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American

Urological
Association
AUA NEWS
| THE OFFICIAL NEWSMAGAZINE OF THE AMERICAN UROLOGICAL ASSOCIATION |

2014 ANNUAL
MEETING HIGHLIGHTS
Castration Resistant Prostate
Cancer
Course #011IC
Establishing an Advanced Prostate Cancer
Clinic: A Guide for the Community Urologist
Course #023IC
AUA Guideline: Castration Resistant Prostate
Cancer Update
Course #051IC
Managing Metastatic Prostate Cancer in Your
Urology Practice: Coding and Science
Course #078IC
Sequencing Novel Agents in Advanced
Prostate Cancer 2014: Case Based Key
Knowledge for Urologists

Plenary Session AUA 2014 ANNUAL MEETING


Take-Home Message: Prostate Cancer

Abstract Highlight
HIGHLIGHTS
AUANews Editor
Gopal H. Badlani, MD
Castration Resistant
Publisher
Prostate Cancer
American Urological Association
1000 Corporate Boulevard
Linthicum, MD 21090

Copyright 2014 by American Urological


Association
None of the contents may be reproduced in any
Support provided by educational grants from:
form without prior written permission of the pub-
lisher. The opinions expressed in this publication are
AbbVie
those of the speakers and do not necessarily reflect
the opinions or recommendations of their affiliated Amgen Inc.
institutions, the publisher, the American Urological
Association or any other persons. Some articles in this Astellas Scientific and Medical Affairs, Inc.
publication may discuss unapproved or off-label
uses of products. Any procedures, medications or Bayer HealthCare Pharmaceuticals
other courses of diagnosis or treatment discussed or
suggested in this publication should not be used by Janssen Biotech, Inc.
clinicians without evaluation of their patients condi-
tions and of possible contraindications or dangers in Medivation
it
ed
use, review of any applicable manufacturers product

Cr
information and comparison with the recommenda-
tions of the authorities.
E
CM
AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 1

CMEINFORMATION

2014 AUA Annual Meeting Highlights: Castration


Resistant Prostate Cancer
Method of Participation reviewers, working with the program Planners
directors and/or editors, will document
To claim CME credit/hours of participa- the mechanism(s) for management and Gopal H. Badlani, MD
tion, the learner must read the overview resolution of the conflict of interest and Professor of Urology, Vice Chair of
of courses 011IC, 023IC, 051IC and final approval of the activity will be Clinical Affairs,
078IC, complete the posttest, passing documented prior to implementation. Director of Urogynecology Regenera-
with 80% accuracy, and submit the eval- Any of the mechanisms below can/will tive Medicine Program
uation and credit request form by visiting be used to resolve conflict of interest: Wake Forest Baptist Medical Center
www.AUAnet.org/university/CRPC14. Peer review for valid, evidence-based Winston-Salem, NC
content of all materials associated with Disclosures: Lithotripsy Group: Invest-
Estimated time to complete an educational activity by the course/ ment Interest; Piedmont Stone & Physician
this activity: 1.25 hours program director, editor, and/or Edu- Discovery: Investment Interest; Society of
Release Date: October 2014 cation Content Review Committee or University Urologists: Leadership Position;
Expiration Date: October 31, 2015 its subgroup NIDDK: Leadership Position
Software Requirements for Limit content to evidence with no rec- Elspeth M. McDougall, MD, FRCSC,
Online Test ommendations MHPE
Introduction of a debate format with Professor of Urologic Sciences
A PC-compatible computer running an unbiased moderator (point-counter- Provincial Coordinator for Health Simu-
Windows XP or later, or a Macintosh point) lation Education
computer running OS X 10.4 or later. Inclusion of moderated panel discus- University of British Columbia
Internet access. Adobe Acrobat Reader sion Chair, AUA Office of Education
9 or newer. Publication of a parallel or rebuttal Gordon & Leslie Diamond Health Care
article for an article that is felt to be Centre
AUA Disclosure Policy
biased Vancouver, B.C., Canada
All persons in a position to control the Limit equipment representatives to Disclosures: Nothing to disclose
content of an educational activity (i.e., providing logistics and operation sup-
activity planners, presenters, authors) port only in procedural demonstra- Tracey Krupski, MD
participating in an educational activity tions Associate Professor, Department of
provided by the AUA are required to Divestiture of the relationship by fac- Urology
disclose to the provider any relevant ulty University of Virginia
financial relationships with any com- Charlottesville, VA
mercial interest. The AUA must deter- Accreditation Statement Disclosures: Nothing to disclose
mine if the individuals relationships The American Urological Association J. Kellogg Parsons, MD
may influence the educational content (AUA) is accredited by the Accreditation Associate Professor, Department of Sur-
and resolve any conflicts of interest prior Council for Continuing Medical Educa- gery
to the commencement of the educational tion (ACCME) to provide continuing UC San Diego Moores Cancer Center
activity. The intent of this disclosure is medical education for physicians. San Diego, CA
not to prevent individuals with relevant Disclosures: AMS: Meeting Participant
financial relationships from participating, Credit Designation or Lecturer; Sophiris: Consultant or
but rather to provide learners informa- The American Urological Association Advisor; Watson: Consultant or Advisor;
tion with which they can make their own designates this enduring material for a Myriad: Consultant or Advisor
judgments. maximum of 1.25 AMA PRA Category 1 Statement of Need
Resolution of Identified Conflict of Credits. Physicians should claim only
Interest the credit commensurate with the extent With the increase in number and variety
of their participation in the activity. of therapeutic approaches, the role of
All disclosures will be reviewed by the This enduring material credit is valid the urologist in the treatment of patients
program/course directors or editors for only for content reformatted from cours- with castration resistant prostate cancer
identification of conflicts of interest. Peer es 011IC, 023IC, 051IC and 078IC. (CRPC) has been expanded. It is criti-
Continued on page 2
2 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS
CMEInformation
Continued from page 1
cal that urologists remain engaged and turer, Scientific Study or Trial; Algeta/ University of Oklahoma
knowledgeable on the management of Bayer: Consultant or Advisor, Meeting Oklahoma City, OK
advanced prostate cancer in the con- Participant or Lecturer; Janssen: Con- Disclosures: Nothing to disclose
temporary setting of a multitude of sultant or Advisor, Meeting Participant Adam S. Kibel, MD, Course
new agents becoming available to treat or Lecturer, Scientific Study or Trial; Co-Director
patients. This CME activity will address Astellas: Consultant or Advisor, Meeting Professor of Urologic Surgery
diagnosis, treatment and management Participant or Lecturer, Scientific Study Harvard Medical School
including sequencing of agents, manag- or Trial; Amgen: Consultant or Advisor, Chief of Urology
ing side effects of treatments and man- Meeting Participant or Lecturer, Scien- Brigham and Womens Hospital
agement of comorbid conditions. Addi- tific Study or Trial; Medivation: Con- Dana-Farber Cancer Institute
tionally, this activity will cover iden- sultant or Advisor, Meeting Participant Boston, MA
tifying potential interactions between or Lecturer, Scientific Study or Trial; Disclosures: Dendreon: Consultant or
immunosuppressive agents and other Mitomics: Consultant or Advisor, Meet- Advisor, Meeting Participant or Lectur-
medications, and patient adherence to ing Participant or Lecturer, Scientific er; Sanofi-Aventis: Consultant or Advi-
medical regimens. Study or Trial; CSSIAH: Consultant or sor, Scientific Study or Trial
Advisor
Target Audience
Gregory R. Hanson, MD, FACS Course #051IC: Managing Meta-
Urologists, urologists in training and Metro Urology static Prostate Cancer in Your
nonphysician providers involved in Coon Rapids, MN Urology Practice: Coding and Sci-
urology. Disclosures: Intuitive Surgical: Consul- ence
tant or Advisor; Genomic Health: Consul-
Course #011IC: Establishing an tant or Advisor Learning Objectives
Advanced Prostate Cancer Clinic: A After participating in this activity, par-
Guide for the Community Urologist Course #023IC: AUA Guideline: ticipants should be able to:
Castration Resistant Prostate Can- 1. Select the correct agents for man-
Learning Objectives cer Update agement of patients with metastatic
After participating in this activity, par- prostate cancer
ticipants should be able to: Learning Objectives
2. Describe the risks and benefits of
1. Diagnose and manage CRPC using After participating in this activity, par- the agent to patients with metastatic
newer oral agents as well as sipuleu- ticipants should be able to: prostate cancer
cel-T immunotherapy infusion 1. Analyze the evidence on the treat- 3. Identify coding and administrative
2. Manage bone health in patients with ment of castration resistant prostate issues associated with use of novel
advanced prostate cancer cancer as outlined in the AUA agents in urology office practice
3. Establish protocols for imaging and guidelines and subsequent publica-
laboratory follow-up for patients tions Faculty
with advanced prostate cancer 2. Improve diagnostic and therapeutic
decision making processes by illus- K.C. Balaji, MD, Course Director
Faculty trating the application of these guide- Chief of Urology
lines in urologic practice W.G. Hefner VA Medical Center
Basir U. Tareen, MD, Course Direc- Salisbury, NC
3. Acquire in-depth knowledge on the
tor Wake Forest University School of Med-
process by which evidence is used
Allina Medical Clinic icine
to develop scientifically rigorous, yet
Faribault, MN Winston-Salem, NC
actionable, guidelines
Disclosures: Endo Pharmaceuticals: Meet- Disclosures: Sanofi-Aventis: Meeting
ing Participant or Lecturer; Dendreon: Faculty Participant or Lecturer; Algeta: Consul-
Consultant or Advisor tant or Advisor
Raoul S. Concepcion, MD, FACS Michael S. Cookson, MD, MMHC, Ronald L. Davis, III, MD, MBA,
Director of Clinical Research Course Co-Director FACS
Urology Associates Chairman and Professor, Department Professor, Department of Urology
Nashville, TN of Urology Wake Forest School of Medicine
Disclosures: Dendreon: Consultant or Donald D. Albers Endowed Chair Winston-Salem, NC
Advisor, Meeting Participant or Lec- Urologic Oncology
Disclosures: Nothing to disclose

