AUANEWSassets.auanet.org/.../pdfs/auanews/AUA18-CRPC-Highlights.pdfdiagnosed with CRPC have metastatic disease. Of those patients without metas-tases, 33% can expect to develop them

AUANEWS| THE OFFICIAL NEWSMAGAZINE OF THE AMERICAN UROLOGICAL ASSOCIATION |

AmericanUrologicalAssociation

2018 ANNUAL MEETING HIGHLIGHTSAdvanced and Castration-Resistant Prostate CancerCourse #005ICChemotherapy and Immunotherapy Options for Genitourinary Malignancies: A Primer for the Advanced Practice Provider

Course #043ICNovel Agents and Concepts in the Manage-ment of Hormone Naïve and Castration-Resis-tant Prostate Cancer

Course #058ICManagement of Common Dilemmas in Pros-tate Cancer Diagnosis, Staging and Treatment

Course #063ICProstate Cancer Update

Course #074ICAUA Castration-Resistant Prostate Cancer (CRPC) Guidelines

Course #078ICManagement of Prostate Cancer: A Case Based Approach with Emphasis on Integrat-ing New Molecular Diagnostics into Clinical Practice

PresentationUrologic Care for the Advanced Practice Pro-vider: 2018 Prostate Cancer Update: Clinical Guidelines & Management

AUANews EditorManoj Monga, MD, FACS

PublisherAmerican Urological Association1000 Corporate BoulevardLinthicum, MD 21090

Copyright © 2018 by the American Urological AssociationNone of the contents may be reproduced in any form without prior written permission of the publisher. The opinions expressed in this publication are those of the speakers and do not necessarily reflect the opinions or recommendations of their affiliated institutions, the publisher, the American Urological Association or any other persons. Some articles in this publication may discuss unapproved or “off-label” uses of products. Any procedures, medications or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients’ conditions and of possible contraindications or dangers in use, review of any applicable manufacturers’ product information and comparison with the recommendations of the authorities.

AUA2018 ANNUAL MEETING HIGHLIGHTS

Advanced and Castration-Resistant Prostate Cancer

CME Credit

Independent educational grant support provided by:

• AbbVie

• Astellas and Pfizer Inc.

• Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC

• Sanofi Genzyme

AUA18CRPCHighlights.indd 1 9/24/18 12:43 PM


AUA2018 SAN FRANCISCO, CA ANNUAL MEETING HIGHLIGHTS 1

▼ Continued on page 2

Method of Participation

To claim CME credit/hours of participa-tion, the learner must read the overview of courses 005IC, 043IC, 058IC, 063IC, 074IC, 078IC, and Urologic Care for the Advanced Practice Provider: 2018 Prostate Cancer Update: Clinical Guide-lines & Management, passing with 80% accuracy, and submit the evaluation and credit request form by visiting AUAU.AUAnet.org/18HLPC. Estimated time to complete this activity: 1.25 hours Release Date: October 2018Expiration Date: October 31, 2019

Accreditation Statement

The American Urological Association (AUA) is accredited by the Accreditation Council for Continuing Medical Educa-tion (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™.

Content

This enduring material credit is valid only for content reformatted from courses 005IC, 043IC, 058IC, 063IC, 074IC, 078IC, and Urologic Care for the Advanced Practice Provider: 2018 Pros-tate Cancer Update: Clinical Guidelines & Management.

Statement of Need

There is a growing need for urologists to be able to effectively manage castra-tion resistant prostate cancer (CRPC). CRPC is defined clinically as a failure of castration or androgen ablation therapy to prevent a worsening of a patient's prostate cancer and is associated with advanced disease. Approximately 28% of patients with prostate cancer will advance to CRPC. The median age at diagnosis of CRPC is 77 years and, as might be expected, these patients often have comorbidities, the most common of which are hypertension, dyspnea and anemia. More than 84% of patients diagnosed with CRPC have metastatic disease. Of those patients without metas-tases, 33% can expect to develop them within 2 years. The median survival of patients with CRPC is 9 to 30 months (median 14 months).

Target Audience

Urologists, urologists in training and non-physician providers involved in urology.

