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American Urological Association AUA NEWS | THE OFFICIAL NEWSMAGAZINE OF THE AMERICAN UROLOGICAL ASSOCIATION | 2016 ANNUAL MEETING HIGHLIGHTS Castration-Resistant Prostate Cancer Course #003PG Management of Prostate Cancer: A Case Based Approach with Emphasis on Integrating New Molecular Diagnostics into Clinical Practice Course #009IC AUA Guideline: Castration-Resistant Prostate Cancer Update Course #054PG Prostate Cancer Update 2016 Course #091PG Novel Agents and Concepts in the Management of Hormone Naïve and Castration-Resistant Prostate Cancer Plenary Sessions Forum: Town Hall on Optimizing Quality of Life in Patients with Advance Cancer AUA 2016 ANNUAL MEETING HIGHLIGHTS Take Home Message: Prostate Cancer Castration-Resistant Prostate Cancer AUANews Editor Manoj Monga, MD, FACS Publisher American Urological Association 1000 Corporate Boulevard Linthicum, MD 21090 Copyright © 2016 by American Urological Association None of the contents may be reproduced in any form without prior written permission of the publisher. The opinions expressed in this publication are those of the speakers and do not necessarily reflect the opinions or recommendations of their affiliated institutions, the publisher, the American Urological Association or any other persons. Some articles in this publication may discuss unapproved or “off-label” uses of products. Any procedures, medications or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients’ conditions and of possible contraindications or dangers in use, review of any applicable manufacturers’ product information and comparison with the recommendations of the authorities. Educational grant support provided by: •AbbVie • Astellas Pharma Global Development, Inc. Medical Affairs, Americas it • Janssen Biotech, Inc., administered by Janssen Scientific Affairs LLC •Medivation CM E ed Cr AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 1 CME INFORMATION 2016 AUA Annual Meeting Highlights: CastrationResistant Prostate Cancer Method of Participation To claim CME credit/hours of participation, the learner must complete a pretest, read the overview of courses 003PG, 009IC, 054PG and 091PG, complete the posttest, passing with 80% accuracy and submit the evaluation and credit request form by visiting www.AUAnet.org/University/CRPC16. Estimated time to complete this activity: 1.25 hours Release Date: October 2016 Expiration Date: October 31, 2017 Accreditation Statement The American Urological Association (AUA) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Credit Designation The American Urological Association designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Other Learners The AUA is not accredited to offer credit to participants who are not MDs or DOs. However, the AUA will issue documentation of participation that states that the activity was certified for AMA PRA Category 1 Credit™. This enduring material credit is valid only for content reformatted from courses 003PG, 009IC, 054PG and 091PG. Statement of Need The role of the urologist in the treatment of patients with castration-resistant prostate cancer (CRPC) continues to expand as the number and variety of therapeutic options increases. It is critical that urologists remain engaged and knowledgeable on the management of CRPC in the contemporary setting of a multitude of new agents becoming available to treat patients. Target Audience Urologists, urologists in training and non-physician providers involved in urology. Course 003PG: Management of Prostate Cancer: A Case Based Approach with Emphasis on Integrating New Molecular Diagnostics into Clinical Practice Learning Objectives At the conclusion of this CME activity, participants should be able to: • Design appropriate screening strategies based on individual demographics, risk factors and prostate specific antigen history, and to incorporate new biomarkers into routine clinical practice • Distinguish and understand the use of new molecular and genomic based tests for decisions on initial and rebiopsy, and choosing and following men on surveillance • Appraise the role of surveillance, focal therapy, surgery and various forms of radiation therapy in patients with low and intermediate risk disease • Enumerate and contrast the benefits and drawbacks of surgery vs radiation based approaches for the management of high risk localized disease • Describe new therapeutic agents for the management of castrate resistant disease and outline a coherent strategy for their use Faculty Eric A. Klein, MD, Course Director Chairman, Glickman Urological and Kidney Institute Professor of Surgery, Lerner College of Medicine Cleveland Clinic Cleveland, OH Disclosures: GenomeDx Biosciences: Consultant or Advisor, Scientific Study or Trial; Genomic Health: Consultant or Advisor; Berg: Consultant or Advisor Andrew J. Stephenson, MD Director, Center for Urologic Oncology Cleveland Clinic Associate Professor, Surgery Case Western Reserve University School of Medicine Cleveland, OH Disclosures: Nothing to disclose Course 009IC: AUA Guideline: Castration-Resistant Prostate Cancer Update Learning Objectives At the conclusion of this CME activity, participants should be able to: • Analyze the evidence on the treatment of castration-resistant prostate cancer as outlined in the AUA guidelines and subsequent publications • Improve diagnostic and therapeutic decision making processes by illustrating the application of these guidelines in urological practice • Acquire in-depth knowledge on the process by which evidence is used to develop scientifically rigorous, yet actionable, guidelines Faculty Michael S. Cookson, MD, Course Director Professor and Chairman, Department of Urology University of Oklahoma College of Medicine Oklahoma City, OK Disclosures: Nothing to disclose ▼ Continued on page 2 2 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS CME Information ▼ Continued from page 1 Adam S. Kibel, MD Chief of Urologic Surgery Dana-Farber Cancer Institute and Brigham and Women's Hospital Professor, Department of Surgery, Harvard University Medical School Boston, MA Disclosures: Sanofi-Aventis: Consultant or Advisor, Scientific Study or Trial; MTG: Consultant or Advisor; Profound: Consultant or Advisor; Dendreon: Consultant or Advisor William T. Lowrance, MD, MPH Assistant Professor, Division of Urology University of Utah School of Medicine Investigator Huntsman Cancer Institute (HCI) Salt Lake City, UT Disclosures: Myriad Genetics: Consultant or Advisor, Scientific Study or Trial; Genome Dx: Scientific Study or Trial; Argos: Scientific Study or Trial; Stream Dx: Investment Interest Course 054PG: Prostate Cancer Update 2016 Learning Objectives At the conclusion of this CME activity, participants should be able to: • Cite important new publications in this field during the past year • Identify the relative strengths and weaknesses of the reports • Appraise how new studies relate to the existing state-of-the-art in clinical practice • Analyze whether they and their colleagues should consider changing their practice based on the new information Trial; deCODE genetics: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; OHMX: Consultant or Advisor, Owner, Product Development; Nanosphere: Consultant or Advisor Douglas M. Dahl, MD Chief, Division of Urologic Oncology Associate Urologist Massachusetts General Hospital Boston, MA Disclosures: Cambridge Endo: Investment Interest Stanley Liauw, MD Associate Professor, Department of Radiation & Cellular Oncology University of Chicago Medicine Chicago, IL Disclosures: Nothing to disclose Stacy Loeb, MD Assistant Professor of Urology and Population Health New York University School of Medicine New York, NY Disclosures: Nothing to disclose Robert B. Nadler, MD Professor, Department of Urology Northwestern University Feinberg School of Medicine Chicago, IL Disclosures: Nothing to disclose Russell Szmulewitz, MD Assistant Professor of Medicine The University of Chicago Medicine Chicago, IL Disclosures: Pfizer: Consultant or Advisor; Genentech: Scientific Study or Trial Course 091PG: Novel Agents and Concepts in the Management of Faculty Hormone Naïve and CastrationWilliam J. Catalona, MD, Course Resistant Prostate Cancer Director Learning Objectives Professor, Department of Urology Northwestern University Feinberg School of Medicine Chicago, IL Disclosures: Beckman Coulter Incorporated: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or At the conclusion of this CME activity, participants should be able to: • Diagnose castration-resistant prostate cancer and have a working knowledge of treatments and the proper order for administration • Manage CRPC with systemic agents by learning the proper candidates for treatment and be able to counsel patients on the pros and cons of therapy • Analyze the mechanism of action and risks/benefits of using systemic agents in the treatment of CRPC • Describe the bone-targeted, radiopharmaceutical agent RADIUM-223 and its sequencing • Review the new generation antiandrogen agent enzalutamide and its sequencing