant prostate cancer (mCRPC) continues as a theme for our second issue. New advancements in include not only mechanisms for the identification of recurrent and progressive disease but also for interpreting resistance patterns and the options of therapeutic decision making. In particular, it is well established that bone metastases and their resultant skeletal complications may have a devastating impact on patient quality of life, individual morbidity as well as significant health economic implications for our prostate cancer patients. This edition’s lead article is entitled, “Bone Metastases and Mortality in Prostate Cancer: Can We Be Doing More?”. Here we present the higher mortality, economic burden, and quality of life impairment experienced by men with bone metastatic disease. The basic science and preclinical development for abiraterone began in the 1990s, and culminated as the 1st oral novel hormonal agents approved for a survival benefit both after and before the use of taxane based therapy. As the Principle Investigator for the Phase III COU-AA-302 clinical trial, Charles Ryan, reflects on the trial’s strategic development: including methodology of the studies two co-primary endpoints as well as the important secondary endpoints. Dr. Ryan’s expert perspective provides clarity and insights regarding the trials design considerations, the data collection, and the key endpoints achieved: overall survival and progression free survival efficacies, which led to its unique registration approval in 2012. While these co-primary endpoints were important for regulatory approval, Dr. Ryan shares why the collective trial data when considered for our mCRPC patients has solidified abiraterone as landmark development for the treatment of advanced prostate cancer. In this edition, Dr. Ryan shares his perspective on the regulatory development chapter of the abiraterone journey leading to its approval. In a forthcoming issue Dr. Ryan will share how to optimally assesses the patient for the selection of abirarterone in clinical practice. 8 As radiographic modalities evolve with greater accuracy, with evidenced based improved sensitivity and specificity, clinicians may detect both micro-and macro metastatic disease earlier and with improved precision. As an example, Axumin™ [18F] fluciclovine is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment, and received FDA approval in May 2016. PET imaging with [11C] choline has been shown to improve detection in men with prostate cancer, however its use has been limited to only medical centers with on-site 11C production capability. The Axumin scan has been shown to provide an accurate imaging approach for patients with very low PSA relapse after interventional modalities, e.g., surgical extirpation or radiation therapy. Karen Linder of Blue Earth Diagnostics Ltd provides us additional insights about the utility of Axumin in the Clinical Update article. She provides an overview on the evidence based data for Axumin and its position amongst comparator imaging modalities. In each issue of Everyday Urology, we will provide a Spotlight section, with rotating topics of interest. This month’s spotlight is provided by Bishoy Faltas, a member of our editorial board and an instructor of medicine at Weill Cornell Medicine and an Assistant Attending in the Genitourinary Oncology Program in the Division of Hematology and Medical Oncology. Dr. Faltas provides commentaries of noteworthy articles he has selected from recently published journals of high impact. We share these journal abstracts along with his commentary. These author commentaries are also shared on UroToday’s section, Beyond the Abstracts. Thank you for your continued interest and for reading this issue of Everyday Urology- Oncology Insights. Sincerely, NEAL SHORE, MD, FACS Neal Shore, MD, FACS is an internationally recognized expert in systemic therapies for patients with advanced urologic cancers and innovative therapies to treat patients suffering from prostate enlargement symptoms. Dr. Shore was recently appointed President-Elect of the Large Urology Group Practice Association (LUGPA), which seeks to provide urologists with all the tools they need to effectively care for patients. Neal D. Shore, MD, FACS, is the Medical Director of the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina. Dr. Shore has conducted more than 100 clinical trials, focusing mainly on prostate and bladder disease. EVERYDAY UROLOGYTM Brought to you by the publishers of Everyday Urology and UroToday.com, a new site for medical oncologists that allows free, convenient access to daily aggregated content by tumor type. SIGN UP TODAY TO RECEIVE NEWS AND UPDATES VIA EMAIL PERSONALIZED BASED ON YOUR PREFERENCES OncToday.com COVER STORY Bone Metastases and Mortality in Prostate Cancer: CAN WE BE DOING MORE? By Neal Shore, MD, FACS 10 EVERYDAY UROLOGYTM NEAL SHORE, MD, FACS is director for the Carolina Urologic Research Center and is the managing partner for Atlantic Urology Clinics in Myrtle Beach, South Carolina. Dr. Shore serves on the boards of the Society of Urologic Oncology Board of Directors, the Society Urologic Oncology Clinical Trials Consortium, the Large Urology Group Practice Association, NCI GU Science Steering Committee and the Urology Times. Prostate cancer is the most common malignancy among US men, with an estimated annual incidence of 180,890, accounting for one in five new cancer cases in men1. The second-most common cause of cancer death in US men, prostate cancer is expected to claim the lives of 26,120 men in this country in 20161. F or men with castration-resistant prostate cancer (CRPC), median survival ranges from nine to 34 months, depending upon numerous factors, including but not limited to, the presence of metastases, the location and volume of metastases, the presence of co-morbidities, the degree of acknowledged and interrogated symptomatology, etc.2. Whereas metastases may be widely disseminated in advanced prostate cancer3, the disease predominantly affects the bone compartment. Indeed, prostate cancer has an affinity to metastasize to bone, which provides a matrix rich in factors that stimulate the growth of tumor cells and promotes a vicious cycle of metastases and bone pathology4. In the early stages of advanced prostate cancer, malignant cells detached from the primary tumor migrate locally, invade blood or lymphatic vessels, and may disperse throughout the body4-6. Once in the bloodstream, metastatic cells (i.e., the “seeds”) have a decreased survival outside of the primary tumor (i.e., the “homeland”) due to the defense of the immune system and thus require the appropriate “soil” for implantation5. Consequently, the “seeds” may preferentially migrate to bone (i.e., the “hostland,” as illustrated in Figure 1)4-6 Approximately 90% of men with advanced prostate cancer will develop bone metastases8, and approximately 50% of men who convert from androgen sensitive state to nonmetastatic (M0) CRPC will develop bone metastases within two years9. Metastases preferentially arise in bones of the spine, pelvis, and ribs, where red marrow is most abundant5, 6, as well as arise in the skull and long bones of the extremities5, 6, 8. VARIABLE MIGRATORY PATHWAYS OF BONE METASTASES Most men with clinically localized prostate cancer who develop bone metastases will do so many years after the primary tumor has been removed, suggesting a delay of time between the initial interventional therapy and the initial indication of biochemical recurrence/PSA relapse, thus suggesting VOLUME 1, ISSUE 2 Figure 1: Prostate cancer has an affinity to metastasize to bone 4, 7 The cancer diaspora. Kenneth J. Pienta et al. Clin Cancer Res 2013;19:5849-5855 micrometastases3. Metastatic prostate cancer cells are thought to remain dormant in the bone marrow for several years before transforming into a proliferative phenotype that drives metastatic progression3. Whole genome sequencing has illuminated the genomic evolution of CRPC, from initial tumorigenesis, through acquisition of metastatic potential, to the development of castration resistance10. Results from genomic studies support the theory of progression from dormancy to proliferation, whereby tumor cells 11 COVER STORY sharing a common heritage travel from one site to another while retaining their genetic imprint10. In those studies, monoclonal and polyclonal metastatic tumor cells have been shown to preferentially and frequently migrate between distant sites rather than as separate waves from the primary tumor (Figure 2)10. Those observations support the “seed and soil” hypothesis, which holds Figure 2: Progression from bone to multiple metastatic sites decreases survival in CRPC 12 that metastatic potential is not always a variable solely of the primary tumor, but may be acquired as a delayed event or occur at distant sites of metastases10. BONE METASTASES ARE ASSOCIATED WITH HIGHER MORTALITY Bone metastatic disease indicates a poor prognosis in men with prostate cancer, and correlates with significant mortality. In a Danish cohort study of 23,087 incident patients with prostate cancer, of the 22,404 men without bone metastases at diagnosis, 56% were alive at five years (95% confidence interval [CI]: 54.956.7), compared to 3% of the 2,578 men who were diagnosed with bone metastases (95% CI: 2.2-3.4)11. The site of metastases may have profound prognostic implications. In an analysis of 3,857 men from the SEER database who presented with metastatic prostate cancer between 1991 and 2009, progression from bone to multiple metastatic sites was associated with increasing mortality (Figure 3)12. In that analysis, the site of metastases, after adjusting for confounders, emerged as an independent prognostic factor12. Notably, patients who had bone metastases alone had a 1.5-fold higher probability of death compared to men with lymph node involvement only (P=0.02)12. Additionally, men with bone plus visceral metastases had a 1.3-fold higher probability of dying versus men who only had bone metastases12. (see Figure 3) IMPACT OF BONE METASTASES ON QUALITY OF LIFE Mortality considerations aside, bone metastases can also significantly impact quality of life as a consequence of their associated effects13. Whereas fatigue is the most stressful symptom cited by men with mCRPC14, patients with bone metastases may also experience pain as well as activity limiting lifestyle, discomfort15, 16, extremity weakness15, neurological impairment17, dyspnea15, impaired mobility15, loss of bladder and bowel function15, mild sensory loss or numbness15, loss of appetite18, sleep disturbance16. Notably, a 2015 US survey commissioned by Bayer HealthCare suggests that nearly seven out of 10 (68%) of men with advanced prostate cancer ignore or under-report their symptoms to their healthcare providers19. The most commonly reported symptoms by survey participants included19: Kaplan-Meier curves depicting time to (a) overall mortality and (b) cancer-specific mortality, after stratifying patients according to the site of metastases.CI = confidence interval; CSM = cancer-specific mortality. Impact of the Site of Metastases on Survival in Patients with Metastatic Prostate Cancer, Gandaglia, G. Et al. European Urology, Volume 68, Issue 2, 2015, 325–334 12 • Fatigue: 85% • All over body pain or aches: 55% • Numbness or weakness: 55% • Difficulty sleeping as a result of pain: 42% • Difficulty performing normal activities: 40% • Anxiety or distress as a result of pain: 40% • Vomiting: 25%18 • Loss of appetite18 Given the frequency—and routine under-reporting—of symptoms, health care professionals need to focus on, and be more proactive about, discussing symptoms with their patients EVERYDAY UROLOGYTM and their caregivers (usually a spouse or another family member) with prostate cancer. ECONOMIC BURDEN OF BONE METASTASES Bone metastatic disease also carries a significant economic burden to the US healthcare system, particularly when patients experience skeletal-related events (SREs). A model drawn from the SEER database estimated a lifetime medical care cost of $140,501 (95% CI: $140,252-$140,780) per person for men ≥65 years old who were diagnosed with prostate cancer from 1991 to 200220. In a matched case-control study of health care utilization costs among of 1,131 elderly patients with stage IV metastatic (M1) prostate cancer and SREs, those undergoing spinal cord compression with concurrent surgery incurred an average cost of $82,868 (95% CI: $67,472-$98,264). The next most expensive SRE groups were those who had bone surgery only ($37,496; 95% CI: $29,684-$45,308), pathological fracture with concurrent surgery ($34,169; 95% CI: $25,837-$42,501), spinal cord compression only ($25,793; 95% CI: 20,933-$30,653), and pathological fracture only ($14,649; 95% CI: 6,537-$22,761)21. IS EARLIER DETECTION OF BONE METASTATIC DISEASE OF VALUE? The significant prognostic and economic implications of bone metastases in prostate cancer have prompted researchers to investigate whether earlier detection of bone metastatic disease is of value. For men with stage M0 castrate-resistant disease (i.e., prostate cancer that has not spread beyond nearby lymph nodes), the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR) group recommends a first imaging scan when the prostate-specific antigen (PSA) level is at least 2 ng/mL. If the previous scan is negative, the RADAR group recommends a second scan when PSA equals 5 ng/mL, and repeat scanning at every doubling of PSA level thereafter, based on PSA testing every three months. The group cautions against overimaging in practice, and therefore does not recommend scanning newly diagnosed low-risk patients and most intermediate-risk patients. In terms of cost-effectiveness, the RADAR group recommends conventional bone scintigraphy using technetium 99 (99mTc) and abdomen/pelvis/chest