Continued on page 3
AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 3
CMEInformation
Continued from page 2
P. George Febbo, MD ity may contain reference(s) to off-label
Course #078IC: Sequencing Novel Chief Medical Officer or unapproved uses of drugs or devices.
Agents in Advanced Prostate Can- Genomic Health, Inc Please consult the product prescrib-
cer 2014: Case Based Key Knowl- San Francisco, CA ing information for full disclosure of
edge for Urologists Disclosures: Nothing to disclose approved uses.

Learning Objectives J. Kellogg Parsons, MD Disclaimer


Associate Professor, Department of Sur-
After participating in this activity, par- gery The opinions and recommendations
ticipants should be able to: UC San Diego Moores Cancer Center expressed by faculty, authors and other
1. Diagnose castrate resistant prostate San Diego, CA experts whose input is included in this
cancer (CRPC), and have a work- Disclosures: AMS: Meeting Participant program are their own and do not nec-
ing knowledge of treatments and the or Lecturer; Sophiris: Consultant or essarily represent the viewpoint of the
proper order for administration Advisor; Watson: Consultant or Advi- AUA.
2. Manage CRPC with systemic agents sor; Myriad: Consultant or Advisor
by learning the proper candidates Reproduction Permission
for treatment and be able to counsel Acknowledgements Reproduction of written materials devel-
patients on the pros and cons of The AUA Office of Education would oped for this AUA course is prohibited
therapy like to thank the companies who sup- without the written permission from
3. Analyze the mechanism of action port continuing education of physicians. individual authors and the American
and risks/benefits of using systemic The AUA recognizes the following com- Urological Association.
agents in the treatment of CRPC panies for providing educational grant
4. Describe the bone-targeted, radio- support:
AUA Privacy and Confidentiality
pharmaceutical agent radium-223 Policy
and its sequencing AbbVie Access the AUA Privacy and
5. Review the new generation antian- Amgen Inc. Confidentiality Policy online at
drogen agent enzalutamide and its Astellas Scientific and Medical Affairs, www.auanet.org/education/confident
sequencing Inc. iality-statement.cfm.
Faculty Bayer HealthCare Pharmaceuticals
Janssen Biotech, Inc.
Judd W. Moul, MD, FACS, Course Medivation
Director
Director, Duke Prostate Center American Urological Association Edu-
James H. Semans, MD Professor of cation & Research, Inc. ensures that all
Surgery educational activities are developed and
Duke University Medical Center implemented independent of the control
Durham, NC and/or influence of any commercial
Disclosures: Sanofi-Aventis: Health Pub- interests (ACCME: SCS1).
lishing, Meeting Participant or Lecturer;
Evidence-Based Content
Dendreon: Consultant or Advisor, Meet-
ing Participant or Lecturer; Theralogix: It is the policy of the AUA to ensure that
Consultant or Advisor; Ferring Phar- the content contained in this CME activ-
maceuticals Inc.: Consultant or Advisor, ity is valid, fair, balanced, scientifically
Meeting Participant or Lecturer; Medi- rigorous, and free of commercial bias.
vation: Consultant or Advisor; Astellas:
Consultant or Advisor; Janssen: Consul- Off-label or Unapproved Use of
tant or Advisor, Meeting Participant or Drugs or Devices
Lecturer; Johnson and Johnson: Consul- It is the policy of the AUA to require the
tant or Advisor, Meeting Participant or disclosure of all references to off-label
Lecturer; Myriad Genetics Inc.: Consul- or unapproved uses of drugs or devices
tant or Advisor; IRIS/Arista Molecular: prior to the presentation of educational
Meeting Participant or Lecturer, Scien- content. The audience is advised that
tific Study or Trial this continuing medical education activ-
4 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS

COURSE #011IC
Establishing an Advanced Prostate Cancer Clinic: A
Guide for the Community Urologist
Basir U. Tareen, MD, Course Director; Gregory R. Hanson, MD and Raoul S. Concepcion, MD, Faculty

