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| THE OFFICIAL NEWSMAGAZINE OF THE AMERICAN UROLOGICAL ASSOCIATION |
2016 ANNUAL
MEETING HIGHLIGHTS
Castration-Resistant Prostate
Cancer
Course #003PG
Management of Prostate Cancer: A
Case Based Approach with Emphasis on
Integrating New Molecular Diagnostics into
Clinical Practice
Course #009IC
AUA Guideline: Castration-Resistant Prostate
Cancer Update
Course #054PG
Prostate Cancer Update 2016
Course #091PG
Novel Agents and Concepts in the
Management of Hormone Naïve and
Castration-Resistant Prostate Cancer
Plenary Sessions
Forum: Town Hall on Optimizing Quality of
Life in Patients with Advance Cancer
AUA 2016 ANNUAL MEETING
HIGHLIGHTS
Take Home Message: Prostate Cancer
Castration-Resistant
Prostate Cancer
AUANews Editor
Manoj Monga, MD, FACS
Publisher
American Urological Association
1000 Corporate Boulevard
Linthicum, MD 21090
Copyright © 2016 by American Urological
Association
None of the contents may be reproduced in any form
without prior written permission of the publisher.
The opinions expressed in this publication are those
of the speakers and do not necessarily reflect the
opinions or recommendations of their affiliated
institutions, the publisher, the American Urological
Association or any other persons. Some articles in this
publication may discuss unapproved or “off-label”
uses of products. Any procedures, medications or
other courses of diagnosis or treatment discussed
or suggested in this publication should not be used
by clinicians without evaluation of their patients’
conditions and of possible contraindications
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manufacturers’ product information and comparison
with the recommendations of the authorities.
Educational grant support provided by:
•AbbVie
• Astellas Pharma Global Development, Inc. Medical Affairs, Americas
it
• Janssen Biotech, Inc., administered by Janssen Scientific Affairs LLC
•Medivation
CM
E
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AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS
1
CME INFORMATION
2016 AUA Annual Meeting Highlights: CastrationResistant Prostate Cancer
Method of Participation
To claim CME credit/hours of participation, the learner must complete a pretest,
read the overview of courses 003PG,
009IC, 054PG and 091PG, complete the
posttest, passing with 80% accuracy and
submit the evaluation and credit request
form by visiting www.AUAnet.org/University/CRPC16.
Estimated time to
complete this activity: 1.25 hours
Release Date: October 2016
Expiration Date: October 31, 2017
Accreditation Statement
The American Urological Association
(AUA) is accredited by the Accreditation
Council for Continuing Medical Education (ACCME) to provide continuing
medical education for physicians.
Credit Designation
The American Urological Association
designates this enduring material for a
maximum of 1.25 AMA PRA Category 1
Credits™. Physicians should claim only
the credit commensurate with the extent
of their participation in the activity.
Other Learners
The AUA is not accredited to offer
credit to participants who are not MDs
or DOs. However, the AUA will issue
documentation of participation that
states that the activity was certified for
AMA PRA Category 1 Credit™.
This enduring material credit is valid
only for content reformatted from courses
003PG, 009IC, 054PG and 091PG.
Statement of Need
The role of the urologist in the treatment
of patients with castration-resistant prostate cancer (CRPC) continues to expand
as the number and variety of therapeutic
options increases. It is critical that urologists remain engaged and knowledgeable
on the management of CRPC in the
contemporary setting of a multitude of
new agents becoming available to treat
patients.
Target Audience
Urologists, urologists in training and
non-physician providers involved in
urology.
Course 003PG: Management of
Prostate Cancer: A Case Based
Approach with Emphasis on Integrating New Molecular Diagnostics
into Clinical Practice
Learning Objectives
At the conclusion of this CME activity,
participants should be able to:
• Design appropriate screening strategies based on individual demographics, risk factors and prostate specific
antigen history, and to incorporate
new biomarkers into routine clinical
practice
• Distinguish and understand the use
of new molecular and genomic based
tests for decisions on initial and rebiopsy, and choosing and following
men on surveillance
• Appraise the role of surveillance,
focal therapy, surgery and various
forms of radiation therapy in patients
with low and intermediate risk disease
• Enumerate and contrast the benefits
and drawbacks of surgery vs radiation based approaches for the management of high risk localized disease
• Describe new therapeutic agents for
the management of castrate resistant
disease and outline a coherent strategy for their use
Faculty
Eric A. Klein, MD, Course Director
Chairman, Glickman Urological and
Kidney Institute
Professor of Surgery, Lerner College of
Medicine
Cleveland Clinic
Cleveland, OH
Disclosures: GenomeDx Biosciences: Consultant or Advisor, Scientific Study or
Trial; Genomic Health: Consultant or
Advisor; Berg: Consultant or Advisor
Andrew J. Stephenson, MD
Director, Center for Urologic Oncology
Cleveland Clinic
Associate Professor, Surgery
Case Western Reserve University
School of Medicine
Cleveland, OH
Disclosures: Nothing to disclose
Course 009IC: AUA Guideline: Castration-Resistant Prostate Cancer
Update
Learning Objectives
At the conclusion of this CME activity,
participants should be able to:
• Analyze the evidence on the treatment of castration-resistant prostate
cancer as outlined in the AUA guidelines and subsequent publications
• Improve diagnostic and therapeutic
decision making processes by illustrating the application of these guidelines in urological practice
• Acquire in-depth knowledge on the
process by which evidence is used
to develop scientifically rigorous, yet
actionable, guidelines
Faculty
Michael S. Cookson, MD, Course
Director
Professor and Chairman, Department of
Urology
University of Oklahoma College of
Medicine
Oklahoma City, OK
Disclosures: Nothing to disclose
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AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS
CME Information
▼ Continued from page 1
Adam S. Kibel, MD
Chief of Urologic Surgery
Dana-Farber Cancer Institute and
Brigham and Women's Hospital
Professor, Department of Surgery,
Harvard University Medical School
Boston, MA
Disclosures: Sanofi-Aventis: Consultant
or Advisor, Scientific Study or Trial;
MTG: Consultant or Advisor; Profound:
Consultant or Advisor; Dendreon: Consultant or Advisor
William T. Lowrance, MD, MPH
Assistant Professor, Division of Urology
University of Utah School of Medicine
Investigator
Huntsman Cancer Institute (HCI)
Salt Lake City, UT
Disclosures: Myriad Genetics: Consultant
or Advisor, Scientific Study or Trial;
Genome Dx: Scientific Study or Trial;
Argos: Scientific Study or Trial; Stream
Dx: Investment Interest
Course 054PG: Prostate Cancer
Update 2016
Learning Objectives
At the conclusion of this CME activity,
participants should be able to:
• Cite important new publications in
this field during the past year
• Identify the relative strengths and
weaknesses of the reports
• Appraise how new studies relate to
the existing state-of-the-art in clinical
practice
• Analyze whether they and their
colleagues should consider changing their practice based on the new
information
Trial; deCODE genetics: Consultant or
Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; OHMX:
Consultant or Advisor, Owner, Product
Development; Nanosphere: Consultant or
Advisor
Douglas M. Dahl, MD
Chief, Division of Urologic Oncology
Associate Urologist
Massachusetts General Hospital
Boston, MA
Disclosures: Cambridge Endo: Investment Interest
Stanley Liauw, MD
Associate Professor, Department of
Radiation & Cellular Oncology
University of Chicago Medicine
Chicago, IL
Disclosures: Nothing to disclose
Stacy Loeb, MD
Assistant Professor of Urology and Population Health
New York University School of Medicine
New York, NY
Disclosures: Nothing to disclose
Robert B. Nadler, MD
Professor, Department of Urology
Northwestern University Feinberg
School of Medicine
Chicago, IL
Disclosures: Nothing to disclose
Russell Szmulewitz, MD
Assistant Professor of Medicine
The University of Chicago Medicine
Chicago, IL
Disclosures: Pfizer: Consultant or Advisor; Genentech: Scientific Study or Trial
Course 091PG: Novel Agents and
Concepts in the Management of
Faculty
Hormone Naïve and CastrationWilliam J. Catalona, MD, Course Resistant Prostate Cancer
Director
Learning Objectives
Professor, Department of Urology
Northwestern University Feinberg
School of Medicine
Chicago, IL
Disclosures: Beckman Coulter Incorporated:
Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or
At the conclusion of this CME activity,
participants should be able to:
• Diagnose castration-resistant prostate
cancer and have a working knowledge of treatments and the proper
order for administration
• Manage CRPC with systemic agents
by learning the proper candidates
for treatment and be able to counsel
patients on the pros and cons of
therapy
• Analyze the mechanism of action