computed tomography (CT) as imaging modalities for initial testing22. Other novel imaging modalities are available (Table 1), and the RADAR group suggests using plain radiography, magnetic resonance imaging (MRI), and 18F-sodium fluoride (NaF) with positron emission tomography (PET) or CT (particularly for detection of osseous metastases); these tests should be conducted at the physician’s discretion when necessary, as they may be needed to clarify equivocal lesions22, 23. As shown in Table 1, PET/CT scans using tracers, such as 18F-NaF, offer sensitivity and specificity that are superior to bone scintigraphy and are frequently incorporated into guidelines22. (see Table 1) VOLUME 1, ISSUE 2 Figure 3: The most common advanced prostate cancer symptoms reported by men with bone metastases in the US 19 85% FATIGUE 71% PAINS OR ACHES IN SPECIFIC AREAS 55% ALL OVER BODY PAIN OR ACHES 55% NUMBNESS OR WEAKNESS 42% DIFFICULTY SLEEPING AS A RESULT OF PAIN 40% ANXIETY OR DISTRESS AS A RESULT OF PAIN 40% DIFFICULTY DOING NORMAL ACTIVITIES 13 COVER STORY USE OF ALP AND PSA TO PREDICT RISK OF BONE METASTATIC DISEASE MONITOR KEY BONE-RELATED PARAMETERS AS PROGNOSTIC FACTORS FOR OVERALL SURVIVAL Bone alkaline phosphatase (ALP), when used in combination with PSA, can be an effective independent marker for predicting the risk of developing bone metastatic disease, as reported in in a study of 203 men with asymptomatic, treatment-naïve prostate cancer (Table 2)26. In multivariate analyses from this study, the combination of elevated ALP and PSA (in which patients with either elevated PSA [>20 ng/mL] OR elevated ALP were categorized as positive) exhibited the best screening value for detecting bone metastases, with a sensitivity of 98.2% and a specificity of 48.6%26. ALP and PSA, along with the RADAR group recommendations, may thus be used to detect the onset of bone metastases in asymptomatic individuals22, 26. (see Table 2) Several bone-related parameters, including those listed in Table 3, have been validated as individual prognostic variables for overall survival in patients with mCRPC27. In an analysis of the prognostic value of multiple bone-specific parameters in 1,901 patients enrolled in an international, multicenter, randomized, double-blind phase 3 trial, the following factors were significantly associated with longer survival27. (see Table 3) CHANGE THERAPEUTIC APPROACH AS DISEASE PROGRESSES The presence or absence of metastases is one of the most important factors affecting the clinical approach to managing prostate cancer22. The site/volume of metastatic prostate cancer may evolve over time for individual patients, a process which has important clinical implications22. When cancer spreads to the bone, the clinician should reconsider the therapeutic approach as one that shifts from treating not only the primary prostate cancer but also for treating the bone metastases, as clinical therapeutic interventions in bone metastatic disease can impact outcomes3, 10. Similarly, when cancer spreads from the bone to the viscera, the clinical approach should focus on treating visceral metastases as well28. Table 1: Sensitivity and specificity of imaging modalities in bone metastasis IMAGING TEST Sensitivity (%)12 Specificity (%)12 18F NaF-PET/CT 100 97 MRI 95 90 SPECT 87 91 18F FDG-PET 98 56 CT 74 56 Bone Scintigraphy 78 48 SUMMARY In devising a treatment plan for prostate cancer, the clinician should consider the implications of how metastatic disease site, location, and tumor burden may evolve over time10, 22. Advanced prostate cancer is notable for predominantly residing in the bones4-6. As the great majority of men with advanced prostate cancer will develop bone metastases, the presence of which indicates a poor prognosis, is also associated increased mortality and morbidity8, 12. Men with bone metastases typically experience multiple and varied symptoms that may negatively impact quality of life13-18. PET: Positron emission tomography; CT: Computed tomography; MRI: Magnetic resonance imaging; SPECT: Single photo emission tomography; 18F FDG: Fluorine 18 labelled fluorodeoxyglucose; 18F NaF: Fluorine 18 labelled sodium flouride. Citation: O’Sulivan GJ, Carty FL, Cronin CG. Imaging of bone metastasis: An update. World J Radiol 2015; 7(8): 202-211 Table 2: The relationship between different levels of serum PSA with GS and ALP 26 Serum PSA Level Metastasis Number of Patients (%) GS P Value ALP P Value Quantitative PSA Value (ng/ml) P Value <20 Positive Negative 6 (7.3%) 76 (92.7%) 6.7 ± 0.5 6.1 ± 1.0 0.09 345.3 ± 109.9 169.4 ± 61.3 0.01 14.5 ± 5.7 11.7 ± 5.1 0.14 =20-50 Positive Negative 14 (23.3%) 46 (76.7%) 7.1 ± 1.0 6.5 ± 0.9 0.04 322.0 ± 146.2 181.3 ± 75.1 0.01 38.0 ± 6.5 34.2 ± 7.9 0.08 ≥50 Positive Negative 35 (57.4%) 26 (42.6%) 7.5 ± 0.9 7.4 ± 0.9 0.51 365.9 ± 183.7 186.4 ± 66.6 0.01 95.2 ± 32.3 84.3 ± 23.7 0.23 M. Moslehi et al. / Rev Esp Med Nucl Imagen Mol. 2013;32(5):286–289 14 EVERYDAY UROLOGYTM Early detection of bone metastases can therefore inform clinical decision-making and may be interrogated by the evaluation of laboratory, clinical, and patient and caregiver symptom assessment. The RADAR group recommends specific strategies for enabling early identification of metastases in patients with prostate cancer22. Additionally, ALP plus PSA can be an effective marker for predicting risk of bone metastatic disease26. Finally, because prostate cancer is associated with increased mortality as the disease migrates from localized to multiple metastatic sites12, it is important for clinicians to adjust their clinical approach as the disease progresses22. Table 3: Multivariate analysis of baseline prognostic variables for overall survival Variable Hazard Ratio (95% CI) P Value PSA <10 ng/ml 0.486 (0.381, 0.619) <0.0001 No previous SRE 0.748 (0.643, 0.871) 0.0002 Pain absent or mild (BFI-SF score ≤4) 0.648 (0.563, 0.745) <0.0001 ALP ≤ median 0.664 (0.559, 0.789) <0.0001 BSAP <146 ug/l 0.683 (0.568, 0.822) <0.0001 Corrected uNTX ≤50 nmol/mmol 0.755 (0.640, 0.889) <0.0008 Hemoglobin > median 0.614 (0.532, 0.709) <0.0001 No visceral metastases 0.733 (0.621, 0.864) 0.0002 ECOG score ≤1 0.755 (0.599, 0.950) 0.0167 Age in years 1.012a (1.003, 1.021) 0.0081 Time from initial diagnosis to bone metastases diagnosis (months) 0.997 (0.995, 0.998) <0.0001 Time from diagnosis of bone metastases to randomization (months) 0.990b (0.986, 0.995) <0.0001 1. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2016. CA: a cancer journal for clinicians, 2016. 66(1): p. 7-30. 2. Kirby, M., C. Hirst, and E.D. Crawford, Characterising the castration-resistant prostate cancer population: a systematic review. International journal of clinical practice, 2011. 65(11): p. 1180-92. 3. van der Toom, E.E., J.E. Verdone, and K.J. Pienta, Disseminated tumor cells and dormancy in prostate cancer metastasis. Current opinion in biotechnology, 2016. 40: p. 9-15. 4. Yin, J.J., C.B. Pollock, and K. Kelly, Mechanisms of cancer metastasis to the bone. Cell research, 2005. 15(1): p. 57-62. 5. Bagi, C.M., Skeletal implications of prostate cancer. Journal of musculoskeletal & neuronal interactions, 2003. 3(2): p. 112-7. 6. Kingsley, L.A., et al., Molecular biology of bone metastasis. Molecular cancer therapeutics, 2007. 6(10): p. 2609-17. 7. Pienta, K.J., et al., The cancer diaspora: Metastasis beyond the seed and soil hypothesis. Clinical cancer research : an official journal of the American Association for Cancer Research, 2013. 19(21): p. 5849-55. 8. Bubendorf, L., et al., Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Human pathology, 2000. 31(5): p. 578-83. 9. Smith, M.R., et al., Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer, 2011. 117(10): p. 2077-85. 10. Gundem, G., et al., The evolutionary history of lethal metastatic prostate cancer. Nature, 2015. 520(7547): p. 353-7. 11. Norgaard, M., et al., Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). The Journal of urology, 2010. 184(1): p. 162-7. 12. Gandaglia, G., et al., Impact of the Site of Metastases on Survival in Patients with Metastatic Prostate Cancer. European urology, 2015. 68(2): p. 325-34. 13. Resnick, M.J. and D.F. Penson, Quality of life with advanced metastatic prostate cancer. The Urologic clinics of North America, 2012. 39(4): p. 505-15. 14. Colloca, G., et al., Incidence and Correlates of Fatigue in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review. Clinical genitourinary cancer, 2016. 14(1): p. 5-11. 15. Farrell, C., Bone metastases: assessment, management and treatment options. British journal of nursing, 2013. 22(10): p. S4, S6, S8-11. 16. Autio, K.A., et al., Prevalence of pain and analgesic use in men with metastatic prostate cancer using a patient-reported outcome measure. Journal of oncology practice / American Society of Clinical Oncology, 2013. 9(5): p. 223-9. 17. Selvaggi, G. and G.V. Scagliotti, Management of bone metastases in cancer: a review. Critical reviews in oncology/hematology, 2005. 56(3): p. 365-78. 18. Hamilton, W., et al., Clinical features of metastatic cancer in primary care: a case-control study using medical records. The British journal of general practice : the journal of the Royal College of General Practitioners, 2015. 65(637): p. e516-22. 19. MenWhoSpeakUp Prostate Cancer Symptoms Survey -- US Results. 2015 May 27, 2016]; Available from: https://www.menwhospeakup.com/prostate-cancer-survey/ 20. Stokes, M.E., et al., Lifetime economic burden of prostate cancer. BMC health services research, 2011. 11: p. 349. 21. Jayasekera, J., et al., The economic burden of skeletal-related events among elderly men with metastatic prostate cancer. PharmacoEconomics, 2014. 32(2): p. 173-91. 22. Crawford, E.D., et al., Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology, 2014. 83(3): p. 664-9. 23. Koo, P.J. and E. David Crawford, (1)(8)F-NaF PET/CT and (1)(1)C-Choline PET/CT for the initial detection of metastatic disease in prostate cancer: overview and potential utilization. Oncology, 2014. 28(12): p. 1057-62, 1064-5. 24. O’Sullivan, G.J., F.L. Carty, and C.G. Cronin, Imaging of bone metastasis: An update. World journal of radiology, 2015. 7(8): p. 202-11. 25. Mhawech-Fauceglia, P., et al., Prostate-specific membrane antigen (PSMA) protein expression in normal and neoplastic tissues and its sensitivity and specificity in prostate adenocarcinoma: an immunohistochemical study using mutiple tumour tissue microarray technique. Histopathology, 2007. 50(4): p. 472-83. 26. Moslehi, M., et al., Predictors of bone metastasis in pre-treatment staging of asymptomatic treatment-naive patients with prostate cancer. Revista espanola de medicina nuclear e imagen molecular, 2013. 32(5): p. 286-9. 27. Fizazi, K., et al., Bone-related Parameters are the Main Prognostic Factors for Overall Survival in Men with Bone Metastases from Castration-resistant Prostate Cancer. European urology, 2015. 68(1): p. 42-50. 28. Halabi, S., et al., Meta-Analysis Evaluating the Impact of Site of Metastasis on Overall Survival in Men With Castration-Resistant Prostate Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2016. 34(14): p. 1652-9. ALP: alkaline phosphatase; BPI-SF: Brief Pain Inventory - Short Form; BSAP: bonespecific alkaline phosphatase; CI: confidence interval; ECOG: Eastern Co-operative Oncology Group; uNTx: urinary N-telopeptide. a: Reflects the change in the hazard for any increase of 1 year b: Reflects the change in the hazard for any increase of 1 month Fizazi ,K. Massard C., Smith, M. et al. Bone-related Parameters are the Main Prognostic Factors for Overall Survival in Men with Bone Metastases from Castration-resistant Prostate Cancer European Urology, Volume 68, Issue 1, Pages 42-50 VOLUME 1, ISSUE 2 15 EXPERT PERSPECTIVE The Story of the COU-AA-302 Clinical Trial: HIGHLIGHTS FROM THE JOURNEY By Charles J. Ryan, MD 16 EVERYDAY UROLOGYTM CHARLES J. RYAN, MD is a leader in medical oncology and was the primary investigator for the COU-AA-302 clinical trial, which led to FDA approval of abiraterone acetate plus prednisone as the first oral therapy for treatment in chemotherapy-naïve metastatic castration-resistant prostate cancer. Dr. Ryan is Professor of Clinical Medicine and Urology and Thomas Perkins Distinguished Professor in Cancer Research, and Program Leader, Genitourinary Medical Oncology at the University of California-San Francisco Helen Diller Family Comprehensive Cancer Center in San Francisco, CA. In the following article, he reflects on the highlights of the COU-AA-302 journey, including the pioneering results and methodology of the study, as well as the voice of the study results including the secondary endpoints on patient outcomes such as pain, time to opiate use, and functional status. In the following article, he reflects on the COU-AA-302 journey, including the pioneering results and methodology of the study: Radiographic Progression-Free Survival As a Response Biomarker was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials. B efore the COU-AA-302 trial, there was no validated level I evidence showing that treatments other than chemotherapy had value in the chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) population. Many of these patients, particularly those with no or minor symptoms, did not want, and did not need, chemotherapy. So there was a great need to develop treatments that could be given in place of, or prior to, chemotherapy. In its final overall survival analysis, the COU-AA-302 trial confirmed the benefit of abiraterone acetate plus prednisone, given prior to docetaxel, in men with mCRPC. Although the final overall survival benefit was less robust than initially anticipated, the trial did prove conclusively that abiraterone acetate plus prednisone was a standard of care prior to starting a docetaxel in this disease. As we prepared for the trial, we discovered an important fact: Only