Faculty Judd W. Moul, MD, FACS, Course Director Professor of Surgery Professor in Anesthesiology Director, Duke Prostate Center Duke University School of Medicine Durham, NC Disclosures: Sanofi-Aventis: Health Publishing, Meeting Participant or Lecturer; Dendreon: Consultant or Advisor, Meeting Participant or Lecturer; Theralogix: Consultant or Advisor; Ferring Pharmaceuticals Inc.: Consultant or Advisor, Meeting Participant or Lecturer; Medivation-Astellas: Consultant or Advisor; Janssen-J and J: Consultant or Advisor, Meeting Participant or Lecturer; Myriad Genetics Inc.: Consultant or Advisor, Meeting Participant or Lecturer. Genomic Health: Meeting Participant or Lecturer Lawrence I. Karsh, MD, FACS Director, Clinical Research Department The Urology Center of Colorado Denver, CO Disclosures: Astellas: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Dendreon: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Bayer: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Janssen: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Medivation: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Genomic Health: Consultant or ▼ Continued on page 3 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 3 CME Information ▼ Continued from page 2 Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Myriad: Consultant or Advisor, Scientific Study or Trial; Swan Valley Medical: Consultant or Advisor, Investment Interest; Amgen: Scientific Study or Trial; Heat Biologics: Scientific Study or Trial; Bavaria Nordic Immunotherapy: Consultant or Advisor, Scientific Study or Trial; MDxHealth: Scientific Study or Trial Christopher Sweeney, MBBS Associate Professor, Department of Medicine Harvard Medical School Medical Oncologist, Medical Oncology Dana-Farber Cancer Institute Boston, MA Disclosures: Sanofi: Consultant or Advisor; Janssen: Consultant or Advisor; BIND: Consultant or Advisor; Astellas: Consultant or Advisor; Bayer: Consultant or Advisor; Genentech Roche: Consultant or Advisor Planners Education Council Manoj Monga, MD, FACS Director, Center for Endourology & Stone Disease Cleveland Clinic Cleveland, OH Disclosures: Fortec: Other; Endourology Society: Leadership Position Victor W. Nitti, MD Professor, Department of Urology Professor, Department of Obstetrics and Gynecology Director, Female Pelvic Medicine and Reconstructive Surgery Program Vice Chair, Department of Urology Director, Female Pelvic Medicine Fellowship Program New York University Langone Medical Center New York, NY Disclosures: Astellas: Health Publishing, Scientific Study or Trial; Allergan: Health Publishing, Scientific Study or Trial; Serenity Pharmaceuticals: Investment Interest; Cook Myosite: Scientific Study or Interest Trial Brant Inman, MD, MS Associate Professor, Surgery Vice Chief, Urology Duke University School of Medicine Durham, NC Disclosures: Dendreon: Scientific Study or Trial; Abbott Laboratories: Scientific Study or Trial; Genentech Inc.: Scientific Study or Trial; Combat Medical: Consultant or Advisor Acknowledgements The AUA Office of Education would like to thank the companies who support continuing education of physicians. The AUA recognizes the following companies for providing educational grant support: • AbbVie • Astellas Pharma Global Development, Inc. Medical Affairs, Americas • Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC • Medivation American Urological Association Education & Research, Inc. ensures that all educational activities are developed and implemented independent of the control and/or influence of any commercial interests (ACCME: SCS1). AUA Disclosure Policy All persons in a position to control the content of an educational activity (i.e., activity planners, presenters, authors) are required to disclose to the provider any relevant financial relationships with any commercial interest. The AUA must determine if the individual’s relationships may influence the educational content and resolve any conflicts of interest prior to the commencement of the educational activity. The intent of this disclosure is not to prevent individuals with relevant financial relationships from participating, but rather to provide learners information with which they can make their own judgments. Resolution of Identified Conflict of All disclosures will be reviewed by the program/course directors or editors for identification of conflicts of interest. Peer reviewers, working with the program directors and/or editors, will document the mechanism(s) for management and resolution of the conflict of interest and final approval of the activity will be documented prior to implementation. Any of the mechanisms below can/will be used to resolve conflict of interest: • Peer review for valid, evidence-based content of all materials associated with an educational activity by the course/program director, editor, and/ or Education Content Review Committee or its subgroup • Limit content to evidence with no recommendations • Introduction of a debate format with an unbiased moderator (point-counterpoint) • Inclusion of moderated panel discussion • Publication of a parallel or rebuttal article for an article that is felt to be biased • Limit equipment representatives to providing logistics and operation support only in procedural demonstrations • Divestiture of the relationship by faculty Evidence-Based Content It is the policy of the AUA to ensure that the content contained in this CME activity is valid, fair, balanced, scientifically rigorous, and free of commercial bias. Off-label or Unapproved Use of Drugs or Devices It is the policy of the AUA to require the disclosure of all references to off-label or unapproved uses of drugs or devices prior to the presentation of educational content. The audience is advised that this continuing medical education activity may contain reference(s) to off-label or unapproved uses of drugs or devices. ▼ Continued on page 4 4 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS CME Information ▼ Continued from page 3 Please consult the prescribing information for full disclosure of approved uses. Disclaimer The opinions and recommendations expressed by faculty, authors and other experts whose input is included in this program are their own and do not necessarily represent the viewpoint of the AUA. AUA Privacy and Confidentiality Policy Reproduction Permission Access the AUA Privacy and Confidentiality Policy online at www.auanet. org/education/confidentiality-statement. cfm. Reproduction of written materials developed for this AUA course is prohibited without the written permission from individual authors and the American Urological Association. AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 5 COURSE #003PG Management of Prostate Cancer: A Case Based Approach with Emphasis on Integrating New Molecular Diagnostics into Clinical Practice Eric A. Klein, MD, Course Director; Andrew J. Stephenson, MD, Faculty Precision medicine is a concept defined by the idea that medical decision making, be it a decision to treat or not to treat, or choosing a specific drug or therapy, is based on the molecular characteristics of the disease or tumor. The theme of our postgraduate course this year was that the era of precision medicine in prostate cancer has arrived. The ability to characterize an individual’s risk of prostate cancer (future risk of disease), the likelihood that he has an aggressive prostate cancer at the moment of consultation (current risk of disease), the need for re-biopsy after an initial negative biopsy, how aggressive the known cancer is, whether the cancer has progressed biologically while on active surveillance, the likely benefit of adjuvant radiotherapy for those with adverse pathology on radical prostatectomy and the specific choice of therapy for those with castrate resistant disease can now be informed by new biomarkers and commercially available genomic based drugs (see Appendix). These efforts at better biological characterization of disease risk and aggressiveness promise to improve clinical decision making, so that the right decision can be made at the right time for every patient along the entire disease spectrum. An exciting use of the precision approach is in deciding which drugs to use for men with progressive metastatic castrate resistant disease. Median survival for such men is around 30 months, and newer drugs such as abiraterone and enzalutamide that target androgen receptor (AR) signaling have been shown in randomized, phase III trials to extend that interval. Although both drugs are well tolerated, clinical experience has demonstrated that approximately 20% to 40% of patients with metastatic castration-resistant prostate cancer (mCRPC) have no response to these agents (at least as measured by prostate specific antigen), demonstrating the presence of intrinsic resistance. Using a peripheral blood based circulating tumor cell assay, Antonarakis et al have shown that resistance to these drugs can be predicted by the presence of a variant of the androgen receptor, AR-V7, in the circulation,1 suggesting that patients who are