and risks/benefits of using systemic
agents in the treatment of CRPC
• Describe the bone-targeted, radiopharmaceutical agent RADIUM-223
and its sequencing
• Review the new generation antiandrogen agent enzalutamide and its
sequencing
Faculty
Judd W. Moul, MD, FACS, Course
Director
Professor of Surgery
Professor in Anesthesiology
Director, Duke Prostate Center
Duke University School of Medicine
Durham, NC
Disclosures: Sanofi-Aventis: Health Publishing, Meeting Participant or Lecturer;
Dendreon: Consultant or Advisor, Meeting Participant or Lecturer; Theralogix:
Consultant or Advisor; Ferring Pharmaceuticals Inc.: Consultant or Advisor,
Meeting Participant or Lecturer; Medivation-Astellas: Consultant or Advisor;
Janssen-J and J: Consultant or Advisor,
Meeting Participant or Lecturer; Myriad Genetics Inc.: Consultant or Advisor,
Meeting Participant or Lecturer. Genomic
Health: Meeting Participant or Lecturer
Lawrence I. Karsh, MD, FACS
Director, Clinical Research Department
The Urology Center of Colorado
Denver, CO
Disclosures: Astellas: Consultant or
Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Dendreon: Consultant or Advisor, Meeting
Participant or Lecturer, Scientific Study
or Trial; Bayer: Consultant or Advisor,
Meeting Participant or Lecturer, Scientific Study or Trial; Janssen: Consultant
or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Medivation: Consultant or Advisor, Meeting
Participant or Lecturer, Scientific Study
or Trial; Genomic Health: Consultant or
▼ Continued on page 3
AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS
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CME Information
▼ Continued from page 2
Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Myriad:
Consultant or Advisor, Scientific Study
or Trial; Swan Valley Medical: Consultant
or Advisor, Investment Interest; Amgen:
Scientific Study or Trial; Heat Biologics:
Scientific Study or Trial; Bavaria Nordic
Immunotherapy: Consultant or Advisor,
Scientific Study or Trial; MDxHealth:
Scientific Study or Trial
Christopher Sweeney, MBBS
Associate Professor, Department of
Medicine
Harvard Medical School
Medical Oncologist, Medical Oncology
Dana-Farber Cancer Institute
Boston, MA
Disclosures: Sanofi: Consultant or Advisor; Janssen: Consultant or Advisor;
BIND: Consultant or Advisor; Astellas:
Consultant or Advisor; Bayer: Consultant or Advisor; Genentech Roche: Consultant or Advisor
Planners
Education Council
Manoj Monga, MD, FACS
Director, Center for Endourology &
Stone Disease
Cleveland Clinic
Cleveland, OH
Disclosures: Fortec: Other; Endourology
Society: Leadership Position
Victor W. Nitti, MD
Professor, Department of Urology
Professor, Department of Obstetrics and
Gynecology
Director, Female Pelvic Medicine and
Reconstructive Surgery Program
Vice Chair, Department of Urology
Director, Female Pelvic Medicine Fellowship Program
New York University Langone Medical
Center
New York, NY
Disclosures: Astellas: Health Publishing, Scientific Study or Trial; Allergan:
Health Publishing, Scientific Study or
Trial; Serenity Pharmaceuticals: Investment
Interest; Cook Myosite: Scientific Study or
Interest
Trial
Brant Inman, MD, MS
Associate Professor, Surgery
Vice Chief, Urology
Duke University School of Medicine
Durham, NC
Disclosures: Dendreon: Scientific Study
or Trial; Abbott Laboratories: Scientific
Study or Trial; Genentech Inc.: Scientific
Study or Trial; Combat Medical: Consultant or Advisor
Acknowledgements
The AUA Office of Education would
like to thank the companies who support continuing education of physicians.
The AUA recognizes the following companies for providing educational grant
support:
• AbbVie
•
Astellas Pharma Global Development, Inc. Medical Affairs, Americas
• Janssen Biotech, Inc., administered
by Janssen Scientific Affairs, LLC
• Medivation
American Urological Association Education & Research, Inc. ensures that all
educational activities are developed and
implemented independent of the control
and/or influence of any commercial
interests (ACCME: SCS1).
AUA Disclosure Policy
All persons in a position to control the
content of an educational activity (i.e.,
activity planners, presenters, authors)
are required to disclose to the provider
any relevant financial relationships with
any commercial interest. The AUA
must determine if the individual’s relationships may influence the educational
content and resolve any conflicts of
interest prior to the commencement of
the educational activity. The intent of
this disclosure is not to prevent individuals with relevant financial relationships
from participating, but rather to provide
learners information with which they
can make their own judgments.
Resolution of Identified Conflict of
All disclosures will be reviewed by the
program/course directors or editors for
identification of conflicts of interest. Peer
reviewers, working with the program
directors and/or editors, will document
the mechanism(s) for management and
resolution of the conflict of interest and
final approval of the activity will be
documented prior to implementation.
Any of the mechanisms below can/will
be used to resolve conflict of interest:
• Peer review for valid, evidence-based
content of all materials associated
with an educational activity by the
course/program director, editor, and/
or Education Content Review Committee or its subgroup
• Limit content to evidence with no
recommendations
• Introduction of a debate format with
an unbiased moderator (point-counterpoint)
• Inclusion of moderated panel discussion
• Publication of a parallel or rebuttal
article for an article that is felt to be
biased
• Limit equipment representatives to
providing logistics and operation
support only in procedural demonstrations
• Divestiture of the relationship by faculty
Evidence-Based Content
It is the policy of the AUA to ensure that
the content contained in this CME activity is valid, fair, balanced, scientifically
rigorous, and free of commercial bias.
Off-label or Unapproved Use of
Drugs or Devices
It is the policy of the AUA to require the
disclosure of all references to off-label
or unapproved uses of drugs or devices
prior to the presentation of educational
content. The audience is advised that
this continuing medical education activity may contain reference(s) to off-label
or unapproved uses of drugs or devices.
▼ Continued on page 4
4
AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS
CME Information
▼ Continued from page 3
Please consult the prescribing information for full disclosure of approved
uses.
Disclaimer
The opinions and recommendations
expressed by faculty, authors and other
experts whose input is included in this
program are their own and do not
necessarily represent the viewpoint of
the AUA.
AUA Privacy and Confidentiality
Policy
Reproduction Permission
Access the AUA Privacy and Confidentiality Policy online at www.auanet.
org/education/confidentiality-statement.
cfm.
Reproduction of written materials
developed for this AUA course is prohibited without the written permission
from individual authors and the American Urological Association.
AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS
5
COURSE #003PG
Management of Prostate Cancer: A Case Based
Approach with Emphasis on Integrating New
Molecular Diagnostics into Clinical Practice
Eric A. Klein, MD, Course Director; Andrew J. Stephenson, MD, Faculty
Precision medicine is a concept defined
by the idea that medical decision making, be it a decision to treat or not to
treat, or choosing a specific drug or
therapy, is based on the molecular
characteristics of the disease or tumor.
The theme of our postgraduate course
this year was that the era of precision
medicine in prostate cancer has arrived.
The ability to characterize an individual’s risk of prostate cancer (future
risk of disease), the likelihood that he
has an aggressive prostate cancer at the
moment of consultation (current risk
of disease), the need for re-biopsy after
an initial negative biopsy, how aggressive the known cancer is, whether the
cancer has progressed biologically while
on active surveillance, the likely benefit
of adjuvant radiotherapy for those with
adverse pathology on radical prostatectomy and the specific choice of therapy
for those with castrate resistant disease
can now be informed by new biomarkers and commercially available genomic
based drugs (see Appendix). These
efforts at better biological characterization of disease risk and aggressiveness
promise to improve clinical decision
making, so that the right decision can be
made at the right time for every patient
along the entire disease spectrum.
An exciting use of the precision
approach is in deciding which drugs
to use for men with progressive metastatic castrate resistant disease. Median
survival for such men is around 30
months, and newer drugs such as abiraterone and enzalutamide that target
androgen receptor (AR) signaling have
been shown in randomized, phase III
trials to extend that interval. Although
both drugs are well tolerated, clinical experience has demonstrated that
approximately 20% to 40% of patients
with metastatic castration-resistant prostate cancer (mCRPC) have no response
to these agents (at least as measured by
prostate specific antigen), demonstrating the presence of intrinsic resistance.
