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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
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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
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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
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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.
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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
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