approximately 45% of men who had mCRPC received chemotherapy. More than half of patients in this setting were not being offered any treatment beyond standard androgen deprivation therapy. Once this therapy failed, many patients were not offered any other options. As a result, there was a real need for new treatments in men diagnosed with mCRPC who have no or few symptoms. In the COU-AA-302 trial, 1088 patients were randomly assigned to receive either abiraterone acetate (1000 mg once daily) plus prednisone (5 mg twice daily) or prednisone plus placebo. The primary trial endpoints were radiographic progression-free survival (PFS) and overall survival (OS). The results of the planned interim analysis performed after 43% of expected deaths had occurred showed that the median radiographic PFS rate was 16.5 months with abiraterone acetate plus prednisone and 8.3 months with prednisone plus placebo (hazard ratio for abiraterone-prednisone vs. prednisone-placebo .53; P <0.001).1 The interim analysis also indicated that over a median follow-up period of 22.2 months, OS rates were improved with the abiraterone-prednisone regimen (median for abiraterone-prednisone not reached in the initial analysis vs. 27.2 months for prednisone plus placebo. Abiraterone acetate plus prednisone VOLUME 1, ISSUE 2 also showed superiority over prednisone plus placebo in time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status.1 Due to the positive initial results for radiographic PFS rates in the COU-AA-302 study, the data and safety monitoring board decided to unblind the trial, which led to significant crossover in the study; patients who had been on placebo were allowed to receive abiraterone acetate. It was the right thing to do ethically and from a patient-care perspective, but it also created a challenge for us as researchers. As a result of patient crossover in the trial, the overall survival data took longer than expected to mature and reach statistical significance. Many people don’t realize that while there was a trend toward improved survival rates with abiraterone acetate plus prednisone in the interim analysis, the P value for the difference in OS rates Due to the positive initial results for radiographic PFS rates in the COU-AA-302 study, the data and safety monitoring board decided to unblind the trial, which led to significant crossover in the study; patients who had been on placebo were allowed to receive abiraterone acetate. was below the standard .05. This may have been due partly to the low number of events and/or the fact that prednisone was an active control. In the trial, approximately 29% of patients treated with prednisone experienced a 50% or greater decline in their prostate-specific antigen (PSA) values in the interim analysis. Yet, the final analysis, published in Lancet Oncology in 2015, showed that OS rates with abiraterone acetate plus prednisone 17 EXPERT PERSPECTIVE Figure 1 were significantly longer (34.7 months) than with prednisone plus placebo (30.3 months) (P =.0033).2 The difference in the OS rates in the final analysis was noteworthy, not only because it was achieved despite considerable patient crossover to abiraterone Since radiographic PFS has been validated as an endpoint correlated with OS, researchers don’t have to wait for final OS data to mature to be able to determine whether a trial is a success or failure. As a result, studies can be performed and completed more rapidly, and new therapies made available to patients much earlier. acetate from placebo, but also because some patients in the placebo group received subsequent docetaxel.3 (see Figure 1) The final analysis also showed that the effect of abiraterone acetate on OS rates was not dependent on whether or not a patient received prior chemotherapy. The OS rates achieved with 18 abiraterone acetate was also not dependent on the Gleason score at initial diagnosis, or duration of previous androgen deprivation therapy. Thus, the COU-AA-302 trial provided a strong rationale for the use of abiraterone acetate plus prednisone therapy early in the clinical course of mCRPC. As oncologists, we should not wait for symptoms to occur—we should prevent symptoms by being proactive with our treatment regimens. The evolution of the survival curve in this trial, and the fact that it was positive, helped to drive home that point. The final safety results for the abiraterone acetate plus prednisone group in the COU-AA-302 trial were also positive. In fact, the safety outcomes in the study were similar to those reported in studies on men with mCRPC who received docetaxel chemotherapy. Grade 3 and 4 adverse events affected 54% of patients in the abiraterone acetate plus prednisone group and 44% of men in the prednisone plus placebo group. The most common adverse events in the abiraterone acetate plus prednisone group were fluid retention/edema, hypokalemia, hypertension, and cardiac disorders. Adverse events that led to discontinuation occurred in 13% of men in the abiraterone acetate plus prednisone group and 10% of men in the prednisone plus placebo group. In addition to its positive final outcomes, the COU-AA-302 clinical trial was also remarkable because it established EVERYDAY UROLOGYTM radiographic PFS as a response biomarker that was highly correlated with overall survival. In the study, radiographic PFS was defined as the time from random assignment to the first occurrence of progression on either bone scan, computed tomography (CT) scan, or magnetic resonance imaging as defined by modified RECIST criteria; or death resulting from any cause. Bone and CT scans were obtained every 8 weeks during the first 24 weeks of the trial and every 12 weeks thereafter.4 COU-AA-302 was the first trial in which radiographic PFS was a co-primary endpoint, and it allowed us for the first time to show that this is a meaningful endpoint. The first interim analysis of the trial results indicated that treatment with abiraterone acetate plus prednisone led to a 57% reduction in the risk of radiographic disease progression or death compared to treatment with prednisone plus placebo. The second interim analysis of OS rates showed that use of abiraterone acetate plus prednisone led to an estimated 25% decrease in the risk of death, and radiographic PFS rates were positively associated with OS rates in both treatment groups. These results suggest that the objective, prospectively defined endpoint of radiographic PFS survival could serve as a response indicator biomarker that can be evaluated in future studies. As a result of the COU-AA-302 trial, other research groups can now devise and run clinical trials that use radiographic PFS as a primary endpoint. Since radiographic PFS has been validated as an endpoint correlated with OS, researchers don’t have to wait for final OS data to mature to be able to determine whether a trial is a success or failure. As a result, studies can be performed and completed more rapidly, and new therapies made available to patients much earlier. In addition to showing that abiraterone acetate plus prednisone delayed radiographic PFS and improved OS rates, the COU-AA-302 clinical trial was a remarkable effort because of the amount of data we collected on quality of life and performance preservation. The study showed that abiraterone acetate plus prednisone therapy has three functions—to preserve function, prevent progression and complications, and prolong life. The patients enrolled in the COU-AA-302 trial had a moderately good quality of life and functional level at baseline. In addition to prolonging radiographic progression-free survival and overall survival, abiraterone acetate plus prednisone therapy allowed patients to preserve function, and prevented complications of their disease. That’s a key message, because for the first time in the treatment of mCRPC, we were treating patients who were in pretty good shape, and telling them: “This therapy won’t make you feel sick, and, better yet, it will help you preserve your quality of life.” Prior therapies were aimed at alleviating the symptoms of patients who were already suffering due to the effects of prostate cancer. The COU-AA-302 trial was a departure from that approach, since it aimed to prevent complications and painful VOLUME 1, ISSUE 2 symptoms. Most patients want to be able to begin therapy before they have painful symptoms—therapy that allows them to preserve their pain-free status. The endpoints of the trial included patient-reported outcomes such as pain and functional status. Pain was measured using the Brief Pain Inventory (Short Form) (BPI-SF) questionnaire, and included notable measures of pain such as intensity (the average pain and worst pain felt during a day) and the extent to which pain interfered with daily activities. The pain measures were COU-AA-302 was the first trial in which radiographic PFS was a co-primary endpoint, and it allowed us for the first time to show that this is a meaningful endpoint. recorded on questionnaires during clinic visits at baseline, day 1 of each treatment cycle, and at the end of the treatment cycle. Functional status was measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) scale. This scale included the FACT-General (made up of 4 subscales that evaluate different domains of general functional status) and the Prostate Cancer Subscale (PCS), which evaluates prostate cancer-specific symptoms. To report their functional status, the patients filled out questionnaires during clinic visits at baseline; day 1 of cycles 3, 5, 7,10 and every 3rd cycle thereafter; and at the end of treatment. The results of the COU-AA-302 trial revealed that the median time to functional status degradation was significantly longer in patients on abiraterone acetate plus prednisone vs. patients on prednisone plus placebo as measured by both the FACT-G and PCS. Patients in the treatment group were also significantly more likely to preserve their function in terms of physical well-being, functional well-being, emotional well-being, and social/family well- being. The COU-AA-302 trial outcomes also showed that patients in the active treatment group were less troubled by pain. The median time to progression of average pain intensity was 26.7 months in the abiraterone acetate plus prednisone group vs. 18.4 months in the prednisone plus placebo group (P =.0490). The median time to progression in pain interference was 10.3 months in the abiraterone acetate plus prednisone group vs. 7.4 months in the prednisone plus placebo group (P =.005). In a post hoc sensitivity analysis, time to progression (at the 25th percentile) of worst pain intensity was 14.8 months in the abiraterone acetate plus prednisone group vs. 12 months in the prednisone plus placebo group (P =.045). (see Figure 2) 19 In the treatment of advanced prostate cancer IT DROPS THAT FAST Start testosterone (T) suppression now with FIRMAGON® (degarelix), the GnRH receptor antagonist that dropped by 88% on day 1 (N=207)1,2* • FIRMAGON (N=207) dropped T by 88%, 94%, 96%, 97%, and 98% on day 1, 3, 7, 14, and 28, respectively2 • Leuprolide (N=201) increased T by 43%, 65%, and 8% on day 1, 3, and 7, respectively, and dropped T by 75% and 97% on day 14 and 28, respectively2 • By day 28, both FIRMAGON and leuprolide achieved similar testosterone levels2 Prostate-specific antigen (PSA) reduction typically follows testosterone suppression† FIRMAGON RESULTED IN A REDUCTION OF PSA LEVELS, A SECONDARY ENDPOINT1 2 weeks 1 month 3 months Median PSA Levels (%) 0 -20 -40 64% 85% FIRMAGON (N=207) -100 PSA is a nonspecific measurement that may indicate cancer progression. These PSA results should be interpreted with caution because of the heterogeneity of the patient population studied. No evidence has shown that the rapidity of PSA decline is related to clinical benefit. Therefore, PSA data should not be viewed independently as evidence of the effectiveness of FIRMAGON.1 GnRH = gonadotropin-releasing hormone. † -60 -80 *The pivotal phase 3 trial (CS21) was a 3-armed, randomized (1:1:1), activecontrolled, open-label, parallel-group, 12-month clinical study of FIRMAGON compared to leuprolide.3 Serum levels of testosterone were measured at screening, on days 0, 1, 3, 7, 14, and 28 in the first month, and then monthly until the end of the study.2 FIRMAGON was shown to maintain testosterone suppression below castration level (50 ng/dL) over 12 months of treatment (primary endpoint).3 95% Indication FIRMAGON® (degarelix for injection) is a GnRH receptor antagonist indicated for treatment of patients with advanced prostate cancer. Important Safety Information FIRMAGON is contraindicated in patients with a known hypersensitivity to degarelix or to any of the product components and in women who are or may become pregnant. FIRMAGON can cause fetal harm when administered to a pregnant woman. Hypersensitivity reactions, including anaphylaxis, urticaria and angioedema, have been reported post-marketing with FIRMAGON. In case of a serious hypersensitivity reaction, discontinue FIRMAGON immediately if the injection has not been completed, and manage as clinically indicated. Patients with a known history of serious hypersensitivity reactions to FIRMAGON should not be re-challenged with FIRMAGON. Long-term androgen deprivation therapy (ADT) prolongs the QT interval. Physicians should consider whether the benefits of ADT outweigh the potential risks in patients with congenital long QT syndrome, electrolyte abnormalities, or congestive heart failure and in patients taking Class IA or Class III antiarrhythmic medications. Please see additional Important Safety Information and Brief Summary of full Prescribing Information on adjacent pages. Start testosterone suppression TODAY and reassess at PSA nadir. Important Safety Information (continued) Therapy with FIRMAGON results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after FIRMAGON may be affected. The therapeutic effect of FIRMAGON should be monitored by measuring serum concentrations of prostate-specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured. The most common adverse reactions (≥10%) during FIRMAGON therapy included injection site reactions (eg, pain, erythema, swelling or induration), hot flashes, increased weight, fatigue, and increases in serum levels of transaminases and gammaglutamyltransferase. The majority of adverse reactions were Grade 1 or 2; 1% or less were Grade 3/4. Injection site reactions were mostly transient, of mild to moderate intensity, occurred primarily with the starting dose and led to few discontinuations (<1%). Learn more at www.FIRMAGON.com REFERENCES: 1. FIRMAGON [package insert]. Parsippany, NJ: Ferring Pharmaceuticals Inc. 2. Data on file. Ferring Pharmaceuticals Inc. 3. Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102(11):1531-1538. FIRMAGON® is a registered trademark of Ferring B.V. © 2016 Ferring B.V. FN/014/2016/USe Printed in U.S.A. February 2016 FIRMAGON® (degarelix for injection) BRIEF SUMMARY Please consult package insert for full Prescribing Information. INDICATIONS AND USAGE FIRMAGON is a GnRH receptor antagonist indicated for treatment of patients with advanced prostate cancer. CONTRAINDICATIONS FIRMAGON is contraindicated in patients with known hypersensitivity to degarelix or to any of the product components. Degarelix is contraindicated in women who are or may become pregnant. Degarelix can cause fetal harm when administered to a pregnant woman. Degarelix given to rabbits during organogenesis at doses that were 0.02% of the clinical loading dose (240 mg) on a mg/m2 basis caused embryo/fetal lethality and abortion. When degarelix was given to female rats during organogenesis, at doses that were just 0.036% of the clinical loading dose on a mg/m2 basis, there was an increase post implantation loss and a decrease in the number of live fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. WARNINGS AND PRECAUTIONS Pregnancy Category X Women who are or may become pregnant should not take FIRMAGON. Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, urticaria and angioedema, have been reported post-marketing with FIRMAGON. In case of a serious hypersensitivity reaction, discontinue FIRMAGON immediately if the injection has not been completed, and manage as clinically indicated. Patients with a known history of serious hypersensitivity reactions to FIRMAGON should not be re-challenged with FIRMAGON. Effect on QT/QTc Interval Androgen deprivation therapy may prolong the QT interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes. In the randomized, active-controlled trial comparing FIRMAGON to leuprolide, periodic electrocardiograms were performed. Seven patients, three (<1%) in the pooled degarelix group and four (2%) patients in the leuprolide 7.5 mg group, had a QTcF ≥500 msec. From baseline to end of study, the median change for FIRMAGON was 12.3 msec and for leuprolide was 16.7 msec. Laboratory Testing Therapy with FIRMAGON results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after FIRMAGON may be affected. The therapeutic effect of FIRMAGON should be monitored by measuring serum concentrations of prostate-specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 1325 patients with prostate cancer received FIRMAGON either as a monthly treatment (60-160 mg) or as a single dose (up to 320 mg). A total of 1032 patients (78%) were treated for at least 6 months and 853 patients (64%) were treated for one year or more. The most commonly observed adverse reactions during FIRMAGON therapy included injection site reactions (e.g., pain, erythema, swelling or induration), hot flashes, increased weight, fatigue, and increases in serum levels of transaminases and gamma-glutamyltransferase (GGT). The majority of the adverse reactions were Grade 1 or 2, with Grade 3/4 adverse reaction incidences of 1% or less. FIRMAGON was studied in an active-controlled trial (N = 610) in which patients with prostate cancer were randomized to receive FIRMAGON (subcutaneous) or leuprolide (intramuscular) monthly for 12 months. Adverse reactions reported in 5% of patients or more are shown in Table 1. Table 1. Adverse Reactions Reported in ≥5% of Patients in an Active Controlled Study Percentage of subjects with adverse events Body as a whole Injection site adverse events Weight increase Fatigue Chills Cardiovascular system Hot flash Hypertension Musculoskeletal system Back pain Arthralgia Urogenital system Urinary tract infection Digestive system Increases in Transaminases and GGT Constipation FIRMAGON 240/160 mg (subcutaneous) N = 202 FIRMAGON 240/80 mg (subcutaneous) N = 207 Leuprolide 7.5 mg (intramuscular) N = 201 83% 79% 78% 44% 11% 6% 4% 35% 9% 3% 5% <1% 12% 6% 0% 26% 7% 26% 6% 21% 4% 6% 4% 6% 5% 8% 9% 2% 5% 9% 10% 10% 5% 3% 5% 5% The most frequently reported adverse reactions at the injection sites were pain (28%), erythema (17%), swelling (6%), induration (4%) and nodule (3%). These adverse reactions were mostly transient, of mild to moderate intensity, occurred primarily with the starting dose and led to few discontinuations (<1%). Grade 3 injection site reactions occurred in 2% or less of patients receiving degarelix. The safety of FIRMAGON administered monthly was evaluated further in an extension study in 385 patients who completed the above active-controlled trial. Of the 385 patients, 251 patients continued treatment with FIRMAGON and 135 patients crossed over treatment from leuprolide to FIRMAGON. The median treatment duration on the extension study was approximately 43 months (range 1 to 58 months). The most common adverse reactions reported in ≥10% of the patients were injection site reactions (e.g., pain, erythema, swelling, induration or inflammation), pyrexia, hot flush, weight loss or gain, fatigue, increases in serum levels of hepatic transaminases and GGT. One percent of patients had injection site infections including abscess. Hepatic laboratory abnormalities in the extension study included the following: Grade 1/2 elevations in hepatic transaminases occurred in 47% of patients and Grade 3 elevations occurred in 1% of patients. Changes in bone density: Decreased bone density has been reported in the medical literature in men who have had orchiectomy or who have been treated with a GnRH agonist. It can be anticipated that long periods of medical castration in men will result in decreased bone density. Anti-degarelix antibody development has been observed in 10% of patients after treatment with FIRMAGON for 1 year. There is no indication that the efficacy or safety of FIRMAGON treatment is affected by antibody formation. DRUG INTERACTIONS No drug-drug interaction studies were conducted. Degarelix is not a substrate for the human CYP450 system. Degarelix is not an inducer or inhibitor of the CYP450 system in vitro. Therefore, clinically significant CYP450 pharmacokinetic drug-drug interactions are unlikely. USE IN SPECIFIC POPULATIONS Pregnancy Category X Women who are or may become pregnant should not take FIRMAGON. When degarelix was given to rabbits during early organogenesis at doses of 0.002 mg/kg/day (about 0.02% of the clinical loading dose on a mg/m2 basis), there was an increase in early post-implantation loss. Degarelix given to rabbits during mid and late organogenesis at doses of 0.006 mg/kg/day (about 0.05% of the clinical loading dose on a mg/m2 basis) caused embryo/fetal lethality and abortion. When degarelix was given to female rats during early organogenesis, at doses of 0.0045 mg/kg/day (about 0.036% of the clinical loading dose on a mg/m2 basis), there was an increase in early post-implantation loss. When degarelix was given to female rats during mid and late organogenesis, at doses of 0.045 mg/kg/day (about 0.36% of the clinical loading dose on a mg/m2 basis), there was an increase in the number of minor skeletal abnormalities and variants. Nursing Mothers FIRMAGON is not indicated for use in women and is contraindicated in women who are or who may become pregnant. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from degarelix, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of subjects in clinical studies of FIRMAGON, 82% were age 65 and over, while 42% were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment No pharmacokinetic studies in renally impaired patients have been conducted. At least 20-30% of a given dose of degarelix is excreted unchanged in the urine. A population pharmacokinetic analysis of data from the randomized study demonstrated that there is no significant effect of mild renal impairment [creatinine clearance (CrCL) 50-80 mL/min] on either the degarelix concentration or testosterone concentration. Data on patients with moderate or severe renal impairment is limited and therefore degarelix should be used with caution in patients with CrCL<50 mL/min. Hepatic Impairment Patients with hepatic impairment were excluded from the randomized trial. A single dose of 1 mg degarelix administered as an intravenous infusion over 1 hour was studied in 16 non-prostate cancer patients with either mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. Compared to non-prostate cancer patients with normal liver function, the exposure of degarelix decreased by 10% and 18% in patients with mild and moderate hepatic impairment, respectively. Therefore, dose adjustment is not necessary in patients with mild or moderate hepatic impairment. However, since hepatic impairment can lower degarelix exposure, it is recommended that in patients with hepatic impairment testosterone concentrations should be monitored on a monthly basis until medical castration is achieved. Once medical castration is achieved, an every-other-month testosterone monitoring approach could be considered. Patients with severe hepatic dysfunction have not been studied and caution is therefore warranted in this group. OVERDOSAGE There have been no reports of overdose with FIRMAGON. In the case of overdose, however, discontinue FIRMAGON, treat the patient symptomatically, and institute supportive measures. As with all prescription drugs, this medicine should be kept out of the reach of children. SEE FIRMAGON PATIENT COUNSELING INFORMATION For more information, go to www.FIRMAGON.com or call 1-888-FERRING (1-888-337-7464) Hepatic laboratory abnormalities were primarily Grade 1 or 2 and were generally reversible. Grade 3 hepatic laboratory abnormalities occurred in less than 1% of patients. In 1-5% of patients the following adverse reactions, not already listed, were considered related to FIRMAGON by the investigator: Body as a whole: Asthenia, fever, night sweats; Digestive system: Nausea; Nervous system: Dizziness, headache, insomnia. The following adverse reactions, not already listed, were reported to be drug-related by the investigator in 1% of patients: erectile dysfunction, gynecomastia, hyperhidrosis, testicular atrophy, and diarrhea. Manufactured for: Ferring Pharmaceuticals Inc., Parsippany, NJ 07054 By: Rentschler Biotechnologie GmbH, Germany 2009054134 FIRMAGON® is a registered trademark of Ferring B.V. © 2016 Ferring B.V. FN/224/2016/US 10/2015 Figure 2 The COU-AA-302 trial showed definitively that the addition of abiraterone acetate to prednisone delayed the development and progression of pain and opiate use. One important piece of data that also came out of the trial was a 10-month difference in the median time to opiate use. In the final analysis, the median time to opiate use for prostate cancer-related pain was 33.4 months in the abiraterone acetate plus prednisone group vs. 23.4 months in the prednisone plus placebo group (HR =.72, P <.0001). Imagine having 10 months of pain that requires opiates—and then imagine that you don’t have that pain, and don’t have to use opiates to reduce that pain. For patients, that’s a lot of time to experience a pain-free life and freedom from opiate use. So not only did abiraterone acetate plus prednisone therapy help preserve quality of life, it also prevented progression of the patients’ disease to the point at which pain becomes a major problem. As oncologists, we want to alleviate pain and suffering, but being able to prevent pain and suffering is even better. Pain is an important and debilitating complication of mCRPC, affecting 50% of men with metastatic disease. So understanding the impact of abiraterone acetate plus prednisone therapy on pain is important and valuable information for decision-makers in the treatment of mCRPC, including patients, clinicians, regulators, and payers. VOLUME 1, ISSUE 2 As well as demonstrating significant differences in OS and radiographic PFS with abiraterone acetate plus prednisone, COU-AA-302 was a landmark study, because it showed that it was feasible to measure the development and progression of pain and analgesic use in a large multicenter trial. To ensure that the patient perspective is captured in clinical research on new oncology drugs, it’s vitally important to assess patient-reported outcomes on pain and function using methodologically rigorous approaches. 1. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. NEJM. 2012;368(2):138-148. 2. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (COU-AA-302): Final overall survival analysis of a randomised double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015; 16:152-160. 3. De Bono JS, Smith MR, Saad F, et al. Subsequent chemotherapy and treatment patterns after abiraterone acetate in patients with metastatic castration-resistant prostate cancer: Post hoc analysis of COU-AA-302. Eur Urol. 2016. In press. http://dx.doi.org/10.1016/j.eururo.2016.06.033. 4. Morris MJ, Molina A, Small EJ, et al. Radiographic progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302 results. J Clin Oncol. 2015; 33:1356-1363. 