Using a peripheral blood based circulating tumor cell assay, Antonarakis et
al have shown that resistance to these
drugs can be predicted by the presence
of a variant of the androgen receptor,
AR-V7, in the circulation,1 suggesting
that patients who are positive for this
marker be treated with a different agent
or agents. This work has recently been
validated by Scher et al, who showed
that patients with AR-V7 had superior
outcomes when treated with taxane
chemotherapy.2 The clear implication
of this study is that measurement of
AR-V7 in men with mCRPC may be
used in practice as a treatment specific
biomarker to guide selection of therapy,
and represents a successful example of
how precision medicine approaches are
able to improve patient outcomes.
Another emerging and exciting precision approach is the recent identification of a higher than previously known
prevalence of defects in DNA repair
genes in the tumors of some patients
with mCRPC. DNA repair is a complex but fundamental cellular process
that serves a housekeeping function to
repair mutations resulting from errors
in cell division or cancer causing perturbations (inflammation, diet, other environmental exposures). Loss of fidelity
or function of the DNA repair process
can promote the accumulation of mutations and contribute to the genomic
instability that fuels cancer progression.
In a landmark study Mateo et al found
that about a third of men with mCRPC
had tumors with mutations in DNA
repair genes, and that 88% of them had
objective responses to a poly adenosine
diphosphatase ribose polymerase inhibitor (olaparib) that targets the perturbed
biochemical processes resulting from
loss of DNA repair gene function.3 In
another study Pritchard et al showed
that almost 12% of men with metastatic
disease had germline (inherited) defects
in DNA repair genes compared to less
than 5% of men with localized disease.4
The implication of this study is that
men with defects in DNA repair genes
are more likely to have metastatic disease, and that agents that target these
pathways might be useful earlier in the
disease process for men with known
mutations. Accumulating data suggest
many other targetable genes for men
with metastatic disease (see table).
Table. Actionable mutations in metastatic CRPC
Gene
% Frequency of
Mutation
Androgen receptor
60
PI3kinase (PTEN)
40
BRCA/DNA repair
25
RAF
10
WNT
6
Cell cycle (CDK)
Less than 5
FGFR
Less than 5
MMR
Less than 5
IDH1
Less than 5
All of this work demonstrates that
recent advances in genomic and biomarker science can be usefully applied
to the treatment of men at risk for and
diagnosed with prostate cancer.
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AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS
Course #003PG
▼ Continued from page 5
Appendix. Current spectrum of precision medicine for prostate cancer
Clinical Scenario
Available Biomarkers
Comment
Risk of developing prostate
cancer (future risk)
Germline allelic variants
Robust test not yet commercially
available
Likelihood of having
aggressive prostate cancer
(current risk) before biopsy
OPKO4k, PCA3, PHI,
ExoDx™, MI-Prostate,
SelectMDx™
All reduce the need for unnecessary
biopsy by about 30%
Need for re-biopsy
PCA3, ConfirmMDx
Predict for the likelihood that an
existing cancer was missed
Consideration of active surveillance
oncotypeDx® prostate,
Prolaris®, Promark
Predict disease aggressiveness and
presence of adverse pathology
Progression of disease while None validated
on active surveillance
Choice of adjuvant or salvage radiation after radical
prostatectomy
Decipher
Choice of therapy for meta- AR-V7
static CRPC
1. Antonarakis ES, Lu C, Wang H et al: AR-V7 and
resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028.
2. Scher H, Lu D, Schreiber NA et al: Association of
AR-V7 on circulating tumor cells as a treatmentspecific biomarker with outcomes and survival in
castration-resistant prostate cancer. JAMA Oncol
2016; doi: 10.1001/jamaoncol.2016.1828.
Under study
Predicts likelihood of metastasis
within 5 years or surgery
Predicts resistance to abiraterone
and enzalutamide
3. Mateo J, Carreira S, Sandhu S et al: DNA-repair
defects and olaparib in metastatic prostate cancer.
N Engl J Med 2015; 373: 1697.
4. Pritchard CC, Mateo J, Walsh MF et al: Inherited
DNA-repair gene mutations in men with metastatic
prostate cancer. N Engl J Med 2016; 375: 443.
COURSE #009IC
AUA Guideline: Castration-Resistant Prostate Cancer
Update
Michael S. Cookson, MD, MMHC, Course Director; Adam Kibel, MD and Will Lowrance, MD, Faculty
The treatment of patients with castration-resistant prostate cancer (CRPC)
continues to evolve, and that is important information for patients who suffer
from the second leading cause of cancer
death in men.1 Improved survival with
6 different therapeutic agents and now
success with the earlier use of some
agents with prior approval have resulted
in annual updates of the AUA guidelines for CRPC. For the fourth consecutive year the AUA has presented these
guidelines in an instructional course
designed to inform clinicians of the
latest changes in evidence-based recommendations for the sequencing and
treatment of castration-resistant disease.
The treatment of men with metastatic CRPC (mCRPC) has changed
significantly in the last decade. Before
2004, once primary androgen deprivation therapy (ADT) failed, treatments were administered solely for palliation. In landmark studies Tannock2
and Petrylak3 et al demonstrated that
docetaxel improved survival in patients
with mCRPC compared to mitoxantrone. Since then 5 additional agents
(abiraterone, sipuleucel-T, cabazitaxel,
enzalutamide and radium-223) that
have all shown a survival benefit have
been approved by the FDA (U.S. Food
and Drug Administration) on the basis
of randomized clinical trials.4-9 These
agents have been tested in multiple disease states of CRPC to determine if or
when patients might benefit from each
treatment. Now these agents and others
are being investigated in earlier stages of
the disease.
At the AUA 2016 Annual Meeting
we presented the updated AUA CRPC
guidelines. A reason for the continued
guidelines update is the rapid evolution
of the field with the new treatments
that are becoming available. The use of
enzalutamide before chemotherapy in
men with asymptomatic or mildly symptomatic mCRPC was discussed. This
major breakthrough was the result of
the PREVAIL trial, a randomized trial
of enzalutamide compared to placebo
in men with mCRPC before docetaxel therapy.9 The study demonstrated
significant improvement in the 2 coprimary end points of overall survival
(HR 0.706, 95% CI 0.60-0.84, p <0.001)
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AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS
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Course #0091C
▼ Continued from page 6
and radiographic progression-free survival (HR 0.186, 95% CI 0.15-0.23) in
patients treated with enzalutamide vs
placebo. Previously, abiraterone plus
prednisone was approved in the prechemotherapy setting (COU-302).4
In addition, the use of an alpha emitting radionuclide therapy was discussed
relative to the FDA approved use of
radium-223 dichloride for the treatment
of mCRPC, symptomatic bone metastases and no visceral metastatic disease.8
These approvals and others anticipated
in the near future highlight the need
for continuous periodic updating of the
AUA guidelines to inform clinicians
regarding the rapidly evolving management of this disease.
The CRPC guidelines were developed using 6 index cases intended to
represent the most common scenarios
encountered in clinical practice. Accordingly, cases with CRPC were categorized based on the presence or absence
of metastases, degree and severity of
symptoms, overall performance status
and prior treatment with docetaxel chemotherapy. Guideline statements for
each of the index cases were rated as a
standard, a recommendation, an option
or an expert opinion based on the grading of the strength and quality of the
evidence, as well as panel assessment
of the benefits and harms of treatment.
The statements were also formatted into
a user-friendly algorithm. A summary
of the CRPC guideline statements for
each index case and respective statement were presented. Moreover, the
guidelines were revised to reflect newly
approved therapies, approval of use of
the therapies in new disease stages and
the proper sequencing of agents.
Index patient 1 is asymptomatic with
an increasing prostate specific antigen
and no radiographic evidence of metastases. There are currently no FDA
approved agents for this scenario. Clinicians should recommend observation
with continued ADT for patients with
nonmetastatic CRPC. Since all agents
have potential side effects and no treatment has been shown to extend survival
or demonstrate a clinically meaningful
delay in the development of metastasis, we must first do no harm. Patients
should be encouraged to enter clinical
trials when available. Clinicians may
also offer treatment with first-generation antiandrogens or first-generation
androgen synthesis inhibitors to select
patients. Systemic chemotherapy or
immunotherapy should be offered to
patients with nonmetastatic CRPC outside the context of a clinical trial.
Index patient 2 is asymptomatic or
has minimal symptoms with metastases
and no prior docetaxel. In this setting
clinicians should offer abiraterone +
prednisone, enzalutamide, docetaxel or
sipuleucel-T. Of note, the addition of
enzalutamide in the pre-chemotherapy
setting was an important addition to this
year’s AUA guidelines update. Clinicians may offer first-generation antiandrogen therapy, first-generation androgen synthesis inhibitors or observation
to index 2 patients who do not want or
cannot have standard therapy. Finally,
some patients may not wish to pursue
any therapy and may wait for the onset
of symptoms to pursue treatment.