Course 005IC: Chemotherapy and Immunotherapy Options for Geni-tourinary Malignancies: A Primer for the Advanced Practice Provider

Learning Objectives

At the conclusion of this CME activity, participants should be able to:• Describe the standard of care chemo-

therapy regimens for genitourinary malignancies

• Recognize newer immunotherapy options in the treatment of genitouri-nary malignancies

• Identify and manage the toxicities with relation to these agents

• Identify the survivorship issues sur-rounding patients on systemic treat-ments for genitourinary malignancies

Faculty

Costas D. Lallas, MD, FACS, Course DirectorVice Chair and Professor of UrologyThomas Jefferson University HospitalPhiladelphia, PADisclosures: Nothing to disclose

Anne E. Calvaresi, MSN, CRNPNurse Practitioner, Urologic OncologyThomas Jefferson UniversityPhiladelphia, PADisclosures: Nothing to disclose

Edouard J. Trabulsi, MD, FACSProfessor and Vice Chair, Department of UrologySidney Kimmel Medical College at Thomas Jefferson UniversityPhiladelphia, PADisclosures: Nothing to disclose

Course 043IC: Novel Agents and Concepts in the Management of Hormone Naïve and Castration-Resistant Prostate Cancer

Learning Objectives

At the conclusion of this CME activity, participants should be able to:• Diagnose CRPC and have a work-

ing 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 radiophar-maceutical agent radium-223 and its sequencing

• Review the new generation antian-drogen agent enzalutamide and its sequencing

2018 AUA Annual Meeting Highlights: Advanced and Castration-Resistant Prostate Cancer

C M E I N F O R M AT I O N


2 AUA2018 SAN FRANCISCO, CA ANNUAL MEETING HIGHLIGHTS

Faculty

Judd W. Moul, MD, FACS, Course DirectorProfessor of SurgeryDuke University Durham, NCDisclosures: Sanofi-Aventis: Health Pub-lishing, Meeting Participant or Lecturer; Dendreon: Consultant or Advisor, Meet-ing Participant or Lecturer; Theralogix: Consultant or Advisor; Ferring Phar-maceuticals Inc: Consultant or Advisor, Meeting Participant or Lecturer; Medi-vation-Astellas: Consultant or Advisor; Janssen-J and J: Consultant or Advisor, Meeting Participant or Lecturer; Myri-ad Genetics Inc: Consultant or Advisor, Meeting Participant or Lecturer; Genomic Health: Meeting Participant or Lecturer

Lawrence I. Karsh, MD, FACSDirector, Clinical Research DepartmentThe Urology Center of ColoradoDenver, CODisclosures: Astellas: Consultant or Advi-sor, Meeting Participant or Lecturer, Scientific Study or Trial; Dendreon: Con-sultant 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, Scientif-ic Study or Trial; Medivation: Consultant or Advisor, Meeting Participant or Lec-turer, Scientific Study or Trial; Genomic Health: Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial; Augmenix: Consultant or Advi-sor, Scientific Study or Trial; Precision Biopsy: Consultant or Advisor, Scien-tific Study or Trial; 3D Biopsy: Con-sultant or Advisor, Scientific Study or Trial; GenomeDx Biosciences: Consultant or Advisor, Scientific Study or Trial; Precision Med: Scientific Study or Trial; Spectrum Pharmaceuticals: Consultant or Advisor, Scientific Study or Trial; FKD: Scientific Study or Trial; Pfizer: Consul-tant or Advisor; Sanofi: Consultant or Advisor; AbbVie: Consultant or Advi-sor; AstraZeneca: Consultant or Advisor; Myriad Genetics: Consultant or Advisor,

Scientific Study or Trial; Swan Valley Medical: Consultant or Advisor, Invest-ment Interest; Amgen: Scientific Study or Trial; Heat Biologics: Scientific Study or Trial; MDxHealth: Scientific Study or Trial; Lawrence Karsh: Health Publish-ing, Consultant or Advisor, Meeting Participant or Lecturer, Scientific Study or Trial, Investment Interest

Christopher Sweeney, MBBSMedical OncologistDana-Farber Cancer InstituteBoston, MADisclosures: Sanofi: Consultant or Advi-sor, Scientific Study or Trial; Janssen: Consultant or Advisor, Scientific Study or Trial; Astellas: Consultant or Advi-sor, Scientific Study or Trial; Bayer: Consultant or Advisor, Scientific Study or Trial; Genentech-Roche: Consultant or Advisor, Scientific Study or Trial

Course 058IC: Management of Common Dilemmas in Prostate Cancer Diagnosis, Staging and Treatment

Learning Objectives

At the conclusion of this CME activity, participants should be able to:• Use shared decision making to test

men with prostate specific antigen (PSA), to decide whom to biopsy and how to biopsy