positive for this marker be treated with a different agent or agents. This work has recently been validated by Scher et al, who showed that patients with AR-V7 had superior outcomes when treated with taxane chemotherapy.2 The clear implication of this study is that measurement of AR-V7 in men with mCRPC may be used in practice as a treatment specific biomarker to guide selection of therapy, and represents a successful example of how precision medicine approaches are able to improve patient outcomes. Another emerging and exciting precision approach is the recent identification of a higher than previously known prevalence of defects in DNA repair genes in the tumors of some patients with mCRPC. DNA repair is a complex but fundamental cellular process that serves a housekeeping function to repair mutations resulting from errors in cell division or cancer causing perturbations (inflammation, diet, other environmental exposures). Loss of fidelity or function of the DNA repair process can promote the accumulation of mutations and contribute to the genomic instability that fuels cancer progression. In a landmark study Mateo et al found that about a third of men with mCRPC had tumors with mutations in DNA repair genes, and that 88% of them had objective responses to a poly adenosine diphosphatase ribose polymerase inhibitor (olaparib) that targets the perturbed biochemical processes resulting from loss of DNA repair gene function.3 In another study Pritchard et al showed that almost 12% of men with metastatic disease had germline (inherited) defects in DNA repair genes compared to less than 5% of men with localized disease.4 The implication of this study is that men with defects in DNA repair genes are more likely to have metastatic disease, and that agents that target these pathways might be useful earlier in the disease process for men with known mutations. Accumulating data suggest many other targetable genes for men with metastatic disease (see table). Table. Actionable mutations in metastatic CRPC Gene % Frequency of Mutation Androgen receptor 60 PI3kinase (PTEN) 40 BRCA/DNA repair 25 RAF 10 WNT 6 Cell cycle (CDK) Less than 5 FGFR Less than 5 MMR Less than 5 IDH1 Less than 5 All of this work demonstrates that recent advances in genomic and biomarker science can be usefully applied to the treatment of men at risk for and diagnosed with prostate cancer. ▼ Continued on page 6 6 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS Course #003PG ▼ Continued from page 5 Appendix. Current spectrum of precision medicine for prostate cancer Clinical Scenario Available Biomarkers Comment Risk of developing prostate cancer (future risk) Germline allelic variants Robust test not yet commercially available Likelihood of having aggressive prostate cancer (current risk) before biopsy OPKO4k, PCA3, PHI, ExoDx™, MI-Prostate, SelectMDx™ All reduce the need for unnecessary biopsy by about 30% Need for re-biopsy PCA3, ConfirmMDx Predict for the likelihood that an existing cancer was missed Consideration of active surveillance oncotypeDx® prostate, Prolaris®, Promark Predict disease aggressiveness and presence of adverse pathology Progression of disease while None validated on active surveillance Choice of adjuvant or salvage radiation after radical prostatectomy Decipher Choice of therapy for meta- AR-V7 static CRPC 1. Antonarakis ES, Lu C, Wang H et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028. 2. Scher H, Lu D, Schreiber NA et al: Association of AR-V7 on circulating tumor cells as a treatmentspecific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol 2016; doi: 10.1001/jamaoncol.2016.1828. Under study Predicts likelihood of metastasis within 5 years or surgery Predicts resistance to abiraterone and enzalutamide 3. Mateo J, Carreira S, Sandhu S et al: DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015; 373: 1697. 4. Pritchard CC, Mateo J, Walsh MF et al: Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016; 375: 443. COURSE #009IC AUA Guideline: Castration-Resistant Prostate Cancer Update Michael S. Cookson, MD, MMHC, Course Director; Adam Kibel, MD and Will Lowrance, MD, Faculty The treatment of patients with castration-resistant prostate cancer (CRPC) continues to evolve, and that is important information for patients who suffer from the second leading cause of cancer death in men.1 Improved survival with 6 different therapeutic agents and now success with the earlier use of some agents with prior approval have resulted in annual updates of the AUA guidelines for CRPC. For the fourth consecutive year the AUA has presented these guidelines in an instructional course designed to inform clinicians of the latest changes in evidence-based recommendations for the sequencing and treatment of castration-resistant disease. The treatment of men with metastatic CRPC (mCRPC) has changed significantly in the last decade. Before 2004, once primary androgen deprivation therapy (ADT) failed, treatments were administered solely for palliation. In landmark studies Tannock2 and Petrylak3 et al demonstrated that docetaxel improved survival in patients with mCRPC compared to mitoxantrone. Since then 5 additional agents (abiraterone, sipuleucel-T, cabazitaxel, enzalutamide and radium-223) that have all shown a survival benefit have been approved by the FDA (U.S. Food and Drug Administration) on the basis of randomized clinical trials.4-9 These agents have been tested in multiple disease states of CRPC to determine if or when patients might benefit from each treatment. Now these agents and others are being investigated in earlier stages of the disease. At the AUA 2016 Annual Meeting we presented the updated AUA CRPC guidelines. A reason for the continued guidelines update is the rapid evolution of the field with the new treatments that are becoming available. The use of enzalutamide before chemotherapy in men with asymptomatic or mildly symptomatic mCRPC was discussed. This major breakthrough was the result of the PREVAIL trial, a randomized trial of enzalutamide compared to placebo in men with mCRPC before docetaxel therapy.9 The study demonstrated significant improvement in the 2 coprimary end points of overall survival (HR 0.706, 95% CI 0.60-0.84, p <0.001) ▼ Continued on page 7 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 7 Course #0091C ▼ Continued from page 6 and radiographic progression-free survival (HR 0.186, 95% CI 0.15-0.23) in patients treated with enzalutamide vs placebo. Previously, abiraterone plus prednisone was approved in the prechemotherapy setting (COU-302).4 In addition, the use of an alpha emitting radionuclide therapy was discussed relative to the FDA approved use of radium-223 dichloride for the treatment of mCRPC, symptomatic bone metastases and no visceral metastatic disease.8 These approvals and others anticipated in the near future highlight the need for continuous periodic updating of the AUA guidelines to inform clinicians regarding the rapidly evolving management of this disease. The CRPC guidelines were developed using 6 index cases intended to represent the most common scenarios encountered in clinical practice. Accordingly, cases with CRPC were categorized based on the presence or absence of metastases, degree and severity of symptoms, overall performance status and prior treatment with docetaxel chemotherapy. Guideline statements for each of the index cases were rated as a standard, a recommendation, an option or an expert opinion based on the grading of the strength and quality of the evidence, as well as panel assessment of the benefits and harms of treatment. The statements were also formatted into a user-friendly algorithm. A summary of the CRPC guideline statements for each index case and respective statement were presented. Moreover, the guidelines were revised to reflect newly approved therapies, approval of use of the therapies in new disease stages and the proper sequencing of agents. Index patient 1 is asymptomatic with an increasing prostate specific antigen and no radiographic evidence of metastases. There are currently no FDA approved agents for this scenario. Clinicians should recommend observation with continued ADT for patients with nonmetastatic CRPC. Since all agents have potential side effects and no treatment has been shown to extend survival or demonstrate a clinically meaningful delay in the development of metastasis, we must first do no harm. Patients should be encouraged to enter clinical trials when available. Clinicians may also offer treatment with first-generation antiandrogens or first-generation androgen synthesis inhibitors to select patients. Systemic chemotherapy or immunotherapy should be offered to patients with nonmetastatic CRPC outside the context of a clinical trial. Index patient 2 is asymptomatic or has minimal symptoms with metastases and no prior docetaxel. In this setting clinicians should offer abiraterone + prednisone, enzalutamide, docetaxel or sipuleucel-T. Of note, the addition of enzalutamide in the pre-chemotherapy setting was an important addition to this year’s AUA guidelines