Index patient 3 is symptomatic, has
metastases and a good performance
status, and has not previously received
docetaxel. Clinicians should offer abiraterone + prednisone, enzalutamide
or docetaxel chemotherapy in this setting. The inclusion of enzalutamide was
also based on the results of the new
PREVAIL trial data.9 Ketoconazole +
steroid, mitoxantrone or radionuclide
therapy may be offered to patients who
do not want or cannot have standard
therapy. For patients with symptomatic
bone metastases and no visceral metastases, clinicians should offer radium-223.
Clinicians should not offer estramustine
or sipuleucel-T to index 3 patients.
Index patient 4 is symptomatic with
metastases, a poor performance status
and no prior docetaxel treatment. Clinicians may offer treatment with abiraterone + prednisone or enzalutamide
to these patients and ketoconazole +
steroid or radionuclide therapy to those
who are unable or unwilling to receive
abiraterone + prednisone or enzalutamide. When performance status is
directly related to the cancer, clinicians
may offer docetaxel or mitoxantrone
chemotherapy. Radium-223 may be
offered to select patients with symptomatic bone metastases and without known
visceral disease, specifically when performance status is directly related to
symptoms of bone metastases. Clinicians should not offer sipuleucel-T to
these patients.
Index patient 5 is symptomatic with
metastases, a good performance status
and a history of docetaxel use. Clinicians should offer treatment with abiraterone + prednisone, cabazitaxel or
enzalutamide to these patients. If the
patient received abiraterone + prednisone before docetaxel chemotherapy,
he should be offered cabazitaxel or
enzalutamide. Ketoconazole + steroid
may be offered to these patients if abiraterone + prednisone, cabazitaxel or
enzalutamide is unavailable. Re-treatment with docetaxel may be suggested
for patients who were benefitting at
the time of docetaxel discontinuation
(due to reversible side effects). New this
year for patients with symptomatic bone
metastases and no visceral metastases,
clinicians should offer radium-223.
Index patient 6 is symptomatic, with
metastases, a poor performance status
and prior docetaxel treatment. The goal
of palliation is to prevent and relieve suffering, and to support the best possible
quality of life for the patient and family.
Palliative radiotherapy can be an option
to control bone pain in some patients,
and should be offered. Alternatively, in
select patients clinicians may offer treatment with abiraterone + prednisone,
enzalutamide, ketoconazole + steroid or
radionuclide therapy. Clinicians should
not offer systemic chemotherapy or
immunotherapy to these patients.
The guidelines also address bone
health and indicate that all patients
with CRPC should be offered preventive treatment (eg supplemental calcium, vitamin D) to reduce the risk of
▼ Continued on page 8
8
AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS
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fractures and skeletal related events.10
Denosumab or zoledronic acid may
be selected as preventive treatment for
skeletal related events in patients with
mCRPC and bony metastases.11, 12
The treatment of CRPC is undergoing rapid evolution with multiple new
agents on the horizon, from immune
modulators to vaccines to novel antiandrogens. In addition, use of approved
agents is rapidly expanding into earlier
disease stages, including the unmet need
for agents in patients without evidence
of radiographic metastases. It is likely
that the guidelines will be modified on
an annual or semiannual basis to keep
urologists abreast of this rapidly chang-
ing treatment landscape.
1. Siegel R, Ma J, Zou Z et al: Cancer statistics, 2014.
CA Cancer J Clin 2014; 64: 9.
2. Tannock IF, de Wit R, Berry WR et al: Docetaxel
plus prednisone or mitoxantrone plus prednisone
for advanced prostate cancer. N Engl J Med 2004;
351: 1502.
3. Petrylak DP, Tangen CM, Hussain MH et al:
Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory
prostate cancer. N Engl J Med 2004; 351: 1513.
4. Ryan CJ, Smith MR, de Bono JS et al: Abiraterone
in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138.
5. Kantoff PW, Higano CS, Shore ND et al: Sipuleucel-T immunotherapy for castration-resistant
prostate cancer. N Engl J Med 2010; 363: 411.
6. de Bono JS, Oudard S, Ozguroglu M et al:
Prednisone plus cabazitaxel or mitoxantrone for
metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised
open-label trial. Lancet 2010; 376: 1147.
7. Scher HI, Fizazi K, Saad F et al: Increased survival
with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187.
8. National Cancer Institute: FDA Approval for
Radium 223 Dichloride. Available at www.cancer.
gov/cancertopics/druginfo/fda-radium-223-dichloride.
9. Beer TM, Armstrong AJ, Rathkopf DE et al:
Enzalutamide in metastatic prostate cancer before
chemotherapy. N Engl J Med 2014; 371: 424.
10.Bischoff-Ferrari HA, Willett WC, Wong JB et al:
Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled
trials. JAMA 2005; 293: 2257.
11.Saad F, Gleason DM, Murray R et al: Long-term
efficacy of zoledronic acid for the prevention of
skeletal complications in patients with metastatic
hormone-refractory prostate cancer. J Natl Cancer
Inst 2004; 96: 879.
12.Fizazi K, Carducci M, Smith M et al: Denosumab
versus zoledronic acid for treatment of bone
metastases in men with castration-resistant prostate
cancer: a randomised, double-blind study. Lancet
2011; 377: 813.
COURSE #054PG
Prostate Cancer Update 2016
William J. Catalona, MD, Course Director; Douglas M. Dahl, MD, Stanley L. Liauw, MD, Stacy Loeb, MD, MSc, Robert B. Nadler, MD and Russell
Szmulewitz, MD, Faculty
This course highlights the important
findings on prostate cancer (PCa) published during the last year.
tion sequencing, and are beginning to
be used for prognosis and guiding treatment.10
Epidemiology
Screening
There has been an 80% decrease in
the proportion of men presenting with
advanced PCa and a 50.3% decrease
in PCa mortality during the prostate
specific antigen (PSA) era. Mortality
has decreased 49% in African-American
(AA) men.1, 2 Confirmed risk factors for
PCa include balding, smoking, alcohol,
processed red meats and occupational
cadmium exposure.3-5 Lycopene is associated with 59% lower mortality for
high risk PCa,6 and statin use is associated with less aggressive disease.7 No
relationship of long-term testosterone
therapy to risk of high grade PCa has
been demonstrated.8
The PLCO (Prostate, Lung, Colorectal, Ovarian) screening trial has been
scrutinized for the frequency of screening among controls, originally reported
as ~50%.11 In reviewing PLCO data,
Shoag et al reported that ~90% of
controls had at least 1 PSA test before
or during the trial.12 As the USPSTF
(United States Preventive Services Task
Force) weighted the PLCO trial heavily in its recommendation against PSA
screening,13 it should now revise its
recommendation. During the PSA era
the incidence of metastatic PCa has
declined, whereas that of metastatic
breast cancer remained stable, suggesting that PSA is a more sensitive screening test.14 Since the USPSTF recommendation, screening and biopsies in the
U.S. have decreased, resulting in fewer
cases detected and a greater percentage
of high risk disease.15-19
The 2016 NCCN® (National Com-
Etiology
The heritability for PCa is 57%, and
genomic heterogeneity is due mainly
to structural variants and copy-number
aberrations.9, 10 Subtypes of PCa are
being delineated through next genera-
prehensive Cancer Network®) guidelines recommend asking about family
history of BRCA1/2 mutations; biopsy
for PSA greater than 3 ng/mL or suspicious digital rectal examination (DRE);
repeat testing at 1 to 4-year intervals for
men older than 75 years, PSA less than
3 ng/mL and no other indications for
biopsy; followup for focal high grade
prostatic intraepithelial neoplasia at 6 to
24 months; and repeat biopsy based on
risk.20 A meta-analysis revealed no effect
of bicycling on PSA levels.21
Biopsy
Repeat biopsy reveals PCa in 34% to
38% of men with atypical small acinar
proliferation and Gleason 7 or greater
disease in 8% to 17%, both increasing with biopsies after 1 year.22, 23 A
new alternative to Gleason score (grade
groups 1 to 5) was validated for predicting risk of biochemical recurrence and
has been adopted by the World Health
Organization classification.24
Biomarkers
A Swedish study showed that clinical
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Course #054PG
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variables, plasma biomarkers and genetic polymorphisms combined improve
PCa screening specificity and identify
Gleason 7 or greater PCa in men 50
to 69 years old with PSA 1 to 3 ng/
mL while reducing biopsies by 32%
and missing 17% of Gleason 6 PCa.25
In AA men the Prostate Health Index26
and a novel biomarker signature27 predict aggressive disease. The Prolaris
test affects treatment selection in 14%
to 21% of patients with low/intermediate risk PCa.28 DNA damage/repair
pathway profiling stratifies risk independently of clinical/pathological variables in high risk patients.29 The Decipher test augments post-prostatectomy
risk stratification in intermediate/high
risk patients.30, 31 Racial variation in
PCa molecular subtypes and androgen receptor signaling reflect anatomic
tumor location.32 A urine exosome gene
expression test predicts high grade PCa
at initial biopsy.33 Comparative marker
studies are needed.