23 CLINICAL UPDATE Axumin™ [Fluciclovine F18]: An Accurate Imaging Approach for Patients with Biochemically Recurrent Prostate Cancer By Karen E. Linder, MS, PhD 24 EVERYDAY UROLOGYTM KAREN E. LINDER, MS, PHD is the senior manager of Clinical Science and Medical Affairs at Blue Earth Diagnostics, Inc., Burlington, MA Prostate cancer [PCa] affects 1 man in 7 in the United States, making this the most commonly diagnosed non-cutaneous cancer in males. Although an ever-increasing number of treatment options exist, an estimated 26,100 men will still die of the disease in the US in 2016, generally after primary local and systemic treatments for prostate cancer have failed1. O ne factor contributing to this statistic is the frequent inability of current diagnostic methods to reliably detect the exact location(s) of disease relapse at a time when curative treatment is still possible. The dilemma of biochemical recurrence (BCR): Up to a third of men treated for prostate cancer will experience recurrent disease,2,3 most often detected only by rising Prostate Specific Antigen [PSA] levels. Conventional imaging tools such as computerized tomography [CT] and bone scintigraphy [BS] frequently fail to identify the site of recurrent disease, presenting a serious challenge to urologists and radiation oncologists charged with the selection of secondary treatment, and causing significant anxiety for these patients. While PCa recurrence may occur locally in the prostate gland or prostate bed, and/or in local lymph nodes in the pelvis, recognition of distant lymph node, bone or other tissue involvement requires different treatment choices. Potentially curative techniques such as salvage lymphadenectomy, radiotherapy or cryotherapy may be used for local recurrences, especially at lower PSA levels, whereas systemic approaches such as the use of anti-hormonal therapy and/or chemo- or immunotherapy may be recommended in the presence of distal metastatic disease. Conventional imaging: Conventional diagnostic imaging with CT and BS is typically of limited utility until PSA values rise to 10-20 ng/ml. Kane et al reported that patients with BCR after radical prostatectomy have a low probability of a positive BS (9.4%) or a positive CT scan (14.0%) within 3 years of biochemical recurrence.4 Similarly, in men with BCR at a median time of 5 years post-surgery, of the 380 bone scans done among hormone-naive subjects, only 24 (6%) were positive, with 356 (94%) negative for metastasis.5 CT images, although highly specific when positive, do not generally raise suspicion if the involved lymph node is <1 cm in diameter, even if the node is cancerous. 18F FDG PET is of limited use in BCR6 because uptake in PCa is generally suboptimal until the patient has metastatic castrate resistant disease, and physiologic excretion of FDG in the bladder may interfere with image interpretation of adjacent structures in the pelvis. However, salvage radiation therapy (SRT) to the prostate should be initiated well before a PSA of 10 – 20 ng/mL is reached, as studies have demonstrated that outcomes are better if SRT is initiated at low VOLUME 1, ISSUE 2 (e.g. <0.5 ng/mL) PSA values7 and refs therein and is not likely to be curative if the disease has progressed to the point where it can be seen on a bone scan. Enter Axumin™: On May 27, 2016 the FDA approved Axumin [fluciclovine F 18 Injection; Blue Earth Diagnostics Ltd, Oxford UK] for PET imaging in men with suspected prostate cancer recurrence based on elevated PSA levels following prior treatment.8 The approval of Axumin ushers in a new era of F 18 PET/CT for the detection of recurrent prostate cancer in the USA. Data submitted to FDA included results from prospective studies at Emory University and the University of Bologna and from clinical use at two sites in Norway9; the pooled data for n= 595 subjects were retrospectively analyzed. Overall, fluciclovine F 18 PET/ CT detected sites of recurrence in 68% (403/595) of patients. For patients with baseline PSA values in the lowest quartile (<0.79 ng/mL, n=128), 75 patients (59%) were negative with fluciclovine F 18 PET/CT, but 53 (41% of patients) had positive fluciclovine scans; 13 (10%) had prostate bed findings only, and 40 (31%) had extra-prostatic disease. As the location of disease recurrence affects appropriate therapy selection, this finding is highly relevant. How it works: Fluciclovine is a synthetic amino acid that is preferably taken up by amino acid transporters in tissues. These transporters, specifically ASCT2 and LAT1, bring amino acids such as glutamine and leucine into cells, where they are used for protein synthesis, cell growth and metabolism. Cancer cells often have an increased requirement for amino acids to support increased metabolism and proliferation.10 Imaging studies with histological confirmation have demonstrated that uptake of fluciclovine F 18 is enhanced in PCa in the prostate bed, involved lymph nodes and bony metastases. Thus, this biochemically relevant localization method may be useful to evaluate suspected nodal or metastatic disease where confirmation or exclusion of pelvic and/or distant disease would directly influence patient management. Fluciclovine image: As an example, the image in Figure 1 is a case from a 61 year-old male with PSA rising to 0.4 ng/mL after robotic-assisted laparoscopic prostatectomy. Fluciclovine F 18 PET/CT detected an 8 mm lymph node proximal to the rectal wall, rendering delivery of salvage radiotherapy problematic. The 25 CLINICAL UPDATE Figure 1: Transverse PET/CT A secondary endpoint of the above study12 analyzed a subset (n=53) to compare the ability of CT and fluciclovine F 18 to detect recurrent disease (see Figure 3). On a whole-body basis, 41/53 fluciclovine PET/CT scans (77.4%) were positive, but only 10/53 scans (18.9%) were positive with CT. Of 33 patients with histological proof of disease, fluciclovine PET/CT detected disease in 31 (93.9%) but CT detected disease in only 4 (12.1%). The authors concluded that the diagnostic performance of fluciclovine PET/CT in recurrent prostate cancer is superior to that of CT, and provides better delineation of prostatic from extra-prostatic recurrence. Detection rate with fluciclovine F 18 was 37.5% at PSA values <1, and increased to 77.8% in a PSA range of 1-2 ng/mL. Comparison to 11C-choline: A prospective study conducted at Bologna University enabled a within-subject Courtesy of Aleris Helse AS comparison of the performance of fluciclovine F 18 PET and 11C-choline PET in patients with BCR post-radical prostatectomy (n=89). Follow-up at 1 year was used as the reference standard. patient went on to receive hormonal therapy (see Figure 1). Diagnostic performance was comparable for both agents at PSA Comparison to other imaging tools: Studies comparing values above 1 ng/mL, but fluciclovine F 18 imaging showed the agent to the gamma-emitting agent ProstaScint, and to CT higher sensitivity in patients with low PSA levels (<1 ng/mL).13 and 11C-choline have been reported, as have descriptions of its 11C-choline has been approved for use in the detection of BCR use in primary prostate cancer and in therapy planning. In an NIH at selected sites in the United States, but the 20 minute half-life of funded prospective RO1 study at Emory University11, 115 patients the 11C isotope limits its use to facilities with a nearby cyclotron. with BCR and negative 99mTc bone scans after radical prosIn contrast, the 110 minute half-life of F 18 in fluciclovine improves tatectomy or radiotherapy were imaged with fluciclovine F 18. the potential for broad patient access. The majority (n=93) also received 111In capromab pendetide Radiation therapy planning: Schreibmann et al14 incor(ProstaScint, a radio-labelled monoclonal antibody that binds to porated fluciclovine F 18 PET/CT into radiotherapy treatment prostate-specific membrane antigen). This study compared the planning to define prostate bed and lymph node target volumes regional sensitivity and specificity of the two agents, relative to in 41 patients. Inclusion of the fluciclovine F 18 images changed histology and clinical follow-up. Sufficient data for truth assessthe planning volumes for 46 abnormalities (83%) of the total 55, ment (histology, response to therapy and clinical follow-up) were with 28 (51%) located in the lymph nodes. Use of fluciclovine F 18 available for 91 patients with prostate/bed findings and for 70 in post-prostatectomy radiotherapy planning was feasible and led patients with extra-prostatic involvement. The following results to augmentation of the target volumes in the majority (30 of 41) of were found (see Figure 2). patients studied (see Figure 4). Of the 77 index lesions used to prove positivity, histological Fluciclovine F 18 image (a) shows uptake in an iliac node proof of PCa was obtained in 74 (96.1%). Fluciclovine F 18 iden(yellow arrow). Original radiotherapy treatment plan (b) was tified 14 more positive prostate bed recurrences (55 vs 41) and for irradiation of the prostate bed only. Observed nodal uptake 18 more subjects with extra-prostatic involvement (22 vs 4). The of fluciclovine caused changed treatment plan, boosting the agent upstaged 25.7% of the patients. For fluciclovine, imaging radiation dose to the iliac node abnormality (c). The color scale was complete within 40 min post-injection (PI), in contrast to 111In ranges from 0 to 77 Gy. capromab pendetide, where images were obtained at 3 days PI. Important safety information: The recent FDA approval of fluciclovine F 18 was based on 11 data from 877 subjects including Figure 2: Diagnostic performance of fluciclovine and 111In capromab pendetide 797 men diagnosed with PCa. Adverse reactions were reported Agent Location Sensitivity Specificity Accuracy PPV NPV in ≤1% of subjects during these clinical studies. The most Fluciclovine F 18 90.2% 40.0% 73.6% 75.3% 66.7% common adverse reactions were (n=91) Prostate/ injection site pain and/or redbed ProstaScint (n=91) 67.2% 56.7% 63.7% 75.9% 45.9% ness, and dysgeusia (abnormal taste in the mouth). Although not Fluciclovine F 18 yet observed, hypersensitivity 55.0% 96.7% 72.9% 95.7% 61.7% Extra(n=70) prostatic reactions, including anaphylaxis, sites may occur in patients who ProstaScint (n=70) 10.0% 86.7% 42.9% 50.0% 41.9% receive radiopharmaceuticals, 26 EVERYDAY UROLOGYTM Figure 3: Whole body positivity rate for fluciclovine F 18 and CT in men with biochemically recurrent PCa 11 so emergency resuscitation equipment and personnel should be immediately available. Axumin use contributes to a patient’s overall long-term cumulative radiation exposure, and safe handling practices should be used to minimize radiation exposure to the patient and health care providers. As with any imaging agent, image interpretation errors can occur with fluciclovine PET imaging. A negative image does not rule out recurrent prostate cancer (if lesions are small, they may be below the resolution of the PET camera) and a positive image does not confirm its presence, as fluciclovine uptake may occur with other cancers and is also seen in tissue affected by benign prostatic hypertrophy (BPH) in primary prostate cancer. Clinical correlation, which may include histopathological evaluation, is recommended. Coming soon to a radiopharmacy near you: FDA approval of Axumin is only the first step. The imaging agent is made on demand at specialized manufacturing facilities for the preparation of radioactive drugs and then shipped to imaging centers that have been trained to administer the product and interpret the images. The agent will become increasingly available in the coming months across the US through the national radiopharmacy network of Blue Earth Diagnostic’s U.S. commercial manufacturer and distributor, Siemens’ PETNET Solutions. For men with BCR, early detection of disease with Axumin (fluciclovine F18) and initiation of appropriate therapy may provide the potential for better long-term outcomes in prostate cancer. 1. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-statistics Accessed Aug 16 2016 2. J Mohler, RR Bahnson, B Boston, et al. NCCN clinical practice guidelines in oncology: prostate cancer. J Natl Compr Canc Netw 2010;8:162-200. 3. JF Ward, ML Blute, J Slezak, et al. The long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy. J Urol 2003;170:1872-76. 4. CJ Kane, CL Amling, PA Johnstone, et al. Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. Urology 2003;61:607-11. 5. DM Moreira, MR Cooperberg, LE Howard, et al. Predicting bone scan positivity after biochemical recurrence following radical prostatectomy in both hormone-naive men and patients receiving androgen-deprivation therapy: results from the SEARCH database. Prostate Cancer Prostatic Dis. 2014;17(1):91-96. 6. CY Yu, B Desai, L Ji, et al. Comparative performance of PET tracers in biochemical recurrence of prostate cancer: a critical analysis of literature. Am J Nucl Med Mol Imaging 2014;4(6):580-601. 7. AJ Stephenson, PT Scardino, MW Kattan, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25(15):2035-41. 8. AxuminTM (Fluciclovine F 18 Injection) package insert. Blue Earth Diagnostics Ltd. August, 2016. 9. TV Bogsrud, C Nanni, P Nieh, et al. Abstract, MP79-19: Impact of intrinsic and extrinsic factors on the detection rate of the PET tracer fluciclovine (18F) in biochemical relapse of prostate cancer: a multi-institutional experience. AUA 2016, San Diego, CA. J Urol 2016;195(4), Suppl e1041–e42. 10. BC Fuchs, BP Bode. Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime? Semin Cancer Biol 2005;15(4):254-66. 11. DM Schuster, PT Nieh, AB Jani, et al. Anti-3-[18F]FACBC Positron Emission TomographyComputerized Tomography and 111In-Capromab pendetide Single Photon Emission Computerized Tomography-Computerized Tomography for recurrent prostate carcinoma: results of a prospective clinical trial. J Urol 2014;191(5):1446-53. 