Introduction sipuleucel-T, which is infused back into nurse champion who will be in charge
the patient during a series of 3 infusions of scheduling and coordinating the leu-
Advanced prostate cancer treatment has (each 2 weeks apart), and uses the bodys kapheresis visits at the American Red
seen a dramatic shift in its treatment T cells to proliferate and fight disease. In Cross, the office infusions, and assisting
paradigm during the last 3 years. The with all the paperwork, prior authoriza-
the landmark IMPACT (Identification
advent of several new drugs has revo- tions and insurance issues.
of Men with a genetic predisposition
lutionized the urologists ability to treat
to ProstAte Cancer) trial 512 patients
this disease and prolong life. With these Oral Agents in Community Practice
were randomized to placebo vs treat-
new therapeutic modalities the commu-
ment.1 Patients treated with sipuleucel-T Oral therapies have been used in
nity urologist has the opportunity to be
had a 4.1-month survival advantage vs advanced prostate cancer for many
the primary physician in a disease that
placebo with a 22% relative risk reduc- years, albeit with limited success and
has historically been managed by our
tion in death. often with significant side effects. Recent-
field.
Establishing a clinic in your office ly 2 newer agents were approved for use
The Changing Landscape is not as complicated as one would in metastatic CRPC. These agents have
expect. The greatest task at the outset is seen rapid acceptance into the com-
Before 2010 the mainstay of advanced identifying appropriate patients, namely munity urologists arsenal due to their
prostate cancer treatment was hormon- those with asymptomatic or minimally efficacy in the pre-chemotherapy setting
al therapy and later cytotoxic chemo- symptomatic metastatic CRPC. When as well as their tolerability profiles.
therapy. In 2010 the U.S. Food and preparing to start an infusion clinic we Abiraterone is an oral therapy that
Drug Administration (FDA) approved recommend identifying several of these inhibits the CYP17A1 enzyme in the ste-
sipuleucel-T for use in patients with patients by flagging them in the months roid biosynthesis pathway. Abiraterone
metastatic castration resistant prostate before opening the infusion clinic or was first approved in April 2011 for
cancer (CRPC). This was soon followed doing a more formal data dive with your post-chemotherapy CRPC followed by
by the approval of abiraterone and electronic medical record (EMR) soft- approval for pre-chemotherapy use in
enzalutamide, 2 oral agents that have ware. December 2012. The use of abiraterone
both been shown to extend survival The simple setup includes a room you requires coadministration of prednisone
significantly. can make available in your office for 2 and metabolic monitoring, typically
In 2012 we saw the approval of radi- hours, a comfortable chair, an IV pole every 4 weeks.
um-223, the most recent therapy spe- and a nurse who can start an 18 gauge Enzalutamide is a second oral therapy
cifically for bone metastatic disease in IV. Most infusion clinics will consider that functions as an androgen receptor
prostate cancer. The addition of these having Demerol 15 mg on hand as antagonist. Current indications are for
new therapies has given urologists a well in case of a significant reaction. patients with metastatic CRPC with
newfound ability to continue point of From a financial standpoint sipuleucel- progression after chemotherapy, but it
care from diagnosis to the latest stages T can be a great benefit to the prac- has been used in the off-label setting in
of advanced disease. tice. Billing is done via an infusion patients who are not candidates for che-
code (96413 $500 per infusion) and motherapy. Approval of enzalutamide in
Establishing a Sipuleucel-T
the medication cost of $30,508 with the pre-chemotherapy setting is thought
Infusion Clinic
reimbursement of $32,070. Overall the to be imminent based on recent data pre-
Sipuleucel-T is a first of its kind drug net profit per infusion is approximately sented at AUA2014. Enzalutamide does
therapy that uses the bodys own den- $1,700 3 infusions or $5,100 per not require the concomitant use of ste-
dritic cells to target prostate cancer. patient treated. roids and the side effect profile is mild,
Leukapheresis is done and the patients We have found the key to a successful with seizures being the most concerning
own antigen presenting cells are exposed infusion clinic is identifying a physician (in fewer than 1% of patients).
to prostatic acid phosphatase. This com- champion whose role is to see all the Incorporating abiraterone and enzalu-
bination of prostatic acid phosphatase initial consults and to make sure the tamide into an advanced prostate cancer
and granulocyte-macrophage colony- patients are appropriately screened and clinic requires some initial setup. We
stimulating factor is the active agent in selected. Perhaps more important is a
Continued on page 5
AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 5
Course #011IC
Continued from page 4
found that limiting the use of these Ultimately studies such as the PRE- Radium-223 in Community Practice
medications to 2 to 3 physicians who DICT trial will allow us to define the
manage advanced prostate cancer was ideal frequency of imaging in men with In 2013 the FDA approved radium-223
an important element. In addition, we M0 CRPC. In the meantime, all patients for use in men with prostate cancer
presented our other partners with cheat with M0 CRPC should have baseline bone metastases. With this novel agent
sheets on these medications to deal with imaging done, and repeat imaging based the radium mimics calcium and tar-
any on call concerns. We also designed on a change in symptoms, PSA doubling gets osteoblastic bone metastases. The
followup order sets through an EMR time, or at a reasonable frequency rang- ALSYMPCA trial showed an overall
system to ensure that patients received ing from every 3 months to every year, survival of more than 3 months in men
appropriate laboratory followup and depending on the patient and clinical treated with radium-223 vs placebo.3
clinic appointments. suspicion. Currently this therapy is delivered by
These medications can be expensive, radiation oncologists or nuclear medi-
typically costing $6,000 to $7,000 a Establishing a Bone Health Clinic cine radiologists. Use of this therapy is
month. We have worked closely with again dependent on urologists having
A well-known result of long-term andro- appropriate imaging on patients with
patient support options through phar- gen deprivation is its effect on bone
maceutical companies to help patients CRPC so that when they convert from
health and subsequent osteoporosis. A M0 to M1 they can be appropriately
with co-pay assistance. Our initial expe- decrease in circulating levels of testoster-
rience also necessitated finding specialty considered for radium-223 when symp-
one leads to decreased levels of estrogen, tomatic bone metastases develop.
pharmacies that could consistently sup- increased osteoclasts, decreased osteo-
ply these medications for our patients. blasts and increased RANK Ligand pro- Summary
duction.2
Role of Imaging in Advanced As urologists we are the experts in pros-
All patients starting long-term andro-
Disease tate cancer, the providers who see this
gen deprivation therapy should have a
The role of imaging in detecting meta- baseline DEXA scan. In addition, it is disease beginning with the increased
static disease has become increasingly ideal to have an extended care provider PSA, to biopsy, and to all stages of
important as the newer therapies (abi- focus on educating patients regarding treatment. It naturally holds that even
raterone, enzalutamide, sipuleucel-T diet (calcium) and exercise, and also once the disease progresses to advanced
and radium-223) require the presence to discuss pharmacological options for stages, urologists should continue to pro-
of documented metastatic disease for maintenance of bone health. vide high quality continuity of care.
approved use. Historical models which Bisphosphonates are a well-known 1. Kantoff PW, Higano CS, Shore ND et al: Sipu-
suggested only those with a prostate spe- class of drugs which have been used leucel-T immunotherapy for castration-resistant
prostate cancer. N Engl J Med 2010; 363: 411.
cific antigen (PSA) greater than 20 ng/ for this indication, although not FDA 2. Lipton A, Uzzo R, Amato RJ et al: The science
ml would have metastatic disease have approved for cancer treatment induced and practice of bone health in oncology: manag-
been changing with the use of sodium bone loss. More recently urologists have ing bone loss and metastasis in patients with solid
tumors. J Natl Compr Canc Netw, suppl., 2009; 7:
fluoride positron emission tomography successfully used denosumab/Prolia/ S1.
(PET) computerized tomography (CT) XGEVA, which is a human monoclo- 3. Parker C, Nilsson S, Heinrich D et al: Alpha emit-
ter radium-223 and survival in metastatic prostate
and C-11 acetate choline PET CT, as nal antibody that binds RANK Ligand cancer. N Engl J Med 2013; 369: 213.
these are significantly more sensitive and reduces osteoclast activity.
than a standard technetium-99m bone
scan.
6 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS

COURSE #023IC

AUA Guideline: Castration Resistant Prostate Cancer


Update
Adam S. Kibel, MD and Michael S. Cookson, MD, MMHC, Course Co-Directors
In response to the rapidly changing the use of radium-223 dichloride for strate a clinically meaningful delay in
landscape in the management of castra- the treatment of patients with mCRPC, the development of metastasis, we must
tion resistant prostate cancer (CRPC), symptomatic bone metastases and no first do no harm. Patients should be
the AUA presented updated guidelines known visceral metastatic disease.8 This encouraged to enter clinical trials when
in an instructional course designed to approval and others anticipated in the available. Clinicians may also offer treat-
inform clinicians of the latest changes near future highlight the need for con- ment with first-generation antiandrogens
in evidence-based recommendations for tinuous periodic updating of the CRPC or first-generation androgen synthesis
the sequencing and treatment of castra- Guidelines to inform clinicians regard- inhibitors to select patients. Clinicians
tion resistant disease. ing the rapidly evolving management of should not offer systemic chemotherapy
Prostate cancer remains the second this disease state. or immunotherapy to patients with non-
leading cause of cancer death in men The CRPC guidelines were devel- metastatic CRPC outside of the context
in the United States with more than oped using 6 index patients who were of a clinical trial.
29,000 deaths from metastatic disease intended to represent the most common Index patient 2 is asymptomatic or has
in 2014 alone.1 While most patients scenarios encountered in clinical prac- minimal symptoms, with metastases and
with advanced prostate cancer respond tice. Accordingly, patients with CRPC no prior docetaxel. In this setting clinicians
initially to androgen deprivation therapy were categorized based on the presence should offer abiraterone + prednisone,
(ADT), ultimately the majority experi- or absence of metastases, degree and docetaxel or sipuleucel-T. Clinicians may
ence disease progression to castration severity of symptoms, overall perfor- offer first-generation antiandrogen ther-
resistance within 1 to 3 years. mance status, and whether they had apy, or first-generation androgen syn-
The treatment of men with metastatic received prior treatment with docetaxel thesis inhibitors or observation to index
CRPC (mCRPC) has changed signifi- chemotherapy. 2 patients who do not want or cannot
cantly during the last decade. Before Guideline statements for each of the have one of the standard therapies.
2004, once primary ADT failed, treat- index patients were rated as a standard, Finally, some patients may not wish to
ments were administered solely for pal- a recommendation, an option or an pursue any therapy and may wait for
liation. In landmark articles Tannock2 expert opinion based on the grading of the onset of symptoms to pursue treat-
and Petrylak3 et al demonstrated that the strength and quality of the evidence, ment.
docetaxel improved survival in patients as well as the panels assessment of the Index patient 3 is symptomatic, has
with mCRPC compared to mitoxan- benefits and harms of treatment. The metastases, has a good performance
trone. Since then 5 additional agents statements were also formatted into a status and has not previously received
(abiraterone, sipuleucel-T, cabazitaxel, user-friendly algorithm, available in a docetaxel. Clinicians should offer
enzalutamide and radium-223) that pocket guide and in a web based format. docetaxel chemotherapy and in this
have all shown a survival benefit have A summary of the CRPC guideline setting they may offer abiraterone +
been approved by the U.S. Food and statements for each index patient and prednisone. Clinicians may also offer
Drug Administration (FDA) on the basis respective statement were presented. ketoconazole + steroid, mitoxantrone
of randomized clinical trials.4-8 These Moreover, the guidelines were revised or radionuclide therapy to patients who
agents have been tested in multiple dis- to reflect newly approved therapies, do not want or cannot have one of the
ease states of CRPC to determine if or approval in new disease states and, standard therapies.
when patients might benefit from each lastly, the proper sequencing of agents. New to the CRPC Guideline this
treatment. Index patient 1 is asymptomatic year, for patients with symptomatic
At the AUA Annual Meeting we with an increasing prostate specific anti- bone metastases and no visceral metas-
presented an update of the AUA CRPC gen and no radiographic evidence of tases, clinicians should offer radium-223.
Guidelines. One of the main reasons for metastases. Clinicians should recom- Clinicians should not offer estramus-
the guidelines update is the rapid evolu- mend observation with continued ADT tine or sipuleucel-T to these index 3
tion of the field with the new treatments to those patients with nonmetastatic patients. While the PREVAIL trial has
that are becoming available. For exam- CRPC. Since all agents have potential demonstrated a survival benefit for
ple, after the 2013 AUA Annual Meet- side effects and no treatment has been enzalutamide in patients who have not
ing the FDA subsequently approved shown to extend survival or demon- received chemotherapy (index patients 2
Continued on page 7
AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 7
Course #023IC
Continued from page 6
and 3), these data were not published in may offer re-treatment with docetaxel to drogens. It is likely that the guidelines
time for the current update.9 We antici- patients who were benefitting at the time will have to be modified on an annual
pate the data will be reviewed formally of docetaxel discontinuation (due to or semiannual basis to keep urologists
by the panel and included in a future reversible side effects). New this year for abreast of this rapidly changing treat-
version of the guideline. patients with symptomatic bone metasta- ment landscape.
Index patient 4 is symptomatic with ses and no visceral metastases, clinicians 1. Siegel R, Ma J, Zou Z et al: Cancer statistics, 2014.
metastases, a poor performance status should offer radium-223. CA Cancer J Clin 2014; 64: 9.
and no prior docetaxel treatment. Cli- Index patient 6 is symptomatic, with 2. Tannock IF, de Wit R, Berry WR et al: Docetaxel
plus prednisone or mitoxantrone plus prednisone
nicians may offer treatment with abi- metastases, a poor performance status for advanced prostate cancer. N Engl J Med 2004;
raterone + prednisone to these patients. and prior docetaxel treatment. The goal 351: 1502.
3. Petrylak DP, Tangen CM, Hussain MH et al:
Clinicians may also offer ketoconazole of palliation is to prevent and relieve suf- Docetaxel and estramustine compared with mito-
+ steroid or radionuclide therapy to fering, and to support the best possible xantrone and prednisone for advanced refractory
prostate cancer. N Engl J Med 2004; 351: 1513.
patients who are unable or unwilling quality of life for the patient and family. 4. Ryan CJ, Smith MR, de Bono JS et al: Abiraterone
to receive abiraterone + prednisone. Palliative radiotherapy can be an option in metastatic prostate cancer without previous che-
motherapy. N Engl J Med 2013; 368: 138.
Clinicians may also offer docetaxel or to control bone pain in some patients. 5. Kantoff PW, Higano CS, Shore ND et al: Sipu-
mitoxantrone chemotherapy in select Clinicians should offer palliative care to leucel-T immunotherapy for castration-resistant
patients, specifically when performance these patients. Alternatively, for select prostate cancer. N Engl J Med 2010; 363: 411.
6. de Bono JS, Oudard S, Ozguroglu M et al: Predni-
status is directly related to the can- patients clinicians may offer treatment sone plus cabazitaxel or mitoxantrone for metastat-
cer. Clinicians may offer radium-223 to with abiraterone + prednisone, enzalu- ic castration-resistant prostate cancer progressing
after docetaxel treatment: a randomised open-label
select patients with symptomatic bone tamide, ketoconazole + steroid or radio- trial. Lancet 2010; 376: 1147.
metastases and without known visceral nuclide therapy. Clinicians should not 7. Scher HI, Fizazi K, Saad F et al: Increased survival
with enzalutamide in prostate cancer after chemo-
disease, specifically when performance offer systemic chemotherapy or immu- therapy. N Engl J Med 2012; 367: 1187.
status is directly related to symptoms of notherapy to these patients. 8. National Cancer Institute: FDA Approval for
Radium 223 Dichloride. Available at www.cancer.
bone metastases. Clinicians should not The guidelines also address bone gov/cancertopics/druginfo/fda-radium-223-dichlo-
offer sipuleucel-T to these patients. health, and state that clinicians should ride.
Index patient 5 is symptomatic with offer all patients with CRPC preven- 9. Beer TM, Armstrong AJ, Rathkopf DE et al:
Enzalutamide in metastatic prostate cancer before
metastases, a good performance status tive treatment (eg supplemental calci- chemotherapy. N Engl J Med 2014; 371: 424.
and a history of docetaxel use. Clini- um, vitamin D) to reduce the risk of 10. Bischoff-Ferrari HA, Willett WC, Wong JB et al:
Fracture prevention with vitamin D supplementa-
cians should offer treatment with abi- fractures and skeletal related events.10 tion: a meta-analysis of randomized controlled
raterone + prednisone, cabazitaxel or Clinicians may choose denosumab or trials. JAMA 2005; 293: 2257.
11. Saad F, Gleason DM, Murray R et al: Long-term
enzalutamide to these patients. If the zoledronic acid when selecting a preven- efficacy of zoledronic acid for the prevention of
patient received abiraterone + predni- tive treatment for skeletal related events skeletal complications in patients with metastatic
hormone-refractory prostate cancer. J Natl Cancer
sone before docetaxel chemotherapy, in patients with mCRPC with bony Inst 2004; 96: 879.
he should be offered cabazitaxel or metastases.11, 12 12. Fizazi K, Carducci M, Smith M et al: Denosumab
enzalutamide. Clinicians may offer keto- The treatment of CRPC is undergo- versus zoledronic acid for treatment of bone
metastases in men with castration-resistant prostate
conazole + steroid to these patients if ing a rapid evolution with multiple new cancer: a randomised, double-blind study. Lancet
abiraterone + prednisone, cabazitaxel or agents on the horizon, from immune 2011; 377: 813.
enzalutamide are unavailable. Clinicians modulators to vaccines to novel antian-
8 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS

COURSE #051IC

Managing Metastatic Prostate Cancer in Your


Urology Practice: Coding and Science
K.C. Balaji, MD, Course Director and Ronald L. Davis, III, MD, MBA, FACS, Faculty
During the last decade several prospec- day. Seizures were reported in 0.9% of tumors demonstrated that zoledronic
tive, randomized, phase III clinical trials patients. A more recent PREVAIL study acid decreased skeletal related events,
demonstrated improvement in overall also showed overall improvement in with 38% in the 4 mg arm and 35% in
survival in patients with castration resis- patients with CRPC given enzalutamide the 4/8 mg arm vs 44% in the placebo
tant prostate contrast (CRPC) by a before chemotherapy.7 arm.12 Two large phase III studies evalu-
variety of agents used concurrently with Radium-223 dichloride, an intrave- ated 120 mg subcutaneous denosumab
androgen deprivation therapy (ADT).1 nously administered radionuclide, was (XGEVA) every 4 weeks in patients
Sipuleucel-T (Provenge) was the first approved for the treatment of patients with nonmetastatic CRPC. Compared
cancer vaccine approved for human with CRPC and symptomatic bone to placebo, denosumab significantly
use based on 4.1 months improvement metastases.8 Radium-223 dichloride is increased bone metastasis-free survival
in overall survival in patients with an alpha particle emitting radiotherapeu- by a median of 4.2 months and time to
asymptomatic or minimally symptom- tic drug that mimics calcium and forms first bone metastasis by 3.7 months.13 In
atic CRPC treated with 3 doses of sip- complexes with hydroxyapatite at areas a head-to-head comparison study with
uleucel-T intravenous infusion every 2 of increased bone turnover such as bone zoledronic acid, denosumab significantly
weeks.2 Three leukapheresis procedures metastases. increased the time to first metastasis to
can be arranged at a local blood bank The ALSYMPCA study demon- 20.7 vs 17.1 months in the zoledronic
and, after processing in a central facility, strated improvement in overall survival acid arm.14 Osteonecrosis of the jaw
they are infused into the patient in the by 3.8 months in the treatment arm occurred in less than 5% of patients.
office 3 days later. Patients may need compared to placebo, and treatment CPT administration codes and
to be premedicated with acetaminophen also delayed the time to first symptom- HCPCS (Healthcare Common Proce-
and antihistamine. atic skeletal related event. The isotope is dure Coding System) codes for these
Abiraterone is an oral antiandrogen administered by slow intravenous injec- drugs are listed in the Appendix. ICD-9-
that inhibits CYP17A1. Oral abiraterone tion over 1 minute every 4 weeks for 6 CM codes will eventually become obso-
improved radiographic progression-free doses. Because of the approximately 2% lete as ICD-10-CM codes are adopted
survival by 8.2 months and overall sur- risk of bone marrow failure a complete in 2015.
vival compared to placebo in patients blood count is recommended before
Administration HCPCS
with CRPC before chemotherapy,3 each injection.
Code
and overall survival in patients who Because patients continue to remain
ZOMETA 96365 1st hour J3487
have undergone chemotherapy by 3.9 on ADT, efforts to preserve or improve
then 96366 for Q2051-
months.4 Abiraterone can be adminis- bone health by supplementation with Medicare
each additional
tered as 1 gm (250 mg tablets 4) once oral calcium and vitamin D are common hour
a day at least 1 to 2 hours after a meal clinical practice, although direct evidence
XGEVA 96401 J0897
along with 5 mg prednisone by mouth of benefit is lacking.9 Denosumab 60 mg
twice a day. A complete metabolic panel (Prolia), a RANK Ligand inhibitor, FIRMAGON 96402 J9155
evaluation once every 4 to 6 weeks may administered subcutaneously once in 6 VANTAS 11981 J9225
be used to monitor the patients. months, or zoledronic acid (Reclast), a Zoladex 96402 J9202
Enzalutamide (Xtandi) is a second- bisphosphonate that inhibits osteoclastic Lupron 96401 J9217
generation androgen receptor (AR) activity, administered as a 4 mg intra- Eligard 96401 J9217
antagonist that binds and prevents the venous infusion annually in patients Provenge 96365 Q2043
translocation of AR to the nucleus.5 with prostate cancer on ADT, improved
Enzalutamide improved survival by 4.8 bone mineral density by several points A sample reimbursement and annual
months compared to placebo in patients compared to placebo.10, 11 net profit calculation for varying doses
with CRPC treated with chemothera- A phase III, double-blind, randomized of Lupron is shown in the table using
py.6 Enzalutamide is administered orally trial comparing intravenous zoledronic North Carolina Medicare reimburse-
as 160 mg (40 mg tablets 4) once a acid (ZOMETA) in patients with solid ment figures.

Continued on page 9
AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 9
Course #051IC
Continued from page 8

Clin Oncol (R Coll Radiol) 2013; 25: 406. denosumab on bone mineral density in men
Lupron Cost Reim- Annual 2. Kantoff PW, Higano CS, Shore ND et al: Sipu- receiving androgen deprivation therapy for pros-
Dose (US $) burse- Net leucel-T immunotherapy for castration-resistant tate cancer. J Urol 2009; 182: 2670.
prostate cancer. N Engl J Med 2010; 363: 411. 11. Michaelson MD, Kaufman DS, Lee H et al:
(mg) ment Profit 3. Ryan CJ, Smith MR, de Bono JS et al: Abiraterone Randomized controlled trial of annual zoledronic
(US $) (US $) in metastatic prostate cancer without previous che- acid to prevent gonadotropin-releasing hormone
motherapy. N Engl J Med 2013; 368: 138. agonist-induced bone loss in men with prostate
7.5 130 273.37 1,720.44 4. de Bono JS, Logothetis CJ, Molina A et al: Abi- cancer. J Clin Oncol 2007; 25: 1038.
22.5 390 679.03 1,156.12 raterone and increased survival in metastatic pros- 12. Rosen LS, Gordon D, Tchekmedyian S et al:
tate cancer. N Engl J Med 2011; 364: 1995. Zoledronic acid versus placebo in the treatment
30 520 881.86 1,085.58 5. Tran C, Ouk S, Clegg NJ et al: Development of a of skeletal metastases in patients with lung cancer
45 780 1,287.52 1,015.04 second-generation antiandrogen for treatment of and other solid tumors: a phase III, double-blind,
advanced prostate cancer. Science 2009; 324: 787. randomized trialthe Zoledronic Acid Lung Can-
This course highlighted the need 6. Scher HI, Fizazi K, Saad F et al: Increased survival cer and Other Solid Tumors Study Group. J Clin
with enzalutamide in prostate cancer after chemo- Oncol 2003; 21: 3150.
and the methods for urologists to con- therapy. N Engl J Med 2012; 367: 1187. 13. Smith MR, Saad F, Coleman R et al: Denosumab
tinue providing multidisciplinary care 7. Beer TM, Armstrong AJ, Rathkopf DE et al: and bone-metastasis-free survival in men with cas-
Enzalutamide in metastatic prostate cancer before tration-resistant prostate cancer: results of a phase
for patients with CRPC. The business chemotherapy. N Engl J Med 2014; 371: 424. 3, randomised, placebo-controlled trial. Lancet
aspects also showcased opportunities 8. Parker C, Nilsson S, Heinrich D et al: Alpha emit- 2012; 379: 39.
ter radium-223 and survival in metastatic prostate 14. Fizazi K, Carducci M, Smith M et al: Denosumab
and challenges in the field. cancer. N Engl J Med 2013; 369: 213. versus zoledronic acid for treatment of bone
9. Datta M and Schwartz GG: Calcium and vitamin metastases in men with castration-resistant prostate
1. Loblaw DA, Walker-Dilks C, Winquist E et al: D supplementation during androgen deprivation cancer: a randomised, double-blind study. Lancet
Systemic therapy in men with metastatic castra- therapy for prostate cancer: a critical review. 2011; 377: 813.
tion-resistant prostate cancer: a systematic review. Oncologist 2012; 17: 1171.
10. Smith MR, Saad F, Egerdie B et al: Effects of

COURSE #078IC
Sequencing Novel Agents in Advanced Prostate Can-
cer 2014: Case Based Key Knowledge for Urologists
Judd W. Moul, MD, FACS, Course Director; J. Kellogg Parsons, MD and P. George Febbo, MD, Faculty
It is an exciting time for physicians who tant drivers of the disease.3, 4 Although oncologists, as well as nurses and other
care for men with advanced prostate ADT has long been known to improve allied health professionals.
cancer and more importantly, it is a survival and offers an excellent progno- We have built our field on the prem-
more optimistic time for patients and sis, a significant number of patients lose ise that urology is a surgical and a
their families. Since 2010, 6 new agents responsiveness to surgical or medical medical specialty, and this blending of
have been approved by the Food and castration (ie castration resistant prostate disciplines is what has drawn many of
Drug Administration (FDA) for castra- cancer) with time. As a result, CRPC us to the specialty since its inception. As
tion resistant prostate cancer (CRPC), is associated with significant morbid- more consolidation takes place in the
including sipuleucel-T (Provenge), ity and mortality, and painful bone academic and private sectors, more large
cabazitaxel (Jevtana), abiraterone ace- metastases develop in more than 85% groups are designating subspecialty care.
tate (Zytiga), denosumab (XGEVA), of patients. It is critical for at least one partner to
enzalutamide (Xtandi) and radium-223 While the treatment goals of CRPC remain at the forefront of advanced
(Xofigo).1 With the exception of caba- include improving survival and miti- prostate cancer and to offer or assist in
zitaxel, these agents are commonly gating disease progression, these aims the offering of these new agents.
available for urologists and oncologists must be balanced with patient quality Of the 6 new medications 5
to prescribe. The new oral hormonal of life.5 CRPC is a heterogeneous dis- (sipuleucel-T, abiraterone, enzalutamide,
agents are particularly appealing for ease in which patients generally present denosumab, radium-223) are squarely
urological use since urologists have been with increasing prostate specific antigen in the realm of urology, being oral
at the forefront of androgen deprivation (PSA). These patients may have non- agents or parenteral agents under our
therapy (ADT) for more than 75 years.2 metastatic disease, asymptomatic meta- prescribing purview. Furthermore, many
Prostate cancer growth is initially static disease or symptomatic metastatic of us also embrace the multidisciplinary
highly dependent on circulating andro- disease. Therefore, current treatment management of prostate cancer and need
gens. However, in patients with dis- options for CRPC require a multidis- to be familiar with these agents to help
ease progression, androgen independent ciplinary approach that involves urolo- cement our expertise and relationship
pathways become increasingly impor- gists, radiation oncologists and medical with our medical oncology colleagues
Continued on page 10
10 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS
Course #078IC
Continued from page 9

and partners. It is critical for us to know the jaw, while others believe that high course of CRPC when their immune
these agents to be able to contribute to risk men with new M1 bony disease system is the most robust. It is important
our patients best interest and care. deserve consideration for denosumab. to select patients for sipuleucel-T who
In this 2014 course we used a case Since denosumab is given as a subcu- have a 3 to 6-month window or longer
based and audience response system to taneous injection, does not affect renal before they will need chemotherapy or
create an interactive educational session function and does not require dose other treatment that might interfere with
on these new agents that urologists may adjustment for renal insufficiency, it is the immune system.
use in patients with CRPC in 2014. becoming more popular for urologists Most recently, Schellhammer et al
to administer. Since the drug can cause examined the response to sipuleucel-T
Degarelix hypocalcemia, urologists must check the by patient PSA at the start of this novel
Many contemporary patients with high serum calcium level before ordering treatment.7 In men who had a PSA in
risk M1 disease are initiated on ADT denosumab, and must ask patients to the lowest quartile of the IMPACT trial
with the pure gonadotropin-releasing take vitamin D and calcium supplements (less than 22 ng/ml), there was a more
hormone antagonist degarelix (FIRMA- while on denosumab. robust overall survival (OS) advantage
GON). This drug was approved by Finally, XGEVA is not approved to for sipuleucel-T. Specifically the esti-
the FDA in December 2008 and has treat men who do not have bone metas- mated 3-year survival for patients on
the advantage of lacking the testos- tases. However, there is a lower dose sipuleucel-T was 62.6% vs 41.6% for
terone surge or flare. We discussed of denosumab that is FDA approved to men randomized to the control arm
this agent and the latest clinical trial prevent bone loss (osteopenia and osteo- of the study. Since most patients with
results.6 Degarelix is commonly used as porosis) in men without bone metastases CRPC who have these lower PSA val-
a starter ADT agent because of the rapid who are taking LHRH for prostate can- ues are in the care of urologists, these lat-
response, lack of testosterone surge and cer. This 60 mg denosumab formulation est data place sipuleucel-T use squarely
lack of clinical flare. is called Prolia and it is given subcuta- with urology practices if they choose to
In the setting of suboptimal testos- neously twice yearly or every 6 months. administer this therapy to their patients.
terone suppression when using a lutein-
Sipuleucel-T Abiraterone and Enzalutamide
izing hormone-releasing hormone
(LHRH) agonist, it is also now common Sipuleucel-T is a novel immunotherapy Abiraterone is a 17-lyase and 17-hydro-
to switch a patient to degarelix to see if that is FDA approved for asymptomatic lase inhibitor, and blocks key pathways
it will decrease testosterone more effec- or minimally symptomatic M1 CRPC. in the steroid synthesis pathways lead-
tively. Sometimes a patient will not have This patient specific agent involves 3 ing to androgen production. Low dose
true CRPC because testosterone is not plasmapheresis procedures followed by prednisone (7.5 to 10 mg daily is a
completely suppressed with the LHRH sipuleucel-T administration a few days physiological dose) is recommended to
agonist, and switching to degarelix will later. The course of treatment is gener- be administered with abiraterone to help
more effectively suppress testosterone ally conducted during approximately limit overproduction of aldosterone, and
and delay the onset of CRPC. 4 weeks. This is an ideal treatment for the side effects of hypertension, hypoka-
urologists and staff to administer since lemia and fluid retention.
Denosumab patients are typically under the care The current FDA approved indica-
Denosumab is prescribed at a dose of urologists during this course of the tion for abiraterone is either before
of 120 mg (XGEVA), subcutaneous- disease and the treatment has few side or after the patient has experienced
ly, monthly, to prevent skeletal related effects. progression on docetaxel based sys-
events common in the later course of The ideal patient for sipuleucel-T will temic chemotherapy. For most patients
advanced metastatic prostate cancer. have documented clinical metastases and treated in 2014 the popular sequencing
Denosumab can be prescribed at the ini- will have an increasing PSA while on of novel agents would place the use of
tial diagnosis of bone metastatic prostate continuous hormonal therapy. He will abiraterone before systemic chemothera-
cancer or it can be withheld until the not have bone or cancer pain requiring py. The dose for abiraterone is 1,000 mg
patient experiences CRPC. In clinical narcotic pain medications. He must have orally given once daily along with a low
trials the patients all had CRPC, but a castrate testosterone level (less than 50 dose steroid (prednisone 5 mg orally,
the FDA approved a broadened indica- ng/dl) and meet the other on-label indi- twice daily).
tion requiring bony metastases but not cations. It is now estimated that more Enzalutamide is another novel oral
requiring the patient to have CRPC. than 99% of insured patients in the U.S. hormonal therapy agent that was FDA
Some clinicians believe we should will be covered for this treatment. Since approved in 2012 to treat men with
only use this agent in CRPC due to this is an active immunotherapy, ideally progression after docetaxel based che-
the cumulative risk of osteonecrosis of patients should be treated early in the motherapy. The drug is taken orally

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AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 11
Course #078IC
Continued from page 10