Imaging
Magnetic resonance imaging/fusion
biopsy improves detection of clinically
significant PCa but requires an experienced multidisciplinary team.34
Active Surveillance
In the U.S. active surveillance (AS)
has increased 40% to 50% for low risk
cases, and surgery has increased for
intermediate/high risk disease.35, 36 A risk
calculator may help avoid low yield AS
biopsies.37 Perineural invasion is associated with a shorter time to progression
on AS.38 Men with biopsy complications
are less likely to undergo subsequent
AS biopsies.39 The CCO (Cancer Care
Ontario)/ASCO (American Society of
Clinical Oncology) guidelines recommend AS for most patients with low
risk disease (watchful waiting if less than
5-year life expectancy), and the AS protocol should include PSA every 3 to 6
months, DRE yearly, and confirmatory
biopsy (12 cores or greater) within 6 to
12 months and then every 2 to 5 years.
Treatment is recommended for most
patients with intermediate risk disease
and when patients are reclassified to a
higher risk category.40 The Johns Hopkins AS study reported grade reclassification in 31% of patients and 57%
received curative treatment (15-year
actuarial rates, median followup 8.5
years).41 The Göteborg trial reported a
hazard ratio for AS failure for low and
intermediate risk disease of 2.2 and 4.8,
respectively, compared to men with
very low risk disease.42 The authors
questioned whether men not in the very
low risk group with a long life expectancy are suitable candidates for AS.42 The
Toronto trial reported development of
metastases in 14% of intermediate risk
patients. Because Gleason pattern 4 conferred a threefold to fourfold increased
risk of metastatic disease, the authors
concluded, “such patients should be
offered surveillance with caution.”43
Focal Therapy
At a FDA/AUA/SUO (Society of Urologic Oncology) sponsored workshop
it was reported that the focal therapy
devices are approved for ablating tissue
but not for clinical effectiveness of focal
therapy. The criteria for patient selection remain debatable and long-term
cancer control remains to be established.
Concerns include the potential for overtreatment of low risk cancer and inadequate treatment of higher risk disease.44
Radical Prostatectomy
A meta-analysis indicated that radical
prostatectomy (RP) is associated with a
lower risk of cancer specific and all-cause
mortality than radiotherapy (RT),45
although questions remain whether the
differences are attributable to biases.46
Nearly half of low risk patients treated
with RP harbor Gleason 7 or greater or
pT3 or greater disease.47 At U.S. hospitals use of the robot for RP increased
to 85% in 2013.48 Trials are currently
under way to evaluate RP in patients
with metastatic disease.49
Radiotherapy
Dose escalation to 81Gy has a role
in intermediate/high risk disease.50
Hyopfractionation (28 days) is noninferior to 41 days for low risk disease51 but
late gastrointestinal/genitourinary toxicity may be worse.52 Extreme hypofractionation (5 days) including the pelvic
nodes should be given with caution.53
A hydrogel spacer improves rectal sparing with RT.54 Androgen deprivation
therapy (ADT) improves dose escalated
intensity modulated RT55, 56 but cardiovascular comorbidity should be considered.57 Patients with locally advanced
(nodal) disease benefit from the addition
of radiation therapy to ADT.58, 59 Postoperative RT does not impair quality
of life (QOL) through 4 years of followup.60 Dose escalated salvage RT (70
Gy) results in mild acute toxicity with
minor differences in urinary QOL.61
Long-term ADT should be considered
with postoperative RT in men with high
risk features.62 Failures after RT usually occur at the initial sites of disease.63
Patients with positive biopsies after RT
have worse outcomes but the natural
history can be long.64 There is increased
risk for bladder and colorectal tumors
after prostate external beam RT.65
Systemic Therapy and Advanced
Disease
Metastasis directed therapy of regional and distant recurrences after curative treatment has no proven benefit.66
Orchiectomy is associated with significantly lower risk of fracture, peripheral
artery disease and cardiac complications
than treatment with luteinizing hormone
releasing hormone (LHRH) agonists.
Men taking LHRH agonists for 35
months or longer also had more diabetes and venous thromboembolism.67
ADT is associated with impaired cognitive performance68 and may increase the
risk of Alzheimer’s disease.69 In the high
risk localized, but not overtly metastatic,
PCa population the GETUG 12 trial
reported that docetaxel + estramustine
improves relapse-free survival, although
further followup is needed to assess
whether this will translate into improved
metastasis-free and overall survival.70
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The final analysis of the COU-AA-302
pre-chemotherapy CRPC trial demonstrates significantly improved progression-free and overall survival with
abiraterone + prednisone vs prednisone alone.71 Retrospective analysis of
patients with metastatic CRPC treated
with sequential abiraterone or enzalutamide revealed a modest benefit with
the second-line therapy, suggesting distinct androgen receptor (AR) resistance
mechanisms.72
For the treatment of metastatic castration sensitive prostate cancer, the
CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in
Prostate Cancer trial) E3805 reported
that 6 cycles of docetaxel + ADT were
superior to ADT alone.73 For high volume disease there was a 17-month gain
in median overall survival. Similarly,
the STAMPEDE (Systemic Therapy in
Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial
demonstrated that docetaxel improved
survival but zoledronic acid did not and
should not be used for castration sensitive metastatic PCa.74 For early CRPC
the STRIVE (Safety and Efficacy Study
of Enzalutamide Versus Bicalutamide
in Men With Prostate Cancer)75 and
TERRAIN76 trials showed that enzalutamide is superior to bicalutamide with
respect to progression-free survival.
Galeterone is a CYP17 antagonist and
an AR degrader, and a phase 3 study of
galeterone vs enzalutamide for AR-V7+
CRPC is ongoing.77 Clinically actionable
mutations are more common in metastatic CRPC than previously believed.78
There is substantial inter-individual but
limited intra-individual genomic diversity among tumors.79 Therefore, biopsy
of a single metastasis may be useful
for selecting treatments on the basis
Figure 1. Courtesy of Prof. Nicholas James; Director of
the Cancer Research Unit, Clinical Trials Unit, Gibbet
Hill Campus; University of Warwick; Coventry, G. CV4
7AL; July 30, 2016.
of predicted molecular vulnerabilities.
For example, olaparib, a small molecule inhibitor of poly ADP ribose polymerase inhibitor, resulted in an 88%
response rate for patients with refractory
CRPC and tumors harboring mutations
in BRCA1/2, ATM, CHEK2. Olaparib
has received breakthrough designation
by the FDA.80
Conclusions
Numerous advances have been made
in PCa care. There is increasing concern that the fewer PSA screenings will
reverse the benefits realized to date. The
use of AS is increasing for favorable
risk disease, and research is ongoing
to improve management of aggressive
PCa.
For the complete list of references for this summary e-mail [email protected].
Figure 2. Courtesy of Prof. Nicholas James, Director of
the Cancer Research Unit, Clinical Trials Unit, Gibbet
Hill Campus; University of Warwick; Coventry, G. CV4
7AL; July 30, 2016.
COURSE #091PG
Novel Agents and Concepts in the Management of
Hormone Naïve and Castration-Resistant Prostate
Cancer
Judd W. Moul, MD, FACS, Course Director; Lawrence I. Karsh, MD, FACS and Christopher Sweeney, MBBS, Faculty
We used a case based and audience
response system to create an interactive educational session that was well
attended. We applaud the AUA for
recognizing that a cadre of urologists,
particularly urologists who specialize in
urological cancer, should remain at the
forefront of research, education and care
for our patients with hormone naïve
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Course #091PG
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and castrate resistant prostate cancer.
We also commend The Large Urology
Group Practice Association for championing the concept of designating key
urologists in their practices to care for
men with advanced prostate cancer.