12. O A Odewole, FI Tade, PT Nieh, et al. Recurrent prostate cancer detection with anti-3-[F]FACBC PET/CT: comparison with CT. Eur J Nucl Med Mol Imaging 2016;43(10):1773-78. 13. C Nanni, L Zanoni, C Pultrone, et al. 18F-FACBC (anti 1-amino-3-18F-fluorocyclobutane-1-carboxylic acid) versus 11C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging 2016; 43(9):1601-10. 14. E Schreibmann, DM Schuster, PJ Rossi, et al. Image-guided planning for prostate carcinomas with incorporation of anti-3-[18F]FACBC (Fluciclovine) positron emission tomography: workflow and initial findings from a randomized trial. Int J Radiation Oncol Biol Phys 2016;96(1):206-13. Figure 4 Using fluciclovine F 18 uptake to guide radiation treatment planning. Fluciclovine F 18 image (a) shows uptake in an iliac node (yellow arrow). Original radiotherapy treatment plan (b) was for irradiation of the prostate bed only. Observed nodal uptake of fluciclovine caused changed treatment plan, boosting the radiation dose to the iliac node abnormality (c). The color scale ranges from 0 to 77 Gy. Image credit: Jani et al, Emory University VOLUME 1, ISSUE 2 27 SPOTLIGHT Spotlight: Beyond the Abstracts At UroToday.com, we strive to publish the latest news and research findings including diagnosis and treatments relating to clinical urology. To further highlight these articles to a wide group of peers and colleagues, we invite authors and readers to provide supplemental content on this clinical investigation or review. This commentary becomes a part of Beyond the Abstract: a daily column/feature published by UroToday. The published Beyond the Abstract contributions are among the most highly read content. Our guest editor, for this Spotlight: Beyond the Abstracts, Dr. Bishoy Falstas provides his commentary on selected abstracts for an expanded view and additional perspective. Topics included: renal cell carcinoma, prostate cancer, urothelial cancer, and more in genitourinary oncology. 28 EVERYDAY UROLOGYTM Dr. Bishoy Morris Faltas is an Instructor in Medicine at Weill Cornell Medicine and an Assistant Attending in the Genitourinary Oncology Program in the Division of Hematology & Medical Oncology. Dr. Faltas has completed his Hematology and Medical Oncology Fellowship at Weill Cornell Medicine, as well as additional training through a one-year research fellowship in the laboratory of Dr. Mark A. Rubin. During this time, he led studies of the clonal evolution and the neoantigenic structure of platinum-resistant urothelial carcinoma. As a physician-scientist, Dr. Faltas conducts research focusing on understanding the molecular profiles of metastatic platinum-resistant urothelial bladder carcinoma. His research focus is on the mechanisms of mutagenesis and drug-resistance in bladder carcinoma, as well as immunogenomic studies of urological malignancies. By understanding the molecular changes that occur as urothelial cancer evolves under the effect of chemotherapy and metastatic spread, Dr. Faltas aims to identify potential drug targets for translation into therapeutic clinical trials. He is an active member of the The Caryl and Israel Englander Institute for Precision Medicine focusing on the VOLUME 1, ISSUE 2 application of genomic approaches to clinical trials by tailoring treatment based on the unique molecular profile of each patient’s cancer. Dr. Faltas is the recipient of several research awards, including the Scott-Wadler Fellow Research award and the Weill Department of Medicine Fellow Award in Research. He has also received the NIH/NCATS CTSC KL2 Scholar grant and the American Society of Clinical Oncology Conquer Cancer Foundation Young Investigator Award. Dr. Faltas has published several articles in peer-reviewed journals such as the New England Journal of Medicine, JAMA Oncology, Journal of Clinical Oncology, European Urology, Urologic Oncology, Clinical Genitourinary Cancer, Clinical Advances in Hematology & Oncology and the American Journal of Medicine. Additionally, he is a reviewer for the American Journal of Medicine, Science Translational Medicine, and Nature Scientific Reports. Dr. Faltas is a member of the editorial boards of the ASCO Post. He also served as an Associate Scientific Advisor for Science Translational Medicine. 29 SPOTLIGHT Somatic ERCC2 Mutations are Associated with a Distinct Genomic Signature in Urothelial Tumors ABSTRACT Alterations in DNA repair pathways are common in tumors and can result in characteristic mutational signatures; however, a specific mutational signature associated with somatic alterations in the nucleotide- excision repair (NER) pathway has not yet been identified. Here we examine the mutational processes operating in urothelial cancer, a tumor type in which the core NER gene ERCC2 is significantly mutated. Analysis of three independent urothelial tumor cohorts demonstrates a strong association between somatic ERCC2 mutations and the activity of a mutational signature characterized by a broad spectrum of base changes. In addition, we note an association between the activity of this signature and smoking that is independent of ERCC2 mutation status, providing genomic evidence of tobacco-related mutagenesis in urothelial cancer. Together, these analyses identify an NER-related mutational signature and highlight the related roles of DNA damage and subsequent DNA repair in shaping tumor mutational landscape. REFERENCES Nature Genetics 2016 Jun;48(6):600-6. doi: 10.1038/ng.3557. Epub 2016 Apr 25. Kim J1, Mouw KW2,3, Polak P1,3,4,5, Braunstein LZ1,3, Kamburov A1,3,4,5, Tiao G1, Kwiatkowski DJ3,6, Rosenberg JE7, Van Allen EM1,3,8, D’Andrea AD2,3,9, Getz G1,3,4,5. Author information 1. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. 2. Department of Radiation Oncology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 3. Harvard Medical School, Boston, Massachusetts, USA. 4. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA. 5. Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, USA. 6. Division of Pulmonary Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA. 7. Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. 8. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 9. Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 30 COMMENTARY Different types of DNA damage result in distinct patterns of mutations in cancer. Understanding these mutational patterns could yield important insights into the pathogenesis of different tumors. A recent study published by Kim et al in Nature Genetics evaluated the different types of mutational signatures in urothelial cancer by analyzing three independent cohorts of patients. The investigators identified four different mutational signatures and compared them with the previously known COSMIC signatures. The most interesting signature was the fourth signature, which was characterized by a broad spectrum of base changes but had an unknown etiology. The investigators identified a strong association between this signature and mutations in the ERCC2 gene. 35 non-silent mutations were identified across the three cohorts that were predicted to affect ERCC2 protein function. The study also identified an association between this ERCC2related signature and smoking. On the other hand, an association between this signature and platinum-response was not found. The authors underline the fact that urothelial cancer is unique as the only known type of cancer in which ERCC2 is mutated but that a similar signature has been identified in other tumor types with no ERCC2 mutations. This suggests that these tumor types may have alterations in other DNA repair pathways. This study is an important step towards defining the molecular landscape of urothelial tumors including those genes that are important biologically but relatively uncommon such as ERCC2. REFERENCES Kim J, Mouw KW, Polak P, Braunstein LZ, Kamburov A, Tiao G, Kwiatkowski DJ, Rosenberg JE, Van Allen EM, D’Andrea AD, Getz G.Nat Genet. 2016 Apr 25. doi: 10.1038/ng.3557. [Epub ahead of print]. Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. EVERYDAY UROLOGYTM Circulating Tumor Cell Composition in Renal Cell Carcinoma ABSTRACT COMMENTARY PURPOSE: Due to their minimal-invasive yet potentially current character circulating tumor cells (CTC) might be useful as a “liquid biopsy” in solid tumors. However, successful application in metastatic renal cell carcinoma (mRCC) has been very limited so far. High plasticity and heterogeneity of CTC morphology challenges currently available enrichment and detection techniques with EpCAM as the usual surface marker being underrepresented in mRCC. We recently described a method that enables us to identify and characterize non-hematopoietic cells in the peripheral blood stream with varying characteristics and define CTC subgroups that distinctly associate to clinical parameters. With this pilot study we wanted to scrutinize feasibility of this approach and its potential usage in clinical studies. Tumor cells enter the circulation during various stages of the natural history of cancer. These circulating tumor cells can reveal information about the biology of the originating tumor and serve as biomarkers. EXPERIMENTAL DESIGN: Peripheral blood was drawn from 14 consecutive mRCC patients at the West German Cancer Center and CTC profiles were analyzed by Multi-Parameter Immunofluorescence Microscopy (MPIM). Additionally angiogenesis-related genes were measured by quantitative RT-PCR analysis. RESULTS: We detected CTC with epithelial, mesenchymal, stem cell-like or mixed-cell characteristics at different time-points during anti-angiogenic therapy. The presence and quantity of N-cadherin-positive or CD133-positive CTC was associated with inferior PFS. There was an inverse correlation between high expression of HIF1A, VEGFA, VEGFR and FGFR and the presence of N-cadherin-positive and CD133-positive CTC. CONCLUSIONS: Patients with mRCC exhibit distinct CTC profiles that may implicate differences in therapeutic outcome. Prospective evaluation of phenotypic and genetic CTC profiling as prognostic and predictive biomarker in mRCC is warranted. REFERENCES Journal information: PLOS ONE, 2016 Apr 21;11(4):e0153018. doi: 10.1371/journal. pone.0153018. eCollection 2016. Nel I1,2, Gauler TC1,3, Bublitz K1, Lazaridis L1, Goergens A4, Giebel B4, Schuler M3,5, Hoffmann AC1,5. 1. Molecular Oncology Risk-Profile Evaluation, Department of Medical Oncology, West German Cancer Center, University Duisburg-Essen, Essen, Germany. 2. ABA GmbH & Co. KG, BMZ2, Dortmund, Germany. 3. Department of Radiotherapy, University of Duisburg-Essen, Essen, Germany. 4. Institute for Transfusion Medicine, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 5. Department of Medical Oncology, West German Cancer Center, University Duisburg-Essen, Essen, Germany. VOLUME 1, ISSUE 2 Early methods for isolation of circulating tumor cells focused on the isolation cells that expressed the Epithelial Cell Adhesion Molecule (EpCAM). This approach could limit the isolation of circulating tumor cells that undergo epithelial-mesnechymal transition (EMT), losing EpCAM expression the process. In a new study published by Nel et al. in the journal PLOS One, investigators developed a new isolation approach using multi-parameter immunofluorescence microscopy that includes both epithelial markers such as EpCAM and cells with mesenchymal and stem cell-like characteristics. The investigators obtained peripheral blood drawn from 14 consecutive mRCC patients from a German center. Using this approach, they isolated circulating tumor cells with epithelial, mesenchymal, stem cell-like or mixed-cell characteristics at different time-points during anti-angiogenic therapy. Interestingly, the investigators identified N-cadherin or CD133-positivity on circulating tumor cells as a marker for lower progression free survival. The study also examined the expression of several anti-angiogenesis genes by quantitative RT-PCR and observed an inverse correlation between high expression of HIF1A, VEGFA, VEGFR and FGFR and the presence of N-cadherin-positive and CD133-positive circulating tumor cells. This study suggests that patients with RCC have a distinct circulating tumor cells profile and open the door for more studies on using circulating tumor cells as biomarkers for response to anti-angioegnic therapy in this disease. REFERENCES Nel I, Gauler TC, Bublitz K, Lazaridis L, Goergens A, Giebel B, Schuler M, Hoffmann AC. Circulating Tumor Cell Composition in Renal Cell Carcinoma.PLoS One. 2016 Apr 21;11(4):e0153018. doi: 10.1371/journal.pone.0153018. eCollection 2016. 31 SPOTLIGHT Whole Exome Xequencing of Urachal Adenocarcinoma Reveals Recurrent NF1 Mutations ABSTRACT Urachal adenocarcinoma is a rare bladder malignancy arising from the urachal remnant. Given its rarity and the lack of knowledge about its genetic characteristics, optimal management of this cancer is not well defined. Practice patterns vary and outcomes remain poor. In order to identify the genomic underpinnings of this malignancy, we performed whole exome sequencing using seven tumor/normal pairs of formalin fixed archival specimens. We identified recurrent evidence of MAPkinase pathway activation as three patients had neurofibromin 1 (NF1) mutations, with one of these patients also harboring an oncogenic KRAS G13D mutation. We also observed recurrent evidence of Wnt/β-catenin pathway activation as three patients had oncogenic mutations in APC or RNF43. In addition, somatic copy number analysis revealed focal chromosome 12p amplifications in three samples, resembling findings from testicular germ cell tumors. We describe the genomic landscape of this malignancy in our institutional cohort and propose investigation of the therapeutic potential for MAP-K pathway inhibition in the subset of patients who show evidence of its activation. REFERENCES Journal information: Oncotarget. 