update. Clinicians may offer first-generation antiandrogen therapy, first-generation androgen synthesis inhibitors or observation to index 2 patients who do not want or cannot have standard therapy. Finally, some patients may not wish to pursue any therapy and may wait for the onset of symptoms to pursue treatment. Index patient 3 is symptomatic, has metastases and a good performance status, and has not previously received docetaxel. Clinicians should offer abiraterone + prednisone, enzalutamide or docetaxel chemotherapy in this setting. The inclusion of enzalutamide was also based on the results of the new PREVAIL trial data.9 Ketoconazole + steroid, mitoxantrone or radionuclide therapy may be offered to patients who do not want or cannot have standard therapy. For patients with symptomatic bone metastases and no visceral metastases, clinicians should offer radium-223. Clinicians should not offer estramustine or sipuleucel-T to index 3 patients. Index patient 4 is symptomatic with metastases, a poor performance status and no prior docetaxel treatment. Clinicians may offer treatment with abiraterone + prednisone or enzalutamide to these patients and ketoconazole + steroid or radionuclide therapy to those who are unable or unwilling to receive abiraterone + prednisone or enzalutamide. When performance status is directly related to the cancer, clinicians may offer docetaxel or mitoxantrone chemotherapy. Radium-223 may be offered to select patients with symptomatic bone metastases and without known visceral disease, specifically when performance status is directly related to symptoms of bone metastases. Clinicians should not offer sipuleucel-T to these patients. Index patient 5 is symptomatic with metastases, a good performance status and a history of docetaxel use. Clinicians should offer treatment with abiraterone + prednisone, cabazitaxel or enzalutamide to these patients. If the patient received abiraterone + prednisone before docetaxel chemotherapy, he should be offered cabazitaxel or enzalutamide. Ketoconazole + steroid may be offered to these patients if abiraterone + prednisone, cabazitaxel or enzalutamide is unavailable. Re-treatment with docetaxel may be suggested for patients who were benefitting at the time of docetaxel discontinuation (due to reversible side effects). New this year for patients with symptomatic bone metastases and no visceral metastases, clinicians should offer radium-223. Index patient 6 is symptomatic, with metastases, a poor performance status and prior docetaxel treatment. The goal of palliation is to prevent and relieve suffering, and to support the best possible quality of life for the patient and family. Palliative radiotherapy can be an option to control bone pain in some patients, and should be offered. Alternatively, in select patients clinicians may offer treatment with abiraterone + prednisone, enzalutamide, ketoconazole + steroid or radionuclide therapy. Clinicians should not offer systemic chemotherapy or immunotherapy to these patients. The guidelines also address bone health and indicate that all patients with CRPC should be offered preventive treatment (eg supplemental calcium, vitamin D) to reduce the risk of ▼ Continued on page 8 8 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS Course #009IC ▼ Continued from page 7 fractures and skeletal related events.10 Denosumab or zoledronic acid may be selected as preventive treatment for skeletal related events in patients with mCRPC and bony metastases.11, 12 The treatment of CRPC is undergoing rapid evolution with multiple new agents on the horizon, from immune modulators to vaccines to novel antiandrogens. In addition, use of approved agents is rapidly expanding into earlier disease stages, including the unmet need for agents in patients without evidence of radiographic metastases. It is likely that the guidelines will be modified on an annual or semiannual basis to keep urologists abreast of this rapidly chang- ing treatment landscape. 1. Siegel R, Ma J, Zou Z et al: Cancer statistics, 2014. CA Cancer J Clin 2014; 64: 9. 2. Tannock IF, de Wit R, Berry WR et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502. 3. Petrylak DP, Tangen CM, Hussain MH et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513. 4. Ryan CJ, Smith MR, de Bono JS et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138. 5. Kantoff PW, Higano CS, Shore ND et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411. 6. de Bono JS, Oudard S, Ozguroglu M et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: 1147. 7. Scher HI, Fizazi K, Saad F et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187. 8. National Cancer Institute: FDA Approval for Radium 223 Dichloride. Available at www.cancer. gov/cancertopics/druginfo/fda-radium-223-dichloride. 9. Beer TM, Armstrong AJ, Rathkopf DE et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424. 10.Bischoff-Ferrari HA, Willett WC, Wong JB et al: Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005; 293: 2257. 11.Saad F, Gleason DM, Murray R et al: Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004; 96: 879. 12.Fizazi K, Carducci M, Smith M et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377: 813. COURSE #054PG Prostate Cancer Update 2016 William J. Catalona, MD, Course Director; Douglas M. Dahl, MD, Stanley L. Liauw, MD, Stacy Loeb, MD, MSc, Robert B. Nadler, MD and Russell Szmulewitz, MD, Faculty This course highlights the important findings on prostate cancer (PCa) published during the last year. tion sequencing, and are beginning to be used for prognosis and guiding treatment.10 Epidemiology Screening There has been an 80% decrease in the proportion of men presenting with advanced PCa and a 50.3% decrease in PCa mortality during the prostate specific antigen (PSA) era. Mortality has decreased 49% in African-American (AA) men.1, 2 Confirmed risk factors for PCa include balding, smoking, alcohol, processed red meats and occupational cadmium exposure.3-5 Lycopene is associated with 59% lower mortality for high risk PCa,6 and statin use is associated with less aggressive disease.7 No relationship of long-term testosterone therapy to risk of high grade PCa has been demonstrated.8 The PLCO (Prostate, Lung, Colorectal, Ovarian) screening trial has been scrutinized for the frequency of screening among controls, originally reported as ~50%.11 In reviewing PLCO data, Shoag et al reported that ~90% of controls had at least 1 PSA test before or during the trial.12 As the USPSTF (United States Preventive Services Task Force) weighted the PLCO trial heavily in its recommendation against PSA screening,13 it should now revise its recommendation. During the PSA era the incidence of metastatic PCa has declined, whereas that of metastatic breast cancer remained stable, suggesting that PSA is a more sensitive screening test.14 Since the USPSTF recommendation, screening and biopsies in the U.S. have decreased, resulting in fewer cases detected and a greater percentage of high risk disease.15-19 The 2016 NCCN® (National Com- Etiology The heritability for PCa is 57%, and genomic heterogeneity is due mainly to structural variants and copy-number aberrations.9, 10 Subtypes of PCa are being delineated through next genera- prehensive Cancer Network®) guidelines recommend asking about family history of BRCA1/2 mutations; biopsy for PSA greater than 3 ng/mL or suspicious digital rectal examination (DRE); repeat testing at 1 to 4-year intervals for men older than 75 years, PSA less than 3 ng/mL and no other indications for biopsy; followup for focal high grade prostatic intraepithelial neoplasia at 6 to 24 months; and repeat biopsy based on risk.20 A meta-analysis revealed no effect of bicycling on PSA levels.21 Biopsy Repeat biopsy reveals PCa in 34% to 38% of men with atypical small acinar proliferation and Gleason 7 or greater disease in 8% to 17%, both increasing with biopsies after 1 year.22, 23 A new alternative to Gleason score (grade groups 1 to 5) was validated for predicting risk of biochemical recurrence and has been adopted by the World Health Organization classification.24 Biomarkers A Swedish study showed that clinical ▼ Continued on page 9 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 9 Course #054PG ▼ Continued from page 8 variables, plasma biomarkers and genetic polymorphisms combined improve PCa screening specificity and identify Gleason 7 or greater PCa in men 50 to 69 years old with PSA 1 to 3 ng/ mL while reducing biopsies by 32% and missing 17% of Gleason 6 PCa.25 In AA men the Prostate Health Index26 and a novel biomarker signature27 predict aggressive disease. The Prolaris test affects treatment selection in 14% to 21% of patients with low/intermediate risk PCa.28 DNA damage/repair pathway profiling stratifies risk independently of clinical/pathological variables in high risk patients.29 The Decipher test augments post-prostatectomy risk stratification in intermediate/high risk patients.30, 31 Racial variation in PCa molecular subtypes and androgen receptor signaling reflect anatomic tumor location.32 A urine exosome