at a dose of 160 mg daily. Enzalu- FDA approved in the pre-chemother- ANSWER: Currently we do not
tamide is a novel oral antiandrogen that apy setting, although a 2013 company know. However, several large tri-
is more potent than prior generation press release reported a radiographic als should answer this question. The
agents such as flutamide, nilutamide and overall survival benefit, prompting PLATO trial is a phase 4, randomized
and bicalutamide. As of August 2014 the data safety monitoring committee to placebo controlled trial with 500 patients
it was only FDA approved in the post- recommend an un-blinding of trial par- planned comparing enzalutamide + abi-
chemotherapy clinical setting. However, ticipants with crossover to active drug in raterone + prednisone to abiraterone +
it also has activity in earlier stage disease the placebo arm. prednisone with progression-free sur-
and will likely soon be approved for use At the 2014 Genitourinary Cancers vival as the primary end point. In addi-
before chemotherapy. At that time it will Symposium the PREVAIL data were tion, the ALLIANCE trial will enroll
be more commonly prescribed by urolo- presented, showing a 2.2-month over- 1,224 chemotherapy nave patients to
gists. all survival benefit of enzalutamide vs enzalutamide alone vs enzalutamide +
Unlike abiraterone, enzalutamide placebo (32.4 vs 30.2 months) with a abiraterone + prednisone. The primary
does not have to be given with low dose median followup of 22.3 months and end point is overall survival with an esti-
prednisone. However, enzalutamide with 516 deaths (30% of the study popu- mated completion in 2019.
does have an approximate 1% risk of lation). This OS difference was statisti- 3. Once one drug is used, will there
seizures associated with its use. While cally significant.9 The table summarizes be a response to the other drug?
both novel oral hormonal agents are the drugs for CRPC and their overall ANSWER: We are starting to get
active in advanced prostate cancer, their survival benefit. some preliminary data that the response
benefit is not necessarily synergistic or There are many unanswered ques- to the second drug (whether abiraterone
cumulative. Patients will likely have an tions that we discussed during the or enzalutamide) is much shorter/less
initial robust response to either agent, course, primarily regarding the use and robust. PSA responses range from 8%
but switching to the other agent will like- sequencing of these novel oral hormonal to 45% and time to progression ranges
ly not result in a sustained response and agents. from 2.7 to 4.9 months.
the response to the second used agent 1. For early pre-chemotherapy meta- 4. In the era of health care reform and
may be more short-lived. Once both static CRPC how should the novel oral potentially fixed reimbursement for epi-
agents (abiraterone and enzalutamide) hormonal agents be sequenced? Putting sodes of care, how will these novel (and
are FDA approved in the pre-chemo- this another way, once enzalutamide expensive) therapies fare?
therapy CRPC setting, urologists will is (likely) FDA approved in the pre- ANSWER: This is a great question.
have an important sequencing choice in chemotherapy space, should we use We do not know, but worry about this
determining which of these 2 agents to abiraterone or enzalutamide first? as taxpayers and citizens. We remember
use first. ANSWER: The correct academic in 1989 when urologists were concerned
In the post-docetaxel setting the clini- answer is that we do not know. There about the then new concept of com-
cal and survival benefits of abiraterone are some patients who may be better bined hormonal therapy with flutamide
and enzalutamide are comparable, and suited for one vs the other. For example, and the $500 to $800 a month price
crossover resistance limits the efficacy of the diabetic patient may be better suited tag. Now we are in a whole new era of
each agent when the other is used first. for enzalutamide to avoid low dose costs. However, for our patients we are
In the pre-chemotherapy setting abi- steroids as opposed to the patient with also excited to have more effective treat-
raterone was FDA approved based on a seizure disorder who would be better ments to offer.
an approximate 8-month radiographic suited for abiraterone. It is unclear how 5. How will use of these new oral
progression-free survival benefit and a to use the overall survival difference (5.2 agents impact the use and efficacy of sys-
5.2-month increase in median OS (35.3 vs 2.2 months), if at all, to make initial temic chemotherapy such as docetaxel
months with abiraterone + prednisone treatment decisions. The PREVAIL trial and/or cabazitaxel?
vs 30.1 months with placebo + predni- had about 12% of patients with visceral ANSWER: Data from PREVAIL
sone). This translated to a 20% reduc- metastases vs none in COU-AA-302, show that chemotherapy can be delayed
tion in the risk of death (HR 0.792; 95% and PREVAIL occurred later, when from 10.8 months with placebo to 28
CI 0.655, 0.956; p=0.0151). more men received post-trial novel sur- months with enzalutamide (17.2 month
Interestingly this 5.2-month OS bene- vival enhancing agents. difference). In COU-AA-302 the delay
fit was not technically statistically signifi- 2. Are these 2 novel oral hormonal to chemotherapy in the prednisone +
cant based on the trial design of examin- agents synergistic? In other words, will placebo arm was 16.8 vs 26.5 months
ing the survival data multiple times.8 As we see a day when both are used with abiraterone + prednisone. Thus,
previously noted enzalutamide is not yet together? we know that chemotherapy will be

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12 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS
Course #078IC
Continued from page 11
delayed. However, it remains unclear 50 kBq (1.35 microcurie) per kg body 3. Cookson MS, Roth BJ, Dahm P et al: Castration-
resistant prostate cancer: AUA Guideline. J Urol
if chemotherapy will be less effective weight, given at 4-week intervals for 6 2013; 190: 429.
if used after the first line of novel oral injections. 4. Heidenreich A, Bastian PJ, Bellmunt J et al: EAU
guidelines on prostate cancer. Part II: Treatment
therapy. One concern is that urologists Urologists may be familiar with earli- of advanced, relapsing, and castration-resistant
may wait too long and miss a window of er generation radiopharmaceuticals such prostate cancer. Eur Urol 2014; 65: 467.
5. Moul JW and Dawson N: Quality of life associ-
opportunity for the effective use of che- as strontium but radium-223 is different. ated with treatment of castration-resistant prostate
motherapy. While we strongly believe It is alpha particle based and does not cancer: a review of the literature. Cancer Invest
that urologists can and should use the affect the bone marrow to the degree 2012; 30: 1.
6. Crawford ED, Shore ND, Moul JW et al: Long-
new agents, we also believe in a multi- of older agents. Thus, radium-223 is term tolerability and efficacy of degarelix: 5-year
disciplinary approach, and encourage much less likely to cause serious bone results from a phase III extension trial with a
1-arm crossover from leuprolide to degarelix.
urologists to work with oncologists to marrow toxicity with low white blood Urology 2014; 83: 1122.
avoid missed opportunities for optimal cell counts. In addition, the use of radi- 7. Schellhammer PF, Chodak G, Whitmore JB et al:
Lower baseline prostate-specific antigen is associ-
sequencing. um-223 was associated with an overall ated with a greater overall survival benefit from
survival benefit,10 whereas the older sipuleucel-T in the Immunotherapy for Prostate
Radium-223 radiopharmaceuticals were never prov- Adenocarcinoma Treatment (IMPACT) trial.
Urology 2013; 81: 1297.
The latest novel agent covered in the en to extend survival. Since radium-223 8. Rathkopf DE, Smith MR, de Bono JS et al: Updat-
has a unique mechanism of action, there ed interim efficacy analysis and long-term safety of
course was radium-223. This new agent abiraterone acetate in metastatic castration-resistant
is a parenteral radiopharmaceutical that might be a cumulative or synergistic prostate cancer patients without prior chemothera-
can be ordered by urologists and pro- effect when combined with other novel py (COU-AA-302). Eur Urol 2014; Epub ahead of
print.
vided in a nuclear medicine or radiation agents such as abiraterone or enzalu- 9. Beer TM, Armstrong AJ, Rathkopf DE et al:
oncology department setting. It is an tamide. However, this phenomenon has Enzalutamide in metastatic prostate cancer before
chemotherapy. N Engl J Med 2014; 371: 424.
alpha emitting liquid radiation product yet to be proven. 10. Parker C, Nilsson S, Heinrich D et al: Alpha emit-
and it received FDA approval in May ter radium-223 and survival in metastatic prostate
1. George D and Moul JW: Emerging treatment cancer. N Engl J Med 2013; 369: 213.
2013. It is indicated for the treatment options for patients with castration-resistant pros-
of patients with CRPC, symptomatic tate cancer. Prostate 2012; 72: 338.
2. Moul JW, Evans CP, Gomella LG et al: Tradition-
bone metastases and no known visceral al approaches to androgen deprivation therapy.
metastatic disease. The dose regimen is Urology, suppl., 2011; 78: S485.

Overall Survival Benefit of Treatments for CRPC


Drug Trial Comparator Mos OS Benefit FDA Approval
Chemotherapy-nave:
Abiraterone acetate +
COU-AA-302 Placebo + prednisone 5.2 Dec 2012
prednisone
Sipuleucel-T IMPACT Placebo 4.1 Apr 2010
Radium-223 ALSYMPCA Placebo 3.6 May 2013
Enzalutamide PREVAIL Placebo 2.2 N/A
Post-chemotherapy:
Abiraterone acetate +
COU-AA-301 Placebo + prednisone 4.6 Apr 2011
prednisone
Enzalutamide AFFIRM Placebo 4.8 Aug 2012
Mitoxantrone +
Cabazitaxel + prednisone TROPIC 2.4 June 2010
prednisone
Mitoxantrone +
Docetaxel + prednisone TAX327 2.4 May 2004
prednisone
AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS 13