2016 Apr 7. doi: 10.18632/oncotarget.8640. [Epub ahead of print] Singh H1,2, Liu Y2, Xiao X3, Lin L2, Kim J4, Van Hummelen P2, Wu CL3, Bass AJ2, Saylor PJ1. AUTHOR INFORMATION 1. Massachusetts General Hospital Cancer Center, Boston, MA, USA. 2. Dana Farber Cancer Institute, Boston, MA, USA. 3. Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. 4. Broad Institute, Cambridge, MA, USA. COMMENTARY Urachal adenocarcinoma is a rare malignancy arising from the urachal embryologic remnant. The genomic landscape of these tumors is largely unexplored to date. A recent study by Singh et al. published in the journal Oncotarget examined the genetic changes in urachal carcinoma. The investigators performed whole exome sequencing of eight tumor/normal pairs of formalin fixed archival urachal carcinoma specimens. The study identified recurrent mutations in P53, NF1 and SMAD4 genes. The investigators also found focal recurrent amplifications of chromosome 12p although the functional significance of this finding is still unknown. The authors note that that the same chromosomal locus is recurrently amplified in testicular germ cell tumors, which is another embryonal tumor. The investigators findings showing the presence of somatic NF1 mutations identified by this study in urachal carcinomas is very interesting and mirrors NF1 mutations in other malignancies like juvenile myelomonocytic leukemia, lung cancer and melanoma. Because NF1 mutations are involved in activating the RAS pathway, there has been interest in utilizing blockade of MEK and other members of the MAP-Kinase pathway. The results of this study suggest that a similar approach merits further study in urachal adenocarcinoma. REFERENCES Singh H, Liu Y, Xiao X, Lin L, Kim J, Van Hummelen P, Wu CL, Bass AJ, Saylor PJ. Whole exome sequencing of urachal adenocarcinoma reveals recurrent NF1 mutations. Oncotarget. 2016 Apr 7. doi: 10.18632/oncotarget.8640. [Epub ahead of print] 32 EVERYDAY UROLOGYTM For men with mCRPC who have progressed on ADT Z Y T I G A® & P R E D N I S O N E LET’S STRONG DO THIS TOGETHER INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. mCRPC = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy. Please see additional Important Safety Information on the next pages. Please see brief summary of full Prescribing Information on subsequent pages. For men with mCRPC who have progressed on ADT ZYTIGA® & PREDNISONE: (abiraterone acetate) For more than 5 years, ZYTIGA® has been prescribed to men battling mCRPC 1 5 years ZYTIGA® has been prescribed for more than 80,000 patients ZYTIGA® was the #1 prescribed oral medication for mCRPC in 20151 in the United States since its approval in April 20111 The median seating capacity of a professional football stadium is 69,000 IMPORTANT SAFETY INFORMATION Hepatotoxicity—In postmarketing experience, there have been ZYTIGA®-associated severe hepatic toxicities, including fulminant hepatitis, acute liver failure and deaths. Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Re-treatment with ZYTIGA® at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN. Permanently discontinue ZYTIGA® for patients who develop a concurrent elevation of ALT greater than 3X ULN and total bilirubin greater than 2X ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation. Janssen Biotech, Inc. © Janssen Biotech, Inc. 2016 06/16 044350-160421 Please see brief summary of full Prescribing Information on subsequent pages. Let’s do this Established safety profile Contraindicated in women who are or may become pregnant; Warnings and Precautions include Mineralocorticoid Excess, Adrenocortical Insufficiency, and Hepatotoxicity The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia ZYTIGA® in geriatric patients Of the total number of patients receiving ZYTIGA® in phase 3 trials, 73% of patients were aged 65 years and over and 30% were aged 75 years and over – No overall differences in safety or effectiveness were observed between these elderly patients and younger patients – Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out IMPORTANT SAFETY INFORMATION—continued ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). 051320-160413 Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. * Greater sensitivity of some older individuals cannot be ruled out. Reference: 1. Data on file. Janssen Biotech, Inc. Learn more today at www.zytigahcp.com STRONG T O G E T H E R ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In postmarketing experience, there have been ZYTIGAassociated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions]. In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. Permanently discontinue ZYTIGA for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. ZYTIGA® (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions]. Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications 5.9 1.4 2.3 0 Fractures5 ZYTIGA® (abiraterone acetate) Tablets ZYTIGA® (abiraterone acetate) Tablets Table 1: Adverse Reactions due to ZYTIGA in Study 1 (continued) ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0. 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness. 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema. 5 Includes all fractures with the exception of pathological fracture. 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia. 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0. 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema. 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws. Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Postmarketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis. Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis. Hepatobiliary Disorders: fulminant hepatitis, including acute hepatic failure and death. DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. ZYTIGA® (abiraterone acetate) Tablets ZYTIGA® (abiraterone acetate) Tablets In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in Phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA should not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: May 2016 051318-160413 SPOTLIGHT Molecular Analysis of Urothelial Cancer Cell Lines for Modeling Tumor Biology and Drug Response ABSTRACT COMMENTARY The utility of tumor-derived cell lines is dependent on their ability to recapitulate underlying genomic aberrations and primary tumor biology. Here, we sequenced the exomes of 25 bladder cancer (BCa) cell lines and compared mutations, copy number alterations (CNAs), gene expression anddrug response to BCa patient profiles in The Cancer Genome Atlas (TCGA). We observed a mutation pattern associated with altered CpGs and APOBEC-family cytosine deaminases similar to mutation signatures derived from somatic alterations in muscle-invasive (MI) primary tumors, highlighting a major mechanism(s) contributing to cancer-associated alterations in the BCa cell line exomes. Non-silent sequence alterations were confirmed in 76 cancer-associated genes, including mutations that likely activate oncogenes TERT and PIK3CA, and alter chromatin-associated proteins (MLL3, ARID1A, CHD6 and KDM6A) and established BCa genes (TP53, RB1, CDKN2A and TSC1). We identified alterations in signaling pathways and proteins with related functions, including the PI3K/mTOR pathway, altered in 60% of lines; BRCA DNA repair, 44%; and SYNE1-SYNE2, 60%. Homozygous deletions of chromosome 9p21 are known to target the cell cycle regulators CDKN2A and CDKN2B. This loci was commonly lost in BCa cell lines and we show the deletions extended to the polyamine enzyme methylthioadenosine (MTA) phosphorylase (MTAP) in 36% of lines, transcription factor DMRTA1 (27%) and antiviral interferon epsilon (IFNE, 19%). Overall, the BCa cell line genomic aberrations were concordant with those found in BCa patient tumors. We used gene expression and copy number data to infer pathway activities for cell lines, then used the inferred pathway activities to build a predictive model of cisplatin response. When applied to platinum-treated patients gathered from TCGA, the model predicted treatment-specific response. Together, these data and analysis represent a valuable community resource to model basic tumor biology and to study the pharmacogenomics of BCa.Oncogene advance online publication, 6 June 2016; doi:10.1038/onc.2016.172. Platinum-resistance is a major clinical problem for urothelial carcinoma. Despite high initial responses, the majority of patients with urothelial carcinoma eventually develop Cisplatin resistance. REFERENCES Oncogene. 2016 Jun 6. doi: 10.1038/onc.2016.172. [Epub ahead of print] Nickerson ML1, Witte N2, Im KM3, Turan S1, Owens C4, Misner K1, Tsang SX5, Cai Z6, Wu S6, Dean M1, Costello JC2,7,8, Theodorescu D4,7,8. AUTHOR INFORMATION 1. Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Frederick, MD, USA. 2. Computational Bioscience Program, University of Colorado, Aurora, CO, USA. 3. Data Science for Genomics, LLC, Ellicott City, MD, USA. 4. Department of Surgery (Urology), University of Colorado, Aurora, CO, USA. 5. BGI-Shenzhen, Shenzhen, China. 6. Shenzhen Second People’s Hospital, Shenzhen, China. 7. Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. 8. University of Colorado Comprehensive Cancer Center, Aurora, CO, USA. VOLUME 1, ISSUE 2 A new study by Nickerson et al. published in the journal Oncogene examined the genomic sequences of 25 bladder cancer cell lines to look at the mutations, copy number alterations and gene expression to correlate them with drug responses. The authors identified mutations affecting protein function in 76 cancer related genes that mirrored mutations identified in the TCGA dataset. They also identified alterations in several signaling pathways including the PI3K/mTOR pathway, SYNE1– SYNE2 altered in 60% of lines and BRCA DNA repair altered in 44% of cell lines. The investigators generated a signature based on altered pathways in cell lines and correlated it with each cell line’s sensitivity to Cisplatin. The same signature was then used this information to build a predictive model for Cisplatin-response in patients treated with chemotherapy from the TCGA dataset. Kaplan–Meier survival analysis showed significant difference among patients treated with platinum-based drugs between those predicted to be sensitive and those predicted to be resistant (P = 0.05, log-rank test). This pharmacogenomics analysis reveals the importance of understanding the genetic architecture of existing bladder cancer cell line models and is a successful example of how this knowledge can be applied to predict response to chemotherapy in patients. REFERENCES Nickerson ML, Witte N, Im KM, Turan S, Owens C, Misner K, Tsang SX, Cai Z, Wu S, Dean M, Costello JC, Theodorescu D. Molecular analysis of urothelial cancer cell lines for modeling tumor biology and drug response. Oncogene. 2016 Jun 6. doi: 10.1038/onc.2016.172. [Epub ahead of print] 39 SPOTLIGHT Efficacy and Safety of Combined Androgen Deprivation Therapy (ADT) and Docetaxel Compared with ADT Alone for Metastatic HormoneNaive Prostate Cancer: A Systematic Review and Meta-Analysis ABSTRACT OBJECTIVE: Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA) and Western Europe. Androgendeprivation therapy alone (ADT) remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT) that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel) for metastatic hormone-naive prostate cancer (mHNPC). METHODS: Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (95% CI). RESULTS: The final analysis included 3 trials comprising 2,264 patients (mHNPC). Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001), and no heterogeneity (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%). The biochemical progression-free survival (bPFS) also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p<0.00001), also with no heterogeneity noted (Chi2 = 0.48; df = 2 [p = 0.79]; I2 = 0%). Finally, the combination of ADT with docetaxel showed a superior overall survival (OS) compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001), with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%). A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002). In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003). Regarding adverse events and severe toxicity (grade ≥3), the group receiving the combined therapy had higher rates of neutropenia, febrile neutropenia and fatigue. CONCLUSION: The combination of ADT with docetaxel improved the clinical progression-free survival, bPFS and OS of patients with mHNPC. A superior OS was seen especially for patients with metastatic and high-volume disease. This contemporary combination therapy may now be offered as a first-line treatment for selected patients. REFERENCES Journal information: PLoS One. 2016 Jun 16;11(6):e0157660. doi:10.1371/journal. pone.0157660. eCollection 2016. AUTHOR INFORMATION Botrel TE1,2, Clark O1,2, Lima Pompeo AC2, Horta Bretas FF2, Sadi MV2, Ferreira U2, Borges Dos Reis R2. 1. Evidencias - A Kantar Health Company, Campinas, São Paulo, Brazil. 2. Comitê Brasileiro de Estudos em Uro-Oncologia - CoBEU, São Paulo, São Paulo, Brazil. 