gene expression test predicts high grade PCa at initial biopsy.33 Comparative marker studies are needed. Imaging Magnetic resonance imaging/fusion biopsy improves detection of clinically significant PCa but requires an experienced multidisciplinary team.34 Active Surveillance In the U.S. active surveillance (AS) has increased 40% to 50% for low risk cases, and surgery has increased for intermediate/high risk disease.35, 36 A risk calculator may help avoid low yield AS biopsies.37 Perineural invasion is associated with a shorter time to progression on AS.38 Men with biopsy complications are less likely to undergo subsequent AS biopsies.39 The CCO (Cancer Care Ontario)/ASCO (American Society of Clinical Oncology) guidelines recommend AS for most patients with low risk disease (watchful waiting if less than 5-year life expectancy), and the AS protocol should include PSA every 3 to 6 months, DRE yearly, and confirmatory biopsy (12 cores or greater) within 6 to 12 months and then every 2 to 5 years. Treatment is recommended for most patients with intermediate risk disease and when patients are reclassified to a higher risk category.40 The Johns Hopkins AS study reported grade reclassification in 31% of patients and 57% received curative treatment (15-year actuarial rates, median followup 8.5 years).41 The Göteborg trial reported a hazard ratio for AS failure for low and intermediate risk disease of 2.2 and 4.8, respectively, compared to men with very low risk disease.42 The authors questioned whether men not in the very low risk group with a long life expectancy are suitable candidates for AS.42 The Toronto trial reported development of metastases in 14% of intermediate risk patients. Because Gleason pattern 4 conferred a threefold to fourfold increased risk of metastatic disease, the authors concluded, “such patients should be offered surveillance with caution.”43 Focal Therapy At a FDA/AUA/SUO (Society of Urologic Oncology) sponsored workshop it was reported that the focal therapy devices are approved for ablating tissue but not for clinical effectiveness of focal therapy. The criteria for patient selection remain debatable and long-term cancer control remains to be established. Concerns include the potential for overtreatment of low risk cancer and inadequate treatment of higher risk disease.44 Radical Prostatectomy A meta-analysis indicated that radical prostatectomy (RP) is associated with a lower risk of cancer specific and all-cause mortality than radiotherapy (RT),45 although questions remain whether the differences are attributable to biases.46 Nearly half of low risk patients treated with RP harbor Gleason 7 or greater or pT3 or greater disease.47 At U.S. hospitals use of the robot for RP increased to 85% in 2013.48 Trials are currently under way to evaluate RP in patients with metastatic disease.49 Radiotherapy Dose escalation to 81Gy has a role in intermediate/high risk disease.50 Hyopfractionation (28 days) is noninferior to 41 days for low risk disease51 but late gastrointestinal/genitourinary toxicity may be worse.52 Extreme hypofractionation (5 days) including the pelvic nodes should be given with caution.53 A hydrogel spacer improves rectal sparing with RT.54 Androgen deprivation therapy (ADT) improves dose escalated intensity modulated RT55, 56 but cardiovascular comorbidity should be considered.57 Patients with locally advanced (nodal) disease benefit from the addition of radiation therapy to ADT.58, 59 Postoperative RT does not impair quality of life (QOL) through 4 years of followup.60 Dose escalated salvage RT (70 Gy) results in mild acute toxicity with minor differences in urinary QOL.61 Long-term ADT should be considered with postoperative RT in men with high risk features.62 Failures after RT usually occur at the initial sites of disease.63 Patients with positive biopsies after RT have worse outcomes but the natural history can be long.64 There is increased risk for bladder and colorectal tumors after prostate external beam RT.65 Systemic Therapy and Advanced Disease Metastasis directed therapy of regional and distant recurrences after curative treatment has no proven benefit.66 Orchiectomy is associated with significantly lower risk of fracture, peripheral artery disease and cardiac complications than treatment with luteinizing hormone releasing hormone (LHRH) agonists. Men taking LHRH agonists for 35 months or longer also had more diabetes and venous thromboembolism.67 ADT is associated with impaired cognitive performance68 and may increase the risk of Alzheimer’s disease.69 In the high risk localized, but not overtly metastatic, PCa population the GETUG 12 trial reported that docetaxel + estramustine improves relapse-free survival, although further followup is needed to assess whether this will translate into improved metastasis-free and overall survival.70 ▼ Continued on page 10 10 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS Course #054PG ▼ Continued from page 9 The final analysis of the COU-AA-302 pre-chemotherapy CRPC trial demonstrates significantly improved progression-free and overall survival with abiraterone + prednisone vs prednisone alone.71 Retrospective analysis of patients with metastatic CRPC treated with sequential abiraterone or enzalutamide revealed a modest benefit with the second-line therapy, suggesting distinct androgen receptor (AR) resistance mechanisms.72 For the treatment of metastatic castration sensitive prostate cancer, the CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer trial) E3805 reported that 6 cycles of docetaxel + ADT were superior to ADT alone.73 For high volume disease there was a 17-month gain in median overall survival. Similarly, the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial demonstrated that docetaxel improved survival but zoledronic acid did not and should not be used for castration sensitive metastatic PCa.74 For early CRPC the STRIVE (Safety and Efficacy Study of Enzalutamide Versus Bicalutamide in Men With Prostate Cancer)75 and TERRAIN76 trials showed that enzalutamide is superior to bicalutamide with respect to progression-free survival. Galeterone is a CYP17 antagonist and an AR degrader, and a phase 3 study of galeterone vs enzalutamide for AR-V7+ CRPC is ongoing.77 Clinically actionable mutations are more common in metastatic CRPC than previously believed.78 There is substantial inter-individual but limited intra-individual genomic diversity among tumors.79 Therefore, biopsy of a single metastasis may be useful for selecting treatments on the basis Figure 1. Courtesy of Prof. Nicholas James; Director of the Cancer Research Unit, Clinical Trials Unit, Gibbet Hill Campus; University of Warwick; Coventry, G. CV4 7AL; July 30, 2016. of predicted molecular vulnerabilities. For example, olaparib, a small molecule inhibitor of poly ADP ribose polymerase inhibitor, resulted in an 88% response rate for patients with refractory CRPC and tumors harboring mutations in BRCA1/2, ATM, CHEK2. Olaparib has received breakthrough designation by the FDA.80 Conclusions Numerous advances have been made in PCa care. There is increasing concern that the fewer PSA screenings will reverse the benefits realized to date. The use of AS is increasing for favorable risk disease, and research is ongoing to improve management of aggressive PCa. For the complete list of references for this summary e-mail [email protected]. Figure 2. Courtesy of Prof. Nicholas James, Director of the Cancer Research Unit, Clinical Trials Unit, Gibbet Hill Campus; University of Warwick; Coventry, G. CV4 7AL; July 30, 2016. COURSE #091PG Novel Agents and Concepts in the Management of Hormone Naïve and Castration-Resistant Prostate Cancer Judd W. Moul, MD, FACS, Course Director; Lawrence I. Karsh, MD, FACS and Christopher Sweeney, MBBS, Faculty We used a case based and audience response system to create an interactive educational session that was well attended. We applaud the AUA for recognizing that a cadre of urologists, particularly urologists who specialize in urological cancer, should remain at the forefront of research, education and care for our patients with hormone naïve ▼ Continued on page 11 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 11 Course #091PG ▼ Continued from page 10 and castrate resistant prostate cancer. We also commend The Large Urology Group Practice Association for championing the concept of designating key urologists in their practices to care for men with advanced prostate cancer. Although castration-resistant prostate cancer (CRPC) continues to be a hot topic in 2016, hormone naïve/hormone sensitive newly diagnosed metastatic (M1) prostate cancer has been hot news with the release of CHAARTED trial data last year and the STAMPEDE trial results in 2016 showing a benefit of up-front docetaxel chemotherapy. Primary hormonal therapy (HT)/androgen deprivation therapy (ADT) had been the only treatment for men with new M1 disease for more than threequarters of a century.1 In the last 2 years CHAARTED taught us that adding 6 cycles of docetaxel (without steroids) within 4 months of