Although castration-resistant prostate
cancer (CRPC) continues to be a hot
topic in 2016, hormone naïve/hormone
sensitive newly diagnosed metastatic
(M1) prostate cancer has been hot news
with the release of CHAARTED trial
data last year and the STAMPEDE
trial results in 2016 showing a benefit of
up-front docetaxel chemotherapy. Primary hormonal therapy (HT)/androgen deprivation therapy (ADT) had
been the only treatment for men with
new M1 disease for more than threequarters of a century.1 In the last 2 years
CHAARTED taught us that adding 6
cycles of docetaxel (without steroids)
within 4 months of starting HT/ADT
resulted in a major survival benefit. For
high volume disease (4 or more bone
metastases and/or visceral metastases),
the addition of chemotherapy resulted
in a 17-month survival advantage compared to ADT alone.2 However, the
hazard ratio also generally supports a
benefit of docetaxel for low volume M1
disease as well.
More recently, the large STAMPEDE
trial confirmed the benefit of docetaxel
and generally supported the use of chemotherapy for all men with new M1 disease.3 Figure 1 shows the novel research
scheme of STAMPEDE which was conducted in Great Britain and reported
by James et al.3 Median overall survival
was 65 months for men randomized to
receive docetaxel vs 43 months for men
randomized to standard of care (fig. 2).
The bottom line in 2016 is that most
if not all men presenting with newly
diagnosed hormone naïve M1 prostate
cancer should be afforded 6 cycles of
docetaxel generally within 4 months of
starting ADT.
In the area of hormone naïve advanced
prostate cancer, we also briefly covered the TOAD trial for biochemically
recurrent/prostate specific antigen (PSA)
recurrent prostate cancer.4 The TOAD
trial is the collaborative TROG 03.06
and VCOG PR 01-03, a randomized,
prospective phase III trial conducted in
Australia. The study objective was to
investigate if immediate ADT improved
overall survival compared to delayed
ADT in patients with PSA relapse after
definitive therapy or in asymptomatic
men with no curative therapy at diagnosis. From September 2004 to July 2012,
293 patients were randomized (ADT
delayed 151, ADT immediate 142) with
a median followup of 5 years. Overall
survival was significantly higher in the
immediate ADT than delayed ADT
group (p = 0.047), with 6-year survival
rates of 86% and 79%, respectively. The
authors concluded that the trial provides
moderate evidence that the use of immediate ADT in men with PSA relapse
after primary therapy or with noncurative disease improves overall survival by
approximately 10% at 5 years. As this
is not a curative approach, the benefit
must be balanced against the morbidity
of the therapy. Fully 80% of immediate
vs 50% of delayed ADT suffered symptoms.
At our course we had a lively discussion about this trial. It took a long time
to enroll fewer than 300 patients. The
results provide some support for early
ADT for PSA relapse and might be
used to support early ADT for high
risk younger, healthier men. We concluded that it will be interesting to see if
the ASCO (American Society of Clinical Oncology), AUA and/or NCCN®
(National Comprehensive Cancer Network®) guidelines are updated to reflect
these findings, or will guideline committees look at this as a small, hypothesisgenerating trial of limited value.
An emerging new concept in advanced
prostate cancer is the idea of offering
definitive local therapy, such as radical
prostatectomy, to men who have limited
metastatic disease.5, 6 While this would
seem to be almost heresy to classically
trained urological oncologists, this idea
of taking an aggressive treatment stance
for men who have oligometastatic dis-
ease is emerging particularly in the era
of presumed better imaging for early
metastases (see Appendix). The audience was intrigued by this new concept
but many questions remain and we are
eager to have this concept addressed at
future AUA meetings and courses.
Since 2010, 6 new agents have been
approved by the U.S. Food and Drug
Administration (FDA) for CRPC including sipuleucel-T, cabazitaxel, abiraterone
acetate, denosumab, enzalutamide and
radium-223.7 Except for cabazitaxel, all
of these agents are commonly available
for urologists and oncologists to prescribe. Some of the new concepts related
to the new agents that urologists may
use for CRPC are discussed.
Denosumab
Denosumab is prescribed at a dose
of 120 mg subcutaneously monthly to
prevent skeletal related events (SREs)
known to be common in the later course
of advanced metastatic prostate cancer.
The FDA also approved a 60 mg dose
of denosumab subcutaneously twice a
year to prevent bone loss (osteopenia
and osteoporosis) in men without bone
metastases who are taking luteinizing
hormone releasing hormone therapy
for prostate cancer. At the course, we
discussed bone health and making sure
urologists remain mindful of using supportive agents.8
Sipuleucel-T
Sipuleucel-T is a novel immunotherapy
approved by the FDA in 2010 for
asymptomatic or minimally symptomatic M1 CRPC.9 The ideal patient for sipuleucel-T will have documented clinical
metastases and a rising PSA level while
on continuous hormonal therapy. He
will not have bone or cancer pain requiring narcotic pain medications. In men
with PSA levels in the lowest quartile of
the IMPACT trial (PSA less than 22 ng/
ml) there was a more robust overall survival advantage to sipuleucel-T.10 Specifically, the estimated 3-year survival in
this group of treated patients was 62.6%
compared to 41.6% for men randomized
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AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS
Course #091PG
▼ Continued from page 11
to the control arm of the study.
Abiraterone and Enzalutamide
Abiraterone is a 17-lyase and 17-hydrolase inhibitor that blocks key pathways
in the steroidal synthesis pathways leading to androgen production. Low dose
prednisone (7.5 to 10 mg daily is a
physiological dose) is recommended to
be administered with abiraterone to
help limit overproduction of aldosterone
as well as side effects of hypertension,
hypokalemia and fluid retention. The
current FDA approved indication for
abiraterone is either before or after disease has progressed on docetaxel based
systemic chemotherapy. The dose for
abiraterone is 1,000 mg orally once
daily along with low dose steroid (5 mg
prednisone orally twice daily). The final
analysis of the pivotal trial for use before
chemotherapy was published and presented at the course showing a durable
and clinically meaningful and overall
survival benefit.11
Enzalutamide is a novel oral hormonal
therapy agent that was FDA approved
in 2012 to treat men with disease that
progressed after docetaxel based chemotherapy and was then approved in
2014 for use before chemotherapy.12
Enzalutamide is taken orally at a dose
of 160 mg daily. Enzalutamide, unlike
abiraterone, does not have to be given
with low dose prednisone. However,
enzalutamide does have an approximate
1% risk of seizures associated with its
use and crosses the blood-brain barrier
implicating it with some risk of falls and
fatigue.
While both novel oral hormonal
agents are active in advanced prostate
cancer, their benefit is not necessarily synergistic or cumulative. In other
words, patients will likely have an initial robust response to either agent but
switching men to the other agent will
likely not result in a sustained response,
and the response to the second agent
may be more short-lived.
One of the new hot topics related to
use of abiraterone and enzalutamide is
molecular profiling. The recent discov-
ery of the AR-V7 mutated variant of the
androgen receptor offers intriguing speculation to the future of individualized
medicine.13 Specifically, the response to
abiraterone or enzalutamide was less
robust in men who harbored this mutation in circulating tumor cells. However,
as of July 2016, there is no U.S. Federal
Drug Administration (FDA) approved
assay for AR-V7 and the broad clinical
use of this concept will remain for future
AUA meetings/courses.
Radium-223
This agent is a parenteral radiopharmaceutical that can be ordered by urologists and will be provided in a nuclear
medicine or radiation oncology department setting.14 The product is an alphaemitting liquid radiation product that
received FDA approval in May 2013.
Radium-223 is indicated for the treatment of patients with CRPC, symptomatic bone metastases and no known
visceral metastatic disease. The dose
regimen is 50 kBq (1.35 microcurie)
per kg body weight, given at 4-week
intervals in 6 injections. Urologists may
have been familiar with earlier generation radiopharmaceuticals such as
strontium but radium-223 is different.
First, it is alpha particle based and
does not affect the bone marrow to the
degree of older agents. In other words,
radium-223 is much less likely to cause
serious bone marrow toxicity with low
white blood cell counts. Secondly, the
use of radium-223 was associated with
an overall survival benefit, whereas the
older radiopharmaceuticals were never
proven to extend survival.
Appendix. Radical prostatectomy for
oligometastatic disease: key teaching
points
• Biological rationale strong
• Population level data favor but
biased
• Retrospective series sparse and
biased but supportive
• Complications higher but not intolerable
• Patient selection key:
- Consider magnetic resonance imaging for local staging
- Avoid radical prostatectomy in
patients with multiple “bad” features
• Await clinical trials (eg MD Anderson Phase II)
1. Moul JW: Hormone naïve prostate cancer: predicting and maximizing response intervals. Asian J
Androl 2015; 17: 929.