• Understand the pros and cons of different types of biopsy and how to select men for surveillance, surgery or external beam radiation therapy

• Determine the new therapies for advanced and metastatic cancer with androgen deprivation therapy, che-motherapy and immunotherapies

• Identify the roles of new staging positron emission tomography scans

Faculty

Gerald Andriole, Jr., MD, Course DirectorProfessor and Chief of Urologic Surgery Washington University School of Medi-cine St. Louis, MO

Disclosures: Augmenix: Consultant or Advisor, Other; Medivation: Scientific Study or Trial; Blue Earth Diagnostics: Sci-entific Study or Trial; Progenics: Scientific Study or Trial; Tolmar Pharmaceuticals: Consultant or Advisor; 3D Biopsy: Con-sultant or Advisor

Anthony D'Amico, MD, PhDChair and Chief, Genitourinary Radia-tion Oncology Dana-Farber Cancer Institute and Brigham and Women’s HospitalBoston, MADisclosures: Nothing to disclose

Adam Kibel, MDChief, Urologic Surgery, Brigham and Women’s HospitalChief, Urologic Surgery, Dana-Farber Cancer Institute Professor, Department of Surgery, Har-vard University Medical SchoolChairman, Harvard Urology Residency Program Co-Leader, Prostate Cancer Program, Dana-Farber/Harvard Cancer CenterBoston, MADisclosures: Profound: Consultant or Advisor; Janssen: Consultant or Advisor

Oliver Sartor, MDMedical Director, Tulane Cancer Cen-ter Professor, Tulane Medical SchoolNew Orleans, LADisclosures: Sanofi-Aventis: Consultant or Advisor, Meeting Participant or Lec-turer, Scientific Study or Trial; Johnson & Johnson: Consultant or Advisor, Sci-entific Study or Trial; Oncogenex: Consul-tant or Advisor; Bellicum: Consultant or Advisor ; Bayer: Consultant or Advisor, Scientific Study or Trial; Bristol-Myers Squibb: Consultant or Advisor; Astra-Zeneca: Consultant or Advisor; Squibb: Consultant or Advisor; Celgene: Consul-tant or Advisor; Dendreon: Consultant or Advisor; EMD Serono: Consultant or Advisor; Endocyte: Consultant or Advi-sor, Scientific Study or Trial; Innocrin: Consultant or Advisor, Scientific Study or Trial; NRG: Leadership Position; Bavarian-Nordic: Consultant or Advisor

CME Information▼ Continued from page 1




Eric H. Kim, MD, AuthorAssistant Professor, Urologic Surgery Washington University School of Medi-cineSt. Louis, MODisclosures: Nothing to disclose

Course 063IC: Prostate Cancer Update

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 chang-ing their practice based on the new information

Faculty

William J. Catalona, MD, Course DirectorProfessor, Department of UrologyDirector, Clinical Prostate Cancer Pro-gramNorthwestern University Chicago, ILDisclosures: Beckman Coulter Incorporated: Consultant or Advisor, Meeting Par-ticipant or Lecturer, Scientific Study or Trial; deCODE Genetics: Consultant or Advisor, Meeting Participant or Lec-turer, Scientific Study or Trial; Nano-sphere: Consultant or Advisor; OHMX: Consultant or Advisor, Scientific Study or Trial, Owner, Product Development

Douglas M. Dahl, MD, FACSChief, Division of Urologic OncologyAssociate Professor of UrologyHarvard Medical School Boston, MADisclosures: Nothing to disclose

Stanley L. Liauw, MDAssociate Professor, Radiation OncologyUniversity of ChicagoChicago, IL

Disclosures: Nothing to disclose

Stacy Loeb, MD, MScAssistant Professor, Department of Urology and Population HealthNew York UniversityNew York, NYDisclosures: Lilly: Consultant or Advisor

Robert B. Nadler, MDProfessor, Department of UrologyNorthwestern University Chicago, ILDisclosures: Allena: Scientific Study or Trial

Russell Szmulewitz, MDAssistant Professor of Medicine, Section of Hematology/OncologyUniversity of ChicagoChicago, IL Disclosures: Pfizer: Consultant or Advi-sor; Genentech: Scientific Study or Trial; Exelixis: Consultant or Advisor; Abbvie: Scientific Study or Trial; Incyte: Scientific Study or Trial; Astellas: Scientific Study or Trial