starting HT/ADT resulted in a major survival benefit. For high volume disease (4 or more bone metastases and/or visceral metastases), the addition of chemotherapy resulted in a 17-month survival advantage compared to ADT alone.2 However, the hazard ratio also generally supports a benefit of docetaxel for low volume M1 disease as well. More recently, the large STAMPEDE trial confirmed the benefit of docetaxel and generally supported the use of chemotherapy for all men with new M1 disease.3 Figure 1 shows the novel research scheme of STAMPEDE which was conducted in Great Britain and reported by James et al.3 Median overall survival was 65 months for men randomized to receive docetaxel vs 43 months for men randomized to standard of care (fig. 2). The bottom line in 2016 is that most if not all men presenting with newly diagnosed hormone naïve M1 prostate cancer should be afforded 6 cycles of docetaxel generally within 4 months of starting ADT. In the area of hormone naïve advanced prostate cancer, we also briefly covered the TOAD trial for biochemically recurrent/prostate specific antigen (PSA) recurrent prostate cancer.4 The TOAD trial is the collaborative TROG 03.06 and VCOG PR 01-03, a randomized, prospective phase III trial conducted in Australia. The study objective was to investigate if immediate ADT improved overall survival compared to delayed ADT in patients with PSA relapse after definitive therapy or in asymptomatic men with no curative therapy at diagnosis. From September 2004 to July 2012, 293 patients were randomized (ADT delayed 151, ADT immediate 142) with a median followup of 5 years. Overall survival was significantly higher in the immediate ADT than delayed ADT group (p = 0.047), with 6-year survival rates of 86% and 79%, respectively. The authors concluded that the trial provides moderate evidence that the use of immediate ADT in men with PSA relapse after primary therapy or with noncurative disease improves overall survival by approximately 10% at 5 years. As this is not a curative approach, the benefit must be balanced against the morbidity of the therapy. Fully 80% of immediate vs 50% of delayed ADT suffered symptoms. At our course we had a lively discussion about this trial. It took a long time to enroll fewer than 300 patients. The results provide some support for early ADT for PSA relapse and might be used to support early ADT for high risk younger, healthier men. We concluded that it will be interesting to see if the ASCO (American Society of Clinical Oncology), AUA and/or NCCN® (National Comprehensive Cancer Network®) guidelines are updated to reflect these findings, or will guideline committees look at this as a small, hypothesisgenerating trial of limited value. An emerging new concept in advanced prostate cancer is the idea of offering definitive local therapy, such as radical prostatectomy, to men who have limited metastatic disease.5, 6 While this would seem to be almost heresy to classically trained urological oncologists, this idea of taking an aggressive treatment stance for men who have oligometastatic dis- ease is emerging particularly in the era of presumed better imaging for early metastases (see Appendix). The audience was intrigued by this new concept but many questions remain and we are eager to have this concept addressed at future AUA meetings and courses. Since 2010, 6 new agents have been approved by the U.S. Food and Drug Administration (FDA) for CRPC including sipuleucel-T, cabazitaxel, abiraterone acetate, denosumab, enzalutamide and radium-223.7 Except for cabazitaxel, all of these agents are commonly available for urologists and oncologists to prescribe. Some of the new concepts related to the new agents that urologists may use for CRPC are discussed. Denosumab Denosumab is prescribed at a dose of 120 mg subcutaneously monthly to prevent skeletal related events (SREs) known to be common in the later course of advanced metastatic prostate cancer. The FDA also approved a 60 mg dose of denosumab subcutaneously twice a year to prevent bone loss (osteopenia and osteoporosis) in men without bone metastases who are taking luteinizing hormone releasing hormone therapy for prostate cancer. At the course, we discussed bone health and making sure urologists remain mindful of using supportive agents.8 Sipuleucel-T Sipuleucel-T is a novel immunotherapy approved by the FDA in 2010 for asymptomatic or minimally symptomatic M1 CRPC.9 The ideal patient for sipuleucel-T will have documented clinical metastases and a rising PSA level while on continuous hormonal therapy. He will not have bone or cancer pain requiring narcotic pain medications. In men with PSA levels in the lowest quartile of the IMPACT trial (PSA less than 22 ng/ ml) there was a more robust overall survival advantage to sipuleucel-T.10 Specifically, the estimated 3-year survival in this group of treated patients was 62.6% compared to 41.6% for men randomized ▼ Continued on page 12 12 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS Course #091PG ▼ Continued from page 11 to the control arm of the study. Abiraterone and Enzalutamide Abiraterone is a 17-lyase and 17-hydrolase inhibitor that blocks key pathways in the steroidal synthesis pathways leading to androgen production. Low dose prednisone (7.5 to 10 mg daily is a physiological dose) is recommended to be administered with abiraterone to help limit overproduction of aldosterone as well as side effects of hypertension, hypokalemia and fluid retention. The current FDA approved indication for abiraterone is either before or after disease has progressed on docetaxel based systemic chemotherapy. The dose for abiraterone is 1,000 mg orally once daily along with low dose steroid (5 mg prednisone orally twice daily). The final analysis of the pivotal trial for use before chemotherapy was published and presented at the course showing a durable and clinically meaningful and overall survival benefit.11 Enzalutamide is a novel oral hormonal therapy agent that was FDA approved in 2012 to treat men with disease that progressed after docetaxel based chemotherapy and was then approved in 2014 for use before chemotherapy.12 Enzalutamide is taken orally at a dose of 160 mg daily. Enzalutamide, unlike abiraterone, does not have to be given with low dose prednisone. However, enzalutamide does have an approximate 1% risk of seizures associated with its use and crosses the blood-brain barrier implicating it with some risk of falls and fatigue. While both novel oral hormonal agents are active in advanced prostate cancer, their benefit is not necessarily synergistic or cumulative. In other words, patients will likely have an initial robust response to either agent but switching men to the other agent will likely not result in a sustained response, and the response to the second agent may be more short-lived. One of the new hot topics related to use of abiraterone and enzalutamide is molecular profiling. The recent discov- ery of the AR-V7 mutated variant of the androgen receptor offers intriguing speculation to the future of individualized medicine.13 Specifically, the response to abiraterone or enzalutamide was less robust in men who harbored this mutation in circulating tumor cells. However, as of July 2016, there is no U.S. Federal Drug Administration (FDA) approved assay for AR-V7 and the broad clinical use of this concept will remain for future AUA meetings/courses. Radium-223 This agent is a parenteral radiopharmaceutical that can be ordered by urologists and will be provided in a nuclear medicine or radiation oncology department setting.14 The product is an alphaemitting liquid radiation product that received FDA approval in May 2013. Radium-223 is indicated for the treatment of patients with CRPC, symptomatic bone metastases and no known visceral metastatic disease. The dose regimen is 50 kBq (1.35 microcurie) per kg body weight, given at 4-week intervals in 6 injections. Urologists may have been familiar with earlier generation radiopharmaceuticals such as strontium but radium-223 is different. First, it is alpha particle based and does not affect the bone marrow to the degree of older agents. In other words, radium-223 is much less likely to cause serious bone marrow toxicity with low white blood cell counts. Secondly, the use of radium-223 was associated with an overall survival benefit, whereas the older radiopharmaceuticals were never proven to extend survival. Appendix. Radical prostatectomy for oligometastatic disease: key teaching points • Biological rationale strong • Population level data favor but biased • Retrospective series sparse and biased but supportive • Complications higher but not intolerable • Patient selection key: - Consider magnetic resonance imaging for local staging - Avoid radical prostatectomy in patients with multiple “bad” features • Await clinical trials (eg MD Anderson Phase II) 1. Moul JW: Hormone naïve prostate cancer: predicting and maximizing response intervals. Asian J Androl 2015; 17: 929. 2. Sweeney CJ, Chen YH, Carducci M et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737. 