2. Sweeney CJ, Chen YH, Carducci M et al: Chemohormonal therapy in metastatic hormone-sensitive
prostate cancer. N Engl J Med 2015; 373: 737.
3. James ND, Sydes MR, Clarke NW et al: Addition
of docetaxel, zoledronic acid, or both to first-line
long-term hormone therapy in prostate cancer
(STAMPEDE): survival results from an adaptive,
multiarm, multistage, platform randomised controlled trial. Lancet 2016; 387: 1163.
4. Duchesne GM, Woo HH, Bassett JK et al: Timing
of androgen-deprivation therapy in patients with
prostate cancer with a rising PSA (TROG 03.06
and VCOG PR 01-03 [TOAD]): a randomised,
multicentre, non-blinded, phase 3 trial. Lancet
Oncol 2016; 17: 727.
5. Heidenreich A, Pfister D and Porres D: Cytoreductive radical prostatectomy in patients with
prostate cancer and low volume skeletal metastases: results of a feasibility and case-control study. J
Urol 2015; 193: 832.
6. Muldermans JL, Romak LB, Kwon ED et al:
Stereotactic body radiation therapy for oligometastatic prostate cancer. Int J Radiat Oncol Biol Phys
2016; 95: 696.
7. Lowrance WT, Roth BJ, Kirkby E et al: Castration-resistant prostate cancer: AUA guideline
amendment 2015. J Urol 2016; 195: 1444.
8. Tripathy D, Durie BG, Mautner B et al: Awareness, concern, and communication between
physicians and patients on bone health in cancer.
Support Care Cancer 2014; 22: 1601.
9. Davis K, Wood S, Dill E et al: Optimizing the efficiency and quality of sipuleucel-T delivery in an
academic institution. Clin J Oncol Nurs 2015; 19:
297.
10. Schellhammer PF, Chodak G, Whitmore JB et al:
Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from
sipuleucel-T in the Immunotherapy for Prostate
Adenocarcinoma Treatment (IMPACT) trial.
Urology 2013; 81: 1297.
11.Ryan CJ, Smith MR, Fizazi K et al: Abiraterone
acetate plus prednisone versus placebo plus
prednisone in chemotherapy-naïve men with
metastatic castration-resistant prostate cancer
(COU-AA-302): final overall survival analysis of
a randomised, double-blind, placebo-controlled
phase 3 study. Lancet Oncol 2015; 16: 152.
12. Beer TM, Armstrong AJ, Rathkopf DE et al:
Enzalutamide in metastatic prostate cancer before
chemotherapy. N Engl J Med 2014; 371: 424.
13. Antonarakis ES, Lu C, Wang H et al: AR-V7 and
resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028.
14. Parker C, Nilsson S, Heinrich D et al: Alpha emitter radium-223 and survival in metastatic prostate
cancer. N Engl J Med 2013; 369: 213.
▼ Continued on page 13
AUA 2016 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS
13
PLENARY SESSIONS
Town Hall: Optimizing Quality of Life for Patients
with Advanced Cancer
Christopher J. Kane, MD, Moderator; William Mitchell, MD (Palliative Care), Gregory R. Polston, MD (Treatment of Cancer Pain), Eric Roeland, MD
(Optimizing Quality of Life), Christopher Onderdonk, LCSW (Preserving Hope and Realism), Jermey Hirst, MD (Managing Anxiety and Depression) and
Eugene Lee, MD (Immunonutrition)
As urologists, we often are the initial
treating physician and the coordinator
of care for patients with genitourinary
malignancies. It is imperative that as we
care for patients through the spectrum
of disease, we keep the goals of prolonging life and curing cancer balanced with
the realism of progression as well as
disease and treatment burden. We were
fortunate to assemble a group of palliative care specialists to lead us through
our Town Hall on optimizing quality of
life for patients with advanced cancer.
These professionals gave the audience
a series of practical recommendations
for improving our skills of assessing and
treating patients with advanced disease.
Palliative Care
Advanced urological illness is commonly a perfect storm of poor symptom control, incomplete patient understanding,
high costs and low physician satisfaction.
Palliative care, a term coined by Balfour
Mount, a urologist at McGill University, provides some solutions. Often
palliative care is offered in late stages of
illness toward the end of a long, difficult
course. However when applied early in
the care of patients with severe illness,
patients have better symptom control,
improved mental health, live longer and
incur lower costs of health care.
Palliative care is the responsibility of
every physician who cares for people
with severe illness. Routinely screen for
and assess symptoms and distress. Work
to improve your symptom management
and communication skills. Refer to specialist palliative care early and often.
Refer to hospice earlier (if you wait until
the patient is dying, you are too late).
Courageously broach the difficult, taboo
topics of prognosis, hospice and death.
Set meaningful expectations and goals
with patients at the outset of therapy.
Communicate clearly about prognosis
and likely outcomes of therapy. Identify a surrogate decision maker and the
patient’s desired place of death.
Treatment of Urological Cancer
Pain
Oral opioids remain the mainstay in
the treatment of cancer associated pain.
Nearly 90% of patients with advanced
disease receive this form of therapy.
Although morphine is the most common
opioid prescribed, pain remains poorly
controlled in nearly half of all patients
with cancer. Some of the reasons for
this include opioid-induced side effects
and limited efficacy of opioid in treating
neuropathic and/or visceral pain. Use of
neuropathic medications, such as anticonvulsants and antidepressants, should
be considered throughout the course of
disease to improve pain relief and limit
opioid-induced side effects.
Interventional procedures have also
been shown to be safe and effective.
Celiac plexus neurolysis for the treatment of upper abdominal cancer pain is
used after conservative measures have
failed and life expectancy is less than 6
months. Neurolytic procedures to the
hypogastric plexus or other peripheral
nerves should be considered if pain is
consistent with the innervation pattern.
Placement of an intrathecal pump is
effective at treating widespread pain
when life expectancy is greater than 3
months, and should be considered early
in treatment when the patient will be
better able to tolerate the surgical procedure. Finally, vertebral augmentation
has been shown to reduce pain and is
well tolerated in patients with symptomatic vertebral metastasis.
Optimizing Quality of Live in
Patients with Advanced Cancer
Optimizing the palliation of symptoms
maximizes quality of life and improves
survival for patients with advanced cancer. Effective pain management is the
cornerstone of optimal palliation requiring a balanced approach to opioid prescribing. All medical providers should
be aware of the differences among tolerance, dependence, addiction and pseudo-addiction. Of note, pseudo-addiction
must be considered and occurs when
patients display behaviors concerning
for addiction, but as a consequence of
undertreated or poorly treated pain. A
balanced approach to opioid prescribing incorporates universal precautions
including the routine use of screening
assessments (eg opioid risk tool), use
of prescription drug monitoring programs, pain contracts and effective communication among providers. When
opioids are prescribed, understanding
the basic pharmacokinetics and route
of excretion allows medical providers
to effectively treat and educate patients
regarding their safe use. Furthermore,
anticipating opioid related side effects
is key. Patients taking opioids may
frequently experience transient nausea
or pruritus. To avoid these anticipated
side effects, consider short courses of
metoclopramide or prochorperazine for
nausea vs ondansetron which causes
constipation, and cetirizine for pruritus
not diphenhydramine which may exacerbate sedation. Lastly, all patients taking opioids, regardless of dose or duration, will experience constipation due to
slowing of gut transit. Opioid-induced
constipation is best treated with the use
of stimulant laxatives (senna or bisacodyl) and not stool softeners (docusate).
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Preserving Hope and Realism
An area of preventable suffering that
palliative care has given considerable
attention to is patient and family communication in response to the fact that,
despite extensive medical provider training, the ability to engage skillfully in
conversations around life and death
is given short shrift. What we know
now is when providers approach these
conversations with the same intention
and skill they would approach any procedure patient and family suffering can
be minimized. This is especially true for
advanced cancer where balancing hope
and realism in the face of worsening
disease is a challenge for providers and
patients/families.
Different models were provided and
specific skills taken from palliative care
were introduced, which urologists could
incorporate into their daily practice
in order to build upon their existing
communication skillset. Specifically,
the power of empathy in patient/family
encounters was highlighted along with
the use of “hope/worry” statements in
cases of medical uncertainty. The culmination of using these skills with intention is a provider-patient/family relationship that is grounded in trust. It is from
this trusting connection with providers
where patients and families find hope,
even in the most challenging and dire
circumstances.