PLENARY SESSIONS

Take-Home Message: Prostate Cancer


Michael Gong, MD, Cleveland, Ohio, provided the audience with highlights of the AUA meeting on prostate cancer. The abstract numbers are indi-
cated in parentheses.
The 2014 AUA Annual Meeting focused sies including the Michigan Urological deprivation therapy trial with HR 0.44
on the detection of higher grade prostate Surgery Improvement Collaborative (PD27-10).
cancer highlighted by encouraging data (MUSIC), a self-reporting collaboration Furthermore, diabetic patients under-
from multiple biological markers and of urologists in Michigan that reported going radical prostatectomy had a high-
multiparametric magnetic resonance a 1% 30-day admission rate for post- er rate of biochemical recurrence than
imaging (MRI). prostate biopsy infections (PD2-01). those without diabetes (31% vs 13%)
Multiple studies addressed prostate However, the infection rate significantly (PD12-08). In this series metformin or
cancer detection and, more importantly, increased to 4% if AUA antibiotic pro- statin use in diabetic patients was associ-
the detection of higher risk prostate phylaxis guidelines were not followed. ated with a decreased rate of biochemical
cancer. Results were reported for the Increased post-biopsy infection rates recurrence (28% and 24%, respectively),
U.S. validation study of the 4Kscore may be due to increased antibiotic resis- and patients on metformin and statin
incorporating total, free and intact pros- tance. Routine rectal swab cultures of had a reduced biochemical recurrence
tate specific antigen (PSA) with human men on active surveillance revealed 24% rate of 15%, suggesting a synergistic
kallikrein 2 in more than 1,000 patients fluoroquinolone resistance with a 2.4 effect of the 2 medications.
(PI-06). The ROC for the 4Kscore of times higher rate in diabetic patients A proof of principle, basic science cor-
detecting Gleason score 7 or greater (PD31-08). ollary study demonstrated that castra-
disease in prostate biopsies was 0.855. There were 50 presentations on MRI tion resistant prostate cancer cells have
The results of a validation study and prostate cancer detection. In a single an over expression of HMG-CoAR
adding urinary TMPRSS2:ERG to the center series of more than 1,000 patients and decreased AMPK activity which
standard Prostate Cancer Prevention who underwent multiparametric MRI are downstream in the AKT pathway
Trial risk calculator and urinary PCA-3 followed by MRI-transrectal ultrasound (PD27-06). Statins block HMG-CoAR
were also reported (PD19-11). By add- fusion biopsy as well as standard 12-core and metformin increases AMPK activ-
ing urinary TMPRSS2:ERG the ROC biopsy, MRI directed biopsies more ity. The combination of simvastatin
improved from 0.739 to 0.761 for the frequently detected upgraded prostate and metformin synergistically inhibited
detection of prostate cancer and from cancers (Gleason grade 4+3 or greater) castration resistant prostate cancer cell
0.752 to 0.779 for the detection of high (OP3-04). For PSA greater than 5.4, growth in vitro and in vivo.
grade disease. 95% of MRI directed upgraded cancers In terms of treatment outcomes, lon-
The future of urinary markers may would be detected (MP67-04). ger term outcomes for high risk prostate
be in prostate cancer specific urinary vol- However, several limitations of MRI cancer after radical prostatectomy were
atiles. In a study of approximately 1,000 were also reported. Of patients without reported. In a series of 1,700 patients
patients, of whom 300 had a diagnosis suspicious MRI lesions who underwent with intermediate and high risk prostate
of prostate cancer, canines successfully radical prostatectomy 26% had disease cancer, 17% had biochemical recurrence
identified urine from patients with pros- upgraded to high grade cancer and 57% with a median time to recurrence of 3
tate cancer with near 100% accuracy, had tumors larger than 0.5 cc (PIV-01). years (PD34-07). Median time from bio-
suggesting prostate cancer specific vola- MRI missed high grade cancers in 26% chemical recurrence to metastasis was 3
tile organic compounds may be a useful of patients who underwent prostatec- years and median time from metastasis
new screening method (PD19-01). tomy (MP53-01). to death was 4 years.
Investigation of genomic markers for Continued compelling evidence of Moreover, in high risk patients if bio-
the prediction of more aggressive disease the protective effects of metformin and chemical recurrence was more than 36
continues to be robust. The cell cycle statins was also presented. In a Danish months after radical prostatectomy, the
progression score was demonstrated to registry study metformin users had a 10-year cause specific mortality was 19%
have a stronger predictive value for bio- decreased risk (OR 0.84) of prostate can- vs 4% if recurrence was in less than 36
chemical recurrence, metastatic disease cer detection (MP31-02). Statin use was months (OP3-06).
and disease specific mortality than PSA associated with a decreased risk (HR In patients with pN+ disease the medi-
or Gleason score (MP79-15, MP79-17, 0.33) of prostate cancer specific death an time to metastasis was 32 months and
MP79-19). in the Finnish Prostate Cancer Screen- 10-year cause specific survival was 70%
Several groups discussed the infec- ing Trial (PD31-03) and in a phase (PD34-05). Patients with Gleason 6 dis-
tious complications of prostate biop- 3 intermittent vs continuous androgen ease undergoing radical prostatectomy
Continued on page 14
14 AUA 2014 ORLANDO, FL ANNUAL MEETING HIGHLIGHTS
Plenary Session
Continued from page 13
had limited metastatic potential in 2 lance but subsequently underwent time to chemotherapy.
large series (PD34-09, MP78-10). radical prostatectomy had higher rates Subset analysis of the IMPACT and
There were 90 presentations on active of increased Gleason grade, locally ProACT immunotherapy trials evaluat-
surveillance. In the third interim update advanced disease and biochemical recur- ing immune responses to prostatic acid
of a series of 1,000 patients at a median rence, suggesting that African-American phosphatase (sipuleucel-T) revealed evi-
followup of 8 years, 60% remained men may need more stringent criteria dence of additional immune responses
on active surveillance, 40% underwent to be candidates for active surveillance to other prostate specific markers includ-
delayed therapy and only 3% had meta- (MP51-05, MP46-15). ing PSA, suggesting that there may
static disease with 2% dying of prostate In advanced disease provocative evi- be additional immunologic benefits and
cancer (PD14-03). dence was reported from the phase 3 that immune responsiveness to PSA pre-
Another large series of 1,000 patients PREVAIL trial comparing enzalutamide dicted increased overall survival (PD27-
with a shorter followup also reported a vs placebo in chemotherapy nave 04).
similar rate for delayed therapy (OP3- patients with newly diagnosed progres- These data provide new encouraging
03). The strongest predictor of progres- sion while on androgen deprivation results for patients with advanced dis-
sion was PSA density (HR 1.58), which therapy (PI-05). The trial was stopped ease and suggest that earlier treatment of
was more predictive in smaller prostates. given the improved outcomes in the advanced disease may have additional
African-American men who were enzalutamide arm with decreased rates outcome benefits.
initially candidates for active surveil- of progression and death and delayed

ABSTRACT HIGHLIGHT

FRII-13: History of Androgen Deprivation Approaches


for Prostate Cancer
Jason Phillips, Vassilis Siomos, Nicholas Westfall, McCabe Kenny, Joshua Spendlove, Thomas Pshak, Robert Larke, Kyle Rove and E. David Crawford,
Denver, CO

(Reprinted from J Urol, suppl., 2014; 191: e631)

Introduction and Objectives Scott then performed bilateral adrenalec- However, in the last five years, seven
tomy and hypophysectomy to eliminate new agents have been developed includ-
The therapeutic landscape for the man-
adrenal androgen production. Larger ing degarelix, sipuleucel-T, denosumab,
agement of advanced prostate cancer
studies were then undertaken to bet- abiraterone, cabazitaxel, enzalutamide,
is rapidly evolving. In the last five
ter assess systemic ADT on prostate and radium-223. The optimal timing
years seven new treatments have been
cancer. The VA Cooperative Urologic and use in combination has yet to be
brought to market. Current controversy
Research Group found that treating discovered.
exists regarding the optimal therapy for
patients with DES was as effective as
patients with metastatic prostate cancer. Conclusions
orchiectomy; however, side effects lim-
A thorough understanding of the his-
ited its use. It wasnt until 40 years later We are now in the golden age of drug
tory and evolution of androgen depriva-
that the first tolerated medical systemic development for metastatic prostate can-
tion therapy is essential for Urologists
therapy, leuprolide acetate, was FDA cer. We challenge Urologists to learn
using these agents.
approved for castrate resistant pros- about the history of these medications
Methods tate cancer. This pivotal therapy was and how they have shaped the current
based on the Nobel Prize winning work treatment landscape. New studies are
The literature was reviewed for seminal of Andrew Schally, who discovered pushing the use of these therapies earlier
articles in androgen deprivation therapy the structure of gonadotropin releas- in the treatment algorithm. Understand-
for prostate cancer. ing hormone. From that time up until ing the path to our current environment
2008, five notable therapies have been lends perspective for the evolution and
Results
brought to market including flutamide, future of androgen deprivation therapy
In 1941, Charles Huggins discovered strontium, mitoxantrone, zolendronic for prostate cancer.
that eliminating testosterone through acid and docetaxel. Of these, only one
castration could delay advanced pros- modern chemotherapy agent (docetaxel)
tate cancer. Huggins along with W.W. demonstrates a clear survival benefit.
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