3. James ND, Sydes MR, Clarke NW et al: Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016; 387: 1163. 4. Duchesne GM, Woo HH, Bassett JK et al: Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol 2016; 17: 727. 5. Heidenreich A, Pfister D and Porres D: Cytoreductive radical prostatectomy in patients with prostate cancer and low volume skeletal metastases: results of a feasibility and case-control study. J Urol 2015; 193: 832. 6. Muldermans JL, Romak LB, Kwon ED et al: Stereotactic body radiation therapy for oligometastatic prostate cancer. Int J Radiat Oncol Biol Phys 2016; 95: 696. 7. Lowrance WT, Roth BJ, Kirkby E et al: Castration-resistant prostate cancer: AUA guideline amendment 2015. J Urol 2016; 195: 1444. 8. Tripathy D, Durie BG, Mautner B et al: Awareness, concern, and communication between physicians and patients on bone health in cancer. Support Care Cancer 2014; 22: 1601. 9. Davis K, Wood S, Dill E et al: Optimizing the efficiency and quality of sipuleucel-T delivery in an academic institution. Clin J Oncol Nurs 2015; 19: 297. 10. Schellhammer PF, Chodak G, Whitmore JB et al: Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology 2013; 81: 1297. 11.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. 12. Beer TM, Armstrong AJ, Rathkopf DE et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424. 13. Antonarakis ES, Lu C, Wang H et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028. 14. Parker C, Nilsson S, Heinrich D et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213. ▼ Continued on page 13 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 13 PLENARY SESSIONS Town Hall: Optimizing Quality of Life for Patients with Advanced Cancer Christopher J. Kane, MD, Moderator; William Mitchell, MD (Palliative Care), Gregory R. Polston, MD (Treatment of Cancer Pain), Eric Roeland, MD (Optimizing Quality of Life), Christopher Onderdonk, LCSW (Preserving Hope and Realism), Jermey Hirst, MD (Managing Anxiety and Depression) and Eugene Lee, MD (Immunonutrition) As urologists, we often are the initial treating physician and the coordinator of care for patients with genitourinary malignancies. It is imperative that as we care for patients through the spectrum of disease, we keep the goals of prolonging life and curing cancer balanced with the realism of progression as well as disease and treatment burden. We were fortunate to assemble a group of palliative care specialists to lead us through our Town Hall on optimizing quality of life for patients with advanced cancer. These professionals gave the audience a series of practical recommendations for improving our skills of assessing and treating patients with advanced disease. Palliative Care Advanced urological illness is commonly a perfect storm of poor symptom control, incomplete patient understanding, high costs and low physician satisfaction. Palliative care, a term coined by Balfour Mount, a urologist at McGill University, provides some solutions. Often palliative care is offered in late stages of illness toward the end of a long, difficult course. However when applied early in the care of patients with severe illness, patients have better symptom control, improved mental health, live longer and incur lower costs of health care. Palliative care is the responsibility of every physician who cares for people with severe illness. Routinely screen for and assess symptoms and distress. Work to improve your symptom management and communication skills. Refer to specialist palliative care early and often. Refer to hospice earlier (if you wait until the patient is dying, you are too late). Courageously broach the difficult, taboo topics of prognosis, hospice and death. Set meaningful expectations and goals with patients at the outset of therapy. Communicate clearly about prognosis and likely outcomes of therapy. Identify a surrogate decision maker and the patient’s desired place of death. Treatment of Urological Cancer Pain Oral opioids remain the mainstay in the treatment of cancer associated pain. Nearly 90% of patients with advanced disease receive this form of therapy. Although morphine is the most common opioid prescribed, pain remains poorly controlled in nearly half of all patients with cancer. Some of the reasons for this include opioid-induced side effects and limited efficacy of opioid in treating neuropathic and/or visceral pain. Use of neuropathic medications, such as anticonvulsants and antidepressants, should be considered throughout the course of disease to improve pain relief and limit opioid-induced side effects. Interventional procedures have also been shown to be safe and effective. Celiac plexus neurolysis for the treatment of upper abdominal cancer pain is used after conservative measures have failed and life expectancy is less than 6 months. Neurolytic procedures to the hypogastric plexus or other peripheral nerves should be considered if pain is consistent with the innervation pattern. Placement of an intrathecal pump is effective at treating widespread pain when life expectancy is greater than 3 months, and should be considered early in treatment when the patient will be better able to tolerate the surgical procedure. Finally, vertebral augmentation has been shown to reduce pain and is well tolerated in patients with symptomatic vertebral metastasis. Optimizing Quality of Live in Patients with Advanced Cancer Optimizing the palliation of symptoms maximizes quality of life and improves survival for patients with advanced cancer. Effective pain management is the cornerstone of optimal palliation requiring a balanced approach to opioid prescribing. All medical providers should be aware of the differences among tolerance, dependence, addiction and pseudo-addiction. Of note, pseudo-addiction must be considered and occurs when patients display behaviors concerning for addiction, but as a consequence of undertreated or poorly treated pain. A balanced approach to opioid prescribing incorporates universal precautions including the routine use of screening assessments (eg opioid risk tool), use of prescription drug monitoring programs, pain contracts and effective communication among providers. When opioids are prescribed, understanding the basic pharmacokinetics and route of excretion allows medical providers to effectively treat and educate patients regarding their safe use. Furthermore, anticipating opioid related side effects is key. Patients taking opioids may frequently experience transient nausea or pruritus. To avoid these anticipated side effects, consider short courses of metoclopramide or prochorperazine for nausea vs ondansetron which causes constipation, and cetirizine for pruritus not diphenhydramine which may exacerbate sedation. Lastly, all patients taking opioids, regardless of dose or duration, will experience constipation due to slowing of gut transit. Opioid-induced constipation is best treated with the use of stimulant laxatives (senna or bisacodyl) and not stool softeners (docusate). ▼ Continued on page 14 14 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS Plenary Sessions ▼ Continued from page 13 Preserving Hope and Realism An area of preventable suffering that palliative care has given considerable attention to is patient and family communication in response to the fact that, despite extensive medical provider training, the ability to engage skillfully in conversations around life and death is given short shrift. What we know now is when providers approach these conversations with the same intention and skill they would approach any procedure patient and family suffering can be minimized. This is especially true for advanced cancer where balancing hope and realism in the face of worsening disease is a challenge for providers and patients/families. Different models were provided and specific skills taken from palliative care were introduced, which urologists could incorporate into their daily practice in order to build upon their existing communication skillset. Specifically, the power of empathy in patient/family encounters was highlighted along with the use of “hope/worry” statements in cases of medical uncertainty. The culmination of using these skills with intention is a provider-patient/family relationship that is grounded in trust. It is from this trusting connection with providers where patients and families find hope, even in the most challenging and dire circumstances. Managing Anxiety and Depression Depression and anxiety are common and distressing symptoms in patients living with serious illness. Being able to differentiate between normal sadness and worries, and the more severe depressive or anxiety disorders is important to ensure optimal patient care. Screening questions such as, “Are you depressed?”, “Have you experienced joy in the past two weeks?”, “Have you been feeling nervous, anxious, on edge, or helpless?” can be very helpful in determining who needs further evaluation and possible treatment. The usual symptoms of depression and anxiety can be misleading in the setting of serious illness. Focusing on a patient’s sense of