Managing Anxiety and Depression
Depression and anxiety are common
and distressing symptoms in patients
living with serious illness. Being able
to differentiate between normal sadness and worries, and the more severe
depressive or anxiety disorders is important to ensure optimal patient care.
Screening questions such as, “Are you
depressed?”, “Have you experienced
joy in the past two weeks?”, “Have you
been feeling nervous, anxious, on edge,
or helpless?” can be very helpful in
determining who needs further evaluation and possible treatment. The usual
symptoms of depression and anxiety
can be misleading in the setting of serious illness. Focusing on a patient’s sense
of meaning, hope and purpose is often
a better way to gauge the degree of psychiatric difficulty.
Nonpharmacologic interventions,
such as psychotherapy, are essential
and should be a frequent referral for
patients suffering from a mood or anxiety disorder. For antidepressants first
consider sertraline (little impact on corrected QT interval, few drug-drug interactions) and escitalopram (few drugdrug interactions), and avoid paroxetine
(anticholinergic and challenging withdrawal) and venlafaxine (challenging
withdrawal). For benzodiazepines first
consider lorazepam (multiple routes and
no active metabolites) and clonazepam
(long-acting), and avoid alprazolam due
to its euphorogenic and short-acting
properties.
Immunonutrition
The final presentation of the Town
Hall was on the interesting topic of
immunonutrition in cancer surgery. In
a randomized trial on immunonutrition
a specialized immunonutrition supplement (SIM) was compared to standard oral nutritional supplement in 29
patients undergoing radical cystectomy.1
Participants receiving SIM had a 33%
reduction in postoperative complication
rate (95% CI 1–64, p = 0.060) and
39% reduction in infection rate (95%
CI 8–70, p = 0.027) during recovery.
Enhanced nutrition and immunonutrition for patients with cancer undergoing surgery have promise to improve
perioperative fitness, and reduce weight
loss, complications and infections.
1. Hamilton-Reeves JM, Bechtel MD, Hand LK et
al: Effects of immunonutrition for cystectomy on
immune response and infection rates: a pilot randomized controlled clinical trial. Eur Urol 2016;
69: 389.
Take Home Message: Prostate Cancer: Shifting the
Risks-Benefits Ratio in Favor of the Patients
Robert Abouassaly, MD, Cleveland, Ohio, provided the audience with highlights of the AUA meeting on prostate cancer. The abstract numbers are in
parentheses.
(Reprinted from AUANews, 2016; Vol. 21,
No. 7, pp 8-9)
This year’s AUA meeting featured more
than 500 high quality presentations covering a range of prostate cancer topics
from basic research and pathophysiology to advanced disease. A few recurrent themes became evident during the
meeting, which I will highlight and
summarize.
The debate continued over the risks
and benefits of prostate cancer screening in the aftermath of the 2012 USPSTF (U.S. Preventive Services Task
Force) recommendations against screening. New evidence was presented from
a reanalysis of the PLCO (Prostate,
Lung, Colorectal, and Ovary) screening
trial casting further doubt over the trial
findings regarding the effectiveness of
prostate cancer screening. The original
article published in 2009 described a
contamination of prostate specific anti-
gen (PSA) testing in the control arm of
approximately 50%.1 A more in-depth
analysis using data from the study’s
Health Status Questionnaire, administered to a subgroup of men in the control group, was presented at a Plenary
session this year.2 The authors suggest
that this was an inaccurate interpretation of PSA testing in the control group
during the trial. They found that greater
than 80% of the men in the control
group, without contamination at the
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time of study entry, reported having
undergone at least 1 PSA test during
the trial. Additionally, more than 50%
reported undergoing testing within the
last year. Overall, including the estimated 10% of control participants with
baseline screening contamination, the
proportion of men in the control arm
having had at least 1 PSA test before or
during the trial approaches 90%. The
authors of this study are urging policymakers and payers who are currently
debating the merits of prostate cancer
screening to consider these data when
formulating their updated recommendations.
Several studies presented at this year’s
meeting described the effects of the
USPSTF recommendation on the diagnosis and management of prostate cancer. Decreases in the number of PSA
screenings were reported for all races
(MP21-07), as well as for different insurance types (MP21-10). Hospitals and
health systems are reporting decreases
in the number of referrals for elevated
PSA, fewer prostate biopsies performed
and a greater proportion of men with
high grade (Gleason score ≥8) or metastatic disease at diagnosis (MP09-06).
Others experienced a decline in the
number of prostatectomies performed,
particularly for low grade disease (Gleason score 6). A greater percentage of
prostatectomies are being done for high
grade disease, and pathologically there
is a trend towards more specimens
with extraprostatic extension (PD03-05).
Whether these observations are a result
of decreased prostate cancer screening
and/or a change in the indications for
surgery remains to be determined.
Roobol et al used data from the
ERSPC (European Randomized Study
of Screening for Prostate Cancer) and
statistical modeling in an attempt to
explain the observed differences in
mortality between the 2 study arms
(PD09-01). They found that more than
80% of the change in mortality could
be explained by an observed stage
shift rather than treatment differences
between the groups as has been suggested by some. Screened men were
diagnosed at an earlier, presumably
more curable stage of disease in the
screening arm compared to men in the
control arm.
Several studies looked at the addition of biomarkers (eg the 4K score,
Prostate Health Index, molecular urine
tests, etc.), magnetic resonance imaging
(MRI) and other clinical markers in an
effort to improve the performance characteristics of prostate cancer screening,
thus reducing the over diagnosis of clinically insignificant prostate cancer. For
example, a group from the Cleveland
Clinic used data from the intervention
arm of the PLCO to determine that
men with a baseline PSA less than 2
ng/ml between the ages of 55 and 60
years were at very low risk for clinically
important prostate cancer at 5 and 13
years of followup (MP39-11).
Another promising method for reducing the diagnosis of low risk prostate
cancer while increasing the diagnosis
of clinically significant prostate cancer
is the use of MRI and MRI/ultrasound
(US) fusion biopsies. A randomized
study from Italy demonstrated that
fusion biopsies were more likely to diagnose Gleason score 7 or greater compared to standard ultrasound guided
biopsy (87.0% vs 61.3%, respectively)
(MP21-17). Also, this approach appears
to be cost-effective. An analysis from the
National Cancer Institute indicated that
MRI/US fusion biopsy in a hypothetical cohort of 100 men with PSA elevation who undergo prostate MRI would
result in an estimated cost savings of
approximately 25% compared with
initial standard transrectal US guided
biopsy (MP53-14).
Efforts at shifting the risk-benefit balance in favor of prostate cancer screening have also focused on decreasing
the overtreatment of clinically indolent
prostate cancer. Active surveillance (AS)
of such low risk prostate cancers is gain-
ing acceptance, and is used in more than
50% of eligible patients and is increasing in some studies.3 Several presentations at this year’s meeting focused on
improving risk stratification of patients
believed to be eligible for AS. Risk calculators/nomograms for progression on
AS were developed (PD08-01, PD0804, PD08-06). Incorporation of data
from MRI and MR/US fusion biopsies
(PD08-10, MP15-18) and the use of
molecular markers (PD08-02, PD08-07,
PD08-11) have been proposed to better
select candidates for AS.
Finally, results from several studies
describing surgical outcomes of patients
initially on AS were presented (PD0302, PD03-04). A higher biochemical
recurrence rate (BCR) in patients treated with radical prostatectomy (RP) after
AS compared to patients who would
have otherwise been candidates for AS
but were immediately treated (16.7%
vs 5.4% after a median followup of 5.7
years). Whereas Auffenberg et al suggested higher grade disease after RP for
AS but with otherwise similar outcomes
(PD03-04), and Savdie et al showed a
greater proportion of predominant Gleason pattern 4 in patients on AS (24.6%
vs. 12%) but with no difference in BCR
(PD03-06). These data highlight the
importance of proper patient selection
when considering AS.
In summary, with increased scrutiny
on the management of this often indolent malignancy, it is imperative that
our specialty continue to work at better
selecting patients who are best served
with active treatment. Additionally, we
need to decrease the morbidity of our
interventions to shift the risk-benefit
ratio in favor of our patients.
1. Andriole GL, Crawford ED, Grubb RL 3rd et
al: Mortality results from a randomized prostatecancer screening trial. N Engl J Med 2009; 360:
1310.
2. Shoag JE, Mittal S and Hu JC: Reevaluating PSA
testing rates in the PLCO trial. N Engl J Med
2016; 374: 1795.
3. Womble PR, Montie JE, Ye Z et al: Contemporary use of initial active surveillance among men
in Michigan with low-risk prostate cancer. Eur
Urol 2015; 67: 44.
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