40 COMMENTARY Androgen-deprivation therapy alone (ADT) continues to be the first line of treatment in most metastatic prostate cancer cases. A combination of docetaxel and prednisone, was the first treatment to significantly improve overall survival in men with metastatic castration-resistant disease. Recent trials tested ADT in combination with docetaxel in the frontline setting with variable results. A recent meta-analysis by Botrel et al. published in the journal PLOS ONE tried to reconcile these results by evaluating the effectiveness and safety of docetaxel associated with standard ADT in patients with metastatic hormone-sensitive metastatic prostate cancer. The authors searched several databases including MEDLINE, EMBASE, LILACS, and CENTRAL for clinical trials testing this combination. The study identified 3 clinical trials (GETUG-AFU 15, CHAARTED, STAMPEDE) including a total of 2,264 patients. The analysis demonstrated that patients receiving chemotherapy in combination with ADT had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001). There was no significant heterogeneity observed between studies (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%). In addition, the combination of ADT with docetaxel was associated with superior overall survival (OS) compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001), with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%). Patients with high-volume disease also increased overall survival with combination chemo- hormonal therapy in the combined analysis (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003). As expected patients receiving chemotherapy had higher rates of toxicity including neutropenia, febrile neutropenia and fatigue. The results of this meta-analysis support the use of Docetaxel in combination with ADT in select patients with hormone sensitive prostate cancer, especially patients with high volume metastatic disease. REFERENCES Efficacy and Safety of Combined Androgen Deprivation Therapy (ADT) and Docetaxel Compared with ADT Alone for Metastatic Hormone-Naive Prostate Cancer: A Systematic Review and Meta-Analysis.Botrel TE, Clark O, Lima Pompeo AC, Horta Bretas FF, Sadi MV, Ferreira U, Borges Dos Reis R. PLoS One. 2016 Jun 16;11(6):e0157660. doi: 10.1371/journal. pone.0157660. eCollection 2016 EVERYDAY UROLOGYTM Higher Preoperative Serum Levels of PD-L1 and B7-H4 are Associated with Invasive and Metastatic Potential and Predictable for Poor Response to VEGF-targeted Therapy and Unfavorable Prognosis of Renal Cell Carcinoma ABSTRACT COMMENTARY Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer. Although antivascular endothelial growth factor (VEGF) therapies achieve impressive responses in some patients, many tumors eventually develop resistance to such therapy. The B7 family molecules such as CTLA-4, PD-1, and PD-L1 are pivotal players in immune checkpoints that positively or negatively regulate various immune responses. Recently, immunotherapy based on blocking immune checkpoints with anti-CTLA4, anti-PD-1, or anti-PD-L1 antibodies has been proposed as a potential new approach to the treatment of metastatic RCC. Higher expression of PD-L1 and B7-H4 in the tumors is associated with a poor prognosis in RCCs, however, the clinical impact of serum levels of B7 family molecules has not been elucidated in patients with metastatic RCCs receiving VEGF-targeted agents. We assessed the preoperative serum levels of B7 family molecules, including CD80, CD86, PD-1, PD-L1, B7-H3, B7-H4, and CTLA-4, and CD28 in RCC patients, and determined their relations with various clinicopathological characteristics. Elevated preoperative serum levels of PD-L1 and B7-H4 were correlated with less differentiated tumors, higher invasive and metastatic potential, a worse response to anti-VEGF therapy, and shorter overall survival. These findings suggested that investigating preoperative serum levels of PD-L1 and B7-H4 might not only be useful to assess the biological aggressiveness of RCCs, but also to predict the efficacy of anti-VEGF therapy and the eventual prognosis, indicating the future design of clinical trials of therapies targeting immune checkpoint in advanced RCCs. Renal cell carcinoma (RCC) is driven by angiogenic signaling. Anti-VGEF therapies targeting this pathway are an integral part of frontline therapy regimens for metastatic RCC. RCC is also characterized by responses to immunotherapy with the recent approval of Nivolumab, a (PD-1) immune checkpoint inhibitor antibody. REFERENCES Additionally, elevated preoperative serum levels of PD-L1 and B7-H4 were correlated with less differentiated tumors and higher invasive and metastatic potential. Serum levels of PD-L1 and B7-H4 also predicted decreased response to antiVEGF therapy, and shorter overall survival. Cancer Medicine 2016 Jun 12. doi: 10.1002/cam4.754. [Epub ahead of print] Fukuda T1, Kamai T1, Masuda A2, Nukui A3, Abe H1, Arai K1, Yoshida KI1. 1. Department of Urology, Dokkyo Medical University, Tochigi, Japan. 2. Dialysis center, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan. 3. Department of Urology, Nasu Red Cross Hospital, Tochigi, Japan. The immune checkpoint family of proteins, PD-1, and PD-L1 are key players in regulating the antitumor immune response and their expression may determine responses to immune checkpoint inhibitors but their effect on response to anti-angiogenic therapy is unknown. A recent study by Fukuda et al. published in the journal Cancer Medicine examined the relationship between serum levels of the immune checkpoint family molecules and clinical responses in patients with metastatic RCCs receiving VEGF-targeted agents. The investigators examined the levels of the B7 family molecules, including CD80, CD86, PD-1, PD-L1, B7-H3, B7-H4, CTLA-4, and CD28 in RCC patients and identified several interesting correlations with clinical outcomes in 181 patients and 25 healthy controls between June 2007 and June 2014. Interestingly, serum VEGF level was closely correlated with that of B7- H4 (r2 = 0.66) but weakly coorelated with that of PD- L1 (r2= 0.39). These results suggest that elevated preoperative serum levels PDL-1 and B7-H4 can be both prognostic and predictive biomarkers. Further prospective and independent validation of these findings is warranted. REFERENCES Fukuda T, Kamai T, Masuda A, Nukui A, Abe H, Arai K, Yoshida KI.Higher preoperative serum levels of PD-L1 and B7-H4 are associated with invasive and metastatic potential and predictable for poor response to VEGF-targeted therapy and unfavorable prognosis of renal cell carcinoma. Cancer Med. 2016 Jun 12. doi: 10.1002/cam4.754. [Epub ahead of print] VOLUME 1, ISSUE 2 41 SPOTLIGHT A Major Step Towards Understanding the Molecular Characteristics of Early-stage Urothelial Carcinoma ABSTRACT Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.. REFERENCES Cancer cell. 2016 Jun 16 Jakob Hedegaard, Philippe Lamy, Iver Nordentoft, Ferran Algaba, Søren Høyer, Benedicte Parm Ulhøi, Søren Vang, Thomas Reinert, Gregers G Hermann, Karin Mogensen, Mathilde Borg Houlberg Thomsen, Morten Muhlig Nielsen, Mirari Marquez, Ulrika Segersten, Mattias Aine, Mattias Höglund, Karin Birkenkamp-Demtröder, Niels Fristrup, Michael Borre, Arndt Hartmann, Robert Stöhr, Sven Wach, Bastian Keck, Anna Katharina Seitz, Roman Nawroth, Tobias Maurer, Cane Tulic, Tatjana Simic, Kerstin Junker, Marcus Horstmann, Niels Harving, Astrid Christine Petersen, M Luz Calle, Ewout W Steyerberg, Willemien Beukers, Kim E M van Kessel, Jørgen Bjerggaard Jensen, Jakob Skou Pedersen, Per-Uno Malmström, Núria Malats, Francisco X Real, Ellen C Zwarthoff, Torben Falck Ørntoft, Lars Dyrskjøt. COMMENTARY Non-muscle invasive bladder cancer (NMIBC) constitutes up to 75 % of new bladder cancer diagnoses and up to 15% of patients with NMIBC eventually develop muscle-invasive bladder cancer (MIBC). The cost and societal burden of recurrent non-muscle invasive disease is quite high. Moreover, the morbidity and mortality for progression to muscle-invasive disease is significant but the biological basis for progression are not well understood. In recent study published in the journal Cancer Cell, Hedegaard et. al. performed an integrated analysis of that NMIBC from 460 patients together with 16 tumors from patients with MIBC. The investigators initially performed RNA sequencing on these samples and identified three major NMIBC clusters, Class 1 and class 2 tumors expressed luminal markers such as uroplakins whereas class 3 was associated with the expression of KRT5 and KRT15 which reflect undifferentiated basal cells. They identified a unique carcinoma in situ signature associated with the risk of progression. The investigators identified a 117-gene classifier to differentiate the different subclasses and applied it to several independent datasets. Additionally, they identified mutations from the RNA sequencing data (after validating their method by comparing mutation calls with whole-exome sequencing in 11 patients). Interestingly the investigators identified that mutations induced by APOBEC (a family of enzymes that mutate cytosines) may drive disease progression in NMIBC. Interestingly, NMIBC class 3 was characterized by the expression long non coding RNAs including NEAT1. This landmark study significantly adds to our knowledge of the molecular characteristics of NMIBC and opens to door to a better understanding of the biological basis for progression from NMIBC to MIBC. REFERENCES Hedegaard J1, Lamy P, Nordentoft I, Algaba F, Høyer S, Ulhøi BP, Vang S, Reinert T, Hermann GG, Mogensen K, Thomsen MB, Nielsen MM, Marquez M, Segersten U, Aine M, Höglund M, Birkenkamp-Demtröder K, Fristrup N, Borre M, Hartmann A, Stöhr R, Wach S, Keck B, Seitz AK, Nawroth R, Maurer T, Tulic C, Simic T, Junker K, Horstmann M, Harving N, Petersen AC, Calle ML, Steyerberg EW, Beukers W, van Kessel KE, Jensen JB, Pedersen JS, Malmström PU, Malats N, Real FX, Zwarthoff EC, Ørntoft TF, Dyrskjøt L. Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma. Cancer Cell. 2016 Jul 11;30(1):27-42. doi: 10.1016/j. ccell.2016.05.004. Epub 2016 Jun 16. 42 EVERYDAY UROLOGYTM A Five-Gene Expression Signature to Predict Progression in T1G3 Bladder Cancer ABSTRACT COMMENTARY The aim of this study was to analyze tumour gene expression profiles of progressive and non-progressive T1G3 bladder cancer (BC) patients to develop a gene expression signature to predict tumour progression. Non-muscle invasive bladder cancer (NMIBC) is a disease characterized by a high risk of after initial therapy. Up to 15% of patients with NMIBC eventually develop muscle-invasive bladder cancer (MIBC). The molecular basis and the risk factors for this progression are not completely understood. Retrospective, multicenter study of 96 T1G3 BC patients without carcinoma in situ (CIS) who underwent a transurethral resection. Formalin-fixed paraffin-embedded tissue samples were collected. Global gene expression patterns were analyzed in 21 selected samples from progressive and non-progressive T1G3 BC patients using Illumina microarrays. Expression levels of 94 genes selected based on microarray data and based on literature were studied by quantitative polymerase chain reaction (qPCR) in an independent series of 75 progressive and non-progressive T1G3 BC patients. Univariate logistic regression was used to identify individual predictors. A variable selection method was used to develop a multiplex biomarker model. Discrimination of the model was measured by area under the receiver-operating characteristic curve. Interaction networks between the genes of the model were built by GeneMANIA Cytoscape plugin. A total of 1294 genes were found differentially expressed between progressive and non-progressive patients. Differential expression of 15 genes was validated by qPCR in an additional set of samples. A five-gene expression signature (ANXA10, DAB2, HYAL2, SPOCD1, and MAP4K1) discriminated progressive from non-progressive T1G3 BC patients with a sensitivity of 79% and a specificity of 86% (AUC = 0.83). Direct interactions between the five genes of the model were not found. Progressive and non-progressive T1G3 bladder tumours have shown different gene expression patterns. To identify T1G3 BC patients with a high risk of progression, a five-gene expression signature has been developed. A recent study published in the European Journal of Cancer by van der Heijden et al. aimed to address this need. In order to develop biomarkers that can distinguish progressive from non-progressive NMIBC, the authors evaluated the global gene expression patterns using microarrays in high grade T1 bladder cancer patients without carcinoma in situ (CIS) who underwent a transurethral resection. The screening phase identified a set of genes that were differentially expressed between patients who progressed and patients without progression. The investigators then validate the expression of 94 genes in an independent validation set 75 progressive and non-progressive T1G3 BC patients by quantitative polymerase chain reaction (qPCR). Univariate logistic regression was then used to identify individual predictors which were then used to build a classifier. The five-gene expression classifier (ANXA10, DAB2, HYAL2, SPOCD1, and MAP4K1) discriminated progressive from non-progressive T1G3 bladder cancer patients with a sensitivity of 79% and a specificity of 86% (AUC = 0.83). Interestingly, there were no obvious functional links between these genes that would explain the reported utility of the signature to discriminate between progressive and non-progressive bladder cancer. This novel study addresses an important need for the development of accurate markers that predict progression of non-muscle invasive disease. More importantly, it highlights the existing knowledge gaps in our understanding of the biology of progressive non-muscle invasive bladder cancer. REFERENCES REFERENCES European journal of cancer (Oxford, England : 1990). 2016 Jul 11 [Epub ahead of print] Antoine G van der Heijden, Lourdes Mengual, Juan J Lozano, Mercedes Ingelmo-Torres, Maria J Ribal, Pedro L Fernández, Egbert Oosterwijk, Jack A Schalken, Antonio Alcaraz, J Alfred Witjes. van der Heijden AG, Mengual L, Lozano JJ, Ingelmo-Torres M, Ribal MJ, Fernández PL, Oosterwijk E, Schalken JA, Alcaraz A, Witjes JA. A five-gene expression signature to predict progression in T1G3 bladder cancer. Eur J Cancer. 2016 Jul 11;64:127-136. doi: 10.1016/j. ejca.2016.06.003. [Epub ahead of print] VOLUME 1, ISSUE 2 43 We hope you enjoyed this issue of Everyday Urology – Oncology Insights! 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