meaning, hope and purpose is often a better way to gauge the degree of psychiatric difficulty. Nonpharmacologic interventions, such as psychotherapy, are essential and should be a frequent referral for patients suffering from a mood or anxiety disorder. For antidepressants first consider sertraline (little impact on corrected QT interval, few drug-drug interactions) and escitalopram (few drugdrug interactions), and avoid paroxetine (anticholinergic and challenging withdrawal) and venlafaxine (challenging withdrawal). For benzodiazepines first consider lorazepam (multiple routes and no active metabolites) and clonazepam (long-acting), and avoid alprazolam due to its euphorogenic and short-acting properties. Immunonutrition The final presentation of the Town Hall was on the interesting topic of immunonutrition in cancer surgery. In a randomized trial on immunonutrition a specialized immunonutrition supplement (SIM) was compared to standard oral nutritional supplement in 29 patients undergoing radical cystectomy.1 Participants receiving SIM had a 33% reduction in postoperative complication rate (95% CI 1–64, p = 0.060) and 39% reduction in infection rate (95% CI 8–70, p = 0.027) during recovery. Enhanced nutrition and immunonutrition for patients with cancer undergoing surgery have promise to improve perioperative fitness, and reduce weight loss, complications and infections. 1. Hamilton-Reeves JM, Bechtel MD, Hand LK et al: Effects of immunonutrition for cystectomy on immune response and infection rates: a pilot randomized controlled clinical trial. Eur Urol 2016; 69: 389. Take Home Message: Prostate Cancer: Shifting the Risks-Benefits Ratio in Favor of the Patients Robert Abouassaly, MD, Cleveland, Ohio, provided the audience with highlights of the AUA meeting on prostate cancer. The abstract numbers are in parentheses. (Reprinted from AUANews, 2016; Vol. 21, No. 7, pp 8-9) This year’s AUA meeting featured more than 500 high quality presentations covering a range of prostate cancer topics from basic research and pathophysiology to advanced disease. A few recurrent themes became evident during the meeting, which I will highlight and summarize. The debate continued over the risks and benefits of prostate cancer screening in the aftermath of the 2012 USPSTF (U.S. Preventive Services Task Force) recommendations against screening. New evidence was presented from a reanalysis of the PLCO (Prostate, Lung, Colorectal, and Ovary) screening trial casting further doubt over the trial findings regarding the effectiveness of prostate cancer screening. The original article published in 2009 described a contamination of prostate specific anti- gen (PSA) testing in the control arm of approximately 50%.1 A more in-depth analysis using data from the study’s Health Status Questionnaire, administered to a subgroup of men in the control group, was presented at a Plenary session this year.2 The authors suggest that this was an inaccurate interpretation of PSA testing in the control group during the trial. They found that greater than 80% of the men in the control group, without contamination at the ▼ Continued on page 15 AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 15 Plenary Sessions ▼ Continued from page 14 time of study entry, reported having undergone at least 1 PSA test during the trial. Additionally, more than 50% reported undergoing testing within the last year. Overall, including the estimated 10% of control participants with baseline screening contamination, the proportion of men in the control arm having had at least 1 PSA test before or during the trial approaches 90%. The authors of this study are urging policymakers and payers who are currently debating the merits of prostate cancer screening to consider these data when formulating their updated recommendations. Several studies presented at this year’s meeting described the effects of the USPSTF recommendation on the diagnosis and management of prostate cancer. Decreases in the number of PSA screenings were reported for all races (MP21-07), as well as for different insurance types (MP21-10). Hospitals and health systems are reporting decreases in the number of referrals for elevated PSA, fewer prostate biopsies performed and a greater proportion of men with high grade (Gleason score ≥8) or metastatic disease at diagnosis (MP09-06). Others experienced a decline in the number of prostatectomies performed, particularly for low grade disease (Gleason score 6). A greater percentage of prostatectomies are being done for high grade disease, and pathologically there is a trend towards more specimens with extraprostatic extension (PD03-05). Whether these observations are a result of decreased prostate cancer screening and/or a change in the indications for surgery remains to be determined. Roobol et al used data from the ERSPC (European Randomized Study of Screening for Prostate Cancer) and statistical modeling in an attempt to explain the observed differences in mortality between the 2 study arms (PD09-01). They found that more than 80% of the change in mortality could be explained by an observed stage shift rather than treatment differences between the groups as has been suggested by some. Screened men were diagnosed at an earlier, presumably more curable stage of disease in the screening arm compared to men in the control arm. Several studies looked at the addition of biomarkers (eg the 4K score, Prostate Health Index, molecular urine tests, etc.), magnetic resonance imaging (MRI) and other clinical markers in an effort to improve the performance characteristics of prostate cancer screening, thus reducing the over diagnosis of clinically insignificant prostate cancer. For example, a group from the Cleveland Clinic used data from the intervention arm of the PLCO to determine that men with a baseline PSA less than 2 ng/ml between the ages of 55 and 60 years were at very low risk for clinically important prostate cancer at 5 and 13 years of followup (MP39-11). Another promising method for reducing the diagnosis of low risk prostate cancer while increasing the diagnosis of clinically significant prostate cancer is the use of MRI and MRI/ultrasound (US) fusion biopsies. A randomized study from Italy demonstrated that fusion biopsies were more likely to diagnose Gleason score 7 or greater compared to standard ultrasound guided biopsy (87.0% vs 61.3%, respectively) (MP21-17). Also, this approach appears to be cost-effective. An analysis from the National Cancer Institute indicated that MRI/US fusion biopsy in a hypothetical cohort of 100 men with PSA elevation who undergo prostate MRI would result in an estimated cost savings of approximately 25% compared with initial standard transrectal US guided biopsy (MP53-14). Efforts at shifting the risk-benefit balance in favor of prostate cancer screening have also focused on decreasing the overtreatment of clinically indolent prostate cancer. Active surveillance (AS) of such low risk prostate cancers is gain- ing acceptance, and is used in more than 50% of eligible patients and is increasing in some studies.3 Several presentations at this year’s meeting focused on improving risk stratification of patients believed to be eligible for AS. Risk calculators/nomograms for progression on AS were developed (PD08-01, PD0804, PD08-06). Incorporation of data from MRI and MR/US fusion biopsies (PD08-10, MP15-18) and the use of molecular markers (PD08-02, PD08-07, PD08-11) have been proposed to better select candidates for AS. Finally, results from several studies describing surgical outcomes of patients initially on AS were presented (PD0302, PD03-04). A higher biochemical recurrence rate (BCR) in patients treated with radical prostatectomy (RP) after AS compared to patients who would have otherwise been candidates for AS but were immediately treated (16.7% vs 5.4% after a median followup of 5.7 years). Whereas Auffenberg et al suggested higher grade disease after RP for AS but with otherwise similar outcomes (PD03-04), and Savdie et al showed a greater proportion of predominant Gleason pattern 4 in patients on AS (24.6% vs. 12%) but with no difference in BCR (PD03-06). These data highlight the importance of proper patient selection when considering AS. In summary, with increased scrutiny on the management of this often indolent malignancy, it is imperative that our specialty continue to work at better selecting patients who are best served with active treatment. Additionally, we need to decrease the morbidity of our interventions to shift the risk-benefit ratio in favor of our patients. 1. Andriole GL, Crawford ED, Grubb RL 3rd et al: Mortality results from a randomized prostatecancer screening trial. N Engl J Med 2009; 360: 1310. 2. Shoag JE, Mittal S and Hu JC: Reevaluating PSA testing rates in the PLCO trial. N Engl J Med 2016; 374: 1795. 3. Womble PR, Montie JE, Ye Z et al: Contemporary use of initial active surveillance among men in Michigan with low-risk prostate cancer. Eur Urol 2015; 67: 44. AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS SA V E q D AT E 18 www.AUA2017.org