Course 074IC: AUA Castration-Resistant Prostate Cancer (CRPC) Guidelines

Learning Objectives

At the conclusion of this CME activity, participants should be able to:• Identify the active agents and their

mechanism of action in the manage-ment of metastatic castration resis-tant prostate cancer (mCRPC)

• Analyze the evidence and outcomes on the treatment of CRPC as out-lined in the AUA guidelines and subsequent amendments

• Improve diagnostic and therapeutic decision making processes by illus-trating the application of these guide-lines in urological practice

• Understand the sequencing and indications for active treatment with approved agents in the management of mCRPC

Faculty

Michael S. Cookson, MD, MMHC,

Course DirectorProfessor and Chair, Department of UrologyUniversity of OklahomaOklahoma City, OKDisclosures: TesoRx Pharma LLC: Con-sultant or Advisor; MDx Health: Consul-tant or Advisor

David F. Jarrard, MDProfessor and Vice Chair, UrologyUniversity of WisconsinAssociate Director, UW Carbone Can-cer CenterMadison, WIDisclosures: Gregor Diagnostics: Consul-tant or Advisor

Adam S. Kibel, MDChief, Urologic Surgery, Brigham and Women’s HospitalChief, Urologic Surgery, Dana-Farber Cancer Institute Professor, Department of Surgery, Har-vard University Medical SchoolChairman, Harvard Urology Residency Program Co-Leader, Prostate Cancer Program, Dana-Farber/Harvard Cancer CenterBoston, MADisclosures: Profound: Consultant or Advisor; Janssen: Consultant or Advisor

Course 078IC: Management of Prostate Cancer: A Case Based Approach with Emphasis on Inte-grating New Molecular Diagnostics into Clinical Practice

Learning Objectives

At the conclusion of this CME activity, participants should be able to:• Design appropriate screening strate-

gies based on individual demograph-ics, risk factors and PSA history, and incorporate new biomarkers into routine clinical practice

• Distinguish and understand the use of new molecular and genomic based tests for decisions on initial and re-biopsy, and choosing and fol-lowing men on surveillance

• Appraise the role of surveillance, focal therapy, surgery, and vari-






ous forms of radiation therapy in patients with low and intermediate risk disease, including adjuvant and salvage radiation

• Review the role of surgery in the multimodality treatment of men presenting with oligometastatic dis-ease

• Describe new therapeutic agents for the management of castrate resis-tant disease and outline a coherent strategy for their use

Faculty

Eric A. Klein, MD, Course DirectorChair, Glickman Urological and Kid-ney InstituteProfessor of Surgery, Lerner College of MedicineCleveland Clinic Cleveland, OHDisclosures: Nothing to disclose

Andrew J. Stephenson, MD Director, Center of Urologic Oncology Cleveland Clinic Cleveland, OH Disclosures: Genomic Health: Consultant or Advisor, Meeting Participant or Lec-turer

Urologic Care for the Advanced Practice Provider: 2018 Prostate Cancer Update: Clinical Guidelines & Management

Learning Objectives

At the conclusion of this CME activity, participants should be able to:• Review the latest guidelines from

the AUA (ASTRO/SUO) for local-ized prostate cancer

• Identify when to use biomarkers and magnetic resonance imaging

• Describe high intensity focused ultrasound as a primary form of treatment

• Discuss the latest update on clinical trials

Faculty

Heather Schultz, RN, MSN, NP-C,

Course Co-DirectorNurse PractitionerDepartment of Urology, University of North Carolina at Chapel Hill Chapel Hill, NCDisclosures: SUNA: Meeting Partici-pant or Lecturer

Kenneth Mitchell, MPAS, PA-C, Course Co-DirectorPhysician AssistantMeharry Medical CollegeNashville, TNDisclosures: Nothing to disclose

Daniel Park, PA, MHADirector, Clinical Operations USC Institute of UrologyLos Angeles, CADisclosures: Nothing to disclose

Planners

Manoj Monga, MD, FACSDirector, Center for Endourology & Stone DiseaseCleveland ClinicCleveland, OHDisclosures: Fortec: Other

Victor W. Nitti, MDProfessor, Department of UrologyProfessor, Department of Obstetrics and GynecologyDirector, Female Pelvic Medicine and Reconstructive SurgeryVice Chair, Department of UrologyNew York University Langone Medi-cal CenterNew York, NYDisclosures: Astellas: Health Publish-ing, Scientific Study or Trial; Aller-gan: Health Publishing, Scientific Study or Trial; Medtronic: Scientific Study or Trial; Serenity Pharmeuticals: Investment Interest

Michael Abern, MDAssistant Professor, UrologyDirector, Urologic OncologyUniversity of Illinois at ChicagoChicago, IllinoisDisclosures: Department of Defense Prostate Cancer Research Program: Scientific Study or Trial, Consultant or Advisor

Acknowledgements

The AUA Office of Education would like to thank the companies who sup-port continuing education of physi-cians. The AUA recognizes the follow-ing companies for providing educa-tional grant support: AbbVie Astellas Janssen Biotech, Inc., administered

by Janssen Scientific Affairs, LLC Medivation, Inc., a Pfizer company Sanofi GenzymeAmerican Urological Association Edu-cation & Research, Inc. ensures that all educational activities are developed and implemented independent of the con-trol 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 rela-tionships 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 rela-tionships from participating, but rather to provide learners information with which they can make their own judg-ments.

Resolution of Identified Conflict of Interest

All disclosures will be reviewed by the program/course directors or editors for identification of conflicts of inter-est. Peer reviewers, working with the program directors and/or editors, will document the mechanism(s) for man-agement and resolution of the conflict of interest and final approval of the activity will be documented prior to implementation. Any of the following mechanisms can/will be used to resolve




conflict of interest:• Peer review for valid, evidence-

based content of all materials associ-ated with an educational activity by the course/program director, editor, and/or Education COI Review Work Group 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 discus-sion

• 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 demon-strations

• 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, scien-tifically rigorous and free of commercial bias.

Off-label or Unapproved Use of Drugs or Devices

The audience is advised that this con-tinuing medical education activity may contain reference(s) to off-label or unap-proved uses of drugs or devices. 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 nec-essarily represent the viewpoint of the AUA.

Reproduction Permission

Reproduction of written materials developed for this AUA course is pro-hibited without the written permission from individual authors and the Ameri-can Urological Association.

AUA Privacy and Confidentiality Policy

Access the AUA Privacy and Confiden-tiality Policy online at www.auanet.org/education/confidentiality-statement.cfm.




C O U R S E # 0 0 5 I C

Chemotherapy and Immunotherapy Options for Geni-tourinary Malignancies: A Primer for the Advanced Practice ProviderCostas D. Lallas, MD, FACS, Course Director; Anne E. Calvaresi, DNP, CRNP and Edouard J. Trabulsi, MD, FACS, Faculty

The paradigm for the treatment of advanced and castration resistant pros-tate cancer (CRPC) has shifted dramati-cally in the last 15 years. Historically the urologist had a very small role in treating these patients beyond first line androgen deprivation therapy (ADT), either surgical or medical. Occasion-ally there could be a brief period of antiandrogen administration and then withdrawal. However, these manipulations often did nothing but delay an inevitable referral to a medical oncologist for con-sideration of cytotoxic chemotherapy. In actuality some urologists would stop treating these patients after failure of primary ADT. This scenario left urolo-gists/urologic oncologists feeling help-less, not only because there was nothing more they could offer these patients, but also because they were being forced to abandon a patient whom they had potentially treated through diagnosis, failure of primary therapy(ies) and fail-ure of first line ADT, a relationship that could have spanned many years. More recently, several agents have become available for advanced and cas-tration resistant disease that not only demonstrate efficacy but can also be safely administered in an office setting, qualities that have attracted urologists to manage prostate cancer beyond pri-mary ADT. In addition, because several of these medications are indicated for patients in whom docetaxel has failed, movement of these patients between the offices of the medical oncologist and the urologic oncologist has become a 2-way street, and the identity of the lead physi-cian, the one who will take charge of these patients, has become less clear. However, instead of creating con-troversy this situation underscores the importance of multidisciplinary care of

genitourinary malignancies and open communication among all clinicians. A team approach allows for the devel-opment of an initial patient specific treatment strategy and an understand-ing of which specialist would be most appropriate to provide a given treatment within that strategy. The team approach would also further allow for revisiting the strategy at appropriate intervals, at which point a decision would be made about the need to continue or revise the strategy. Accordingly, as the patient dis-ease state evolves, so might the clinician who dictates care. Treatment of patients with advanced prostate cancer has provided a unique opportunity for the advanced practice provider (APP), who often interacts with these patients and serves as the first line clinician for discussions on survivorship related issues. This role requires an intimate knowledge of these newer agents, including their relative efficacies and unique side effect profiles. In fact, at a well organized institution with APPs (nurse practitioner or physi-cian assistant) who have focused train-ing in urologic oncology, significant input regarding patient care would fall on that clinician, who would be serving as an extender for a urologic oncologist. Accordingly, our course at AUA2018 focused on advanced prostate cancer and CRPC and the knowledge that we considered important for the APP. Some of the newer agents currently available for the treatment of advanced and CRPC include sipuleucel-T, abi-raterone, enzalutamide, apalutamide, cabazitaxel and radium-223. Certainly the androgen receptor (AR) targeted therapies are popular among practicing urologists, in part because abiraterone and enzalutamide are regularly pre-scribed by urologists.1

Since we last wrote this review 1 year ago apalutamide, a new kid on the block, has arrived with potential in an earlier space of CRPC, and it may also readily be prescribed by urologic oncologists. For urologists to prescribe these medications for advanced pros-tate cancer, basic knowledge of their mechanisms, indications and potential side effects is paramount. Additionally, because many of these patients are on a continuous and repeating cycle of 3 to 6-month office visits for prostate specific antigen (PSA) and wellness checks, this responsibility often falls on the APP. Abiraterone acetate is an inhibitor of CYP17A1 and targets 17-hydroxy-lase and 17-20-lyase activities, thereby inhibiting residual androgen biosynthe-sis. Concurrent administration of low dose prednisone (5 mg twice daily) is required to prevent hypokalemia, hypertension and fluid retention due to adrenocorticotropic generated mineralo-corticoid excess. Abiraterone was first approved for progressive CRPC in patients with prior docetaxel therapy in a phase III placebo controlled trial after an interim analy-sis demonstrated better than expected results,2 and this was later expanded into the chemotherapy naïve setting.3

However, it is the results of the LATI-TUDE and STAMPEDE trials that have thrust this medication further into the realm of urologists.4,5 Both trials demonstrated increased overall survival in men with locally advanced or hormone sensitive met-astatic prostate cancer when adding abiraterone to standard of care ADT. Abiraterone can have multiple drug interactions and requires dose reduction or possible discontinuation in patients with liver dysfunction. As a result, in addition to PSA checks these patients




require monthly physical examinations focusing on fluid retention, as well as electrolyte monitoring and liver function tests. Although intensive, this routine can easily be performed by the APP. Enzalutamide is a second-generation, nonsteroidal AR inhibitor that affects the AR pathway in multiple, synergistic pathways. It is also approved for the post-chemotherapy CRPC space and shows activity in the pre-chemotherapy space.6,7 Enzalutamide can have sig-nificant drug-drug interactions, and is contraindicated in patients with severe hepatic dysfunction and/or seizure dis-order, a history of closed head injury or stroke. Like other antiandrogens it is orally administered on a daily basis. Because urologists have significant expe-rience prescribing the older generation antiandrogens, they (and their physician extenders) are likely to prescribe enzalu-tamide. Apalutamide binds the AR with five-fold greater affinity than bicalutamide. It has a lower central nervous sys-tem penetration with reduced effect on γ-aminobutyric acid inhibition, the mech-anism believed to increase the risk of sei-zure during enzalutamide therapy. The positive results of the SPARTAN trial in patients with nonmetastatic CRPC were released in April 2018, demonstrating a significant difference in metastasis-free survival when apalutamide was added to ADT in this disease setting.8 Addi-tionally, apalutamide is well tolerated and, thus, can be easily administered in a urology office. The only idiosyncratic side effect is hypothyroidism, for which regular thyroid stimulating hormone monitoring is recommended, with varia-

tions managed with increases in or ini-tiation of thyroid replacement therapy. These responsibilities will likely fall on an APP well trained in urologic oncol-ogy. Along with understanding the hor-mone dependency of prostate cancer, a clinician who treats advanced prostate cancer must grasp the clinical implica-tions of a prolonged state of castration. Beyond this, interventions that miti-gate these potentially severe side effects from years of androgen deprivation should consistently be explained to the patients. Again, because many of these patients are on a repeating 3-month cycle of PSA checks and injection of a gonadotropin-releasing hormone agonist, these appointments are often quickly transitioned to the APP. This extender should be prepared to coun-sel the patient regarding behavioral, dietary and pharmacological interven-tions to counteract the metabolic, mus-culoskeletal, cardiovascular, cognitive and psychosocial side effects of these therapies. Additionally, when appro-priate, the APP in urologic oncology should know when to order and how to interpret a dual-energy x-ray absorp-tiometry scan to screen for osteoporotic changes with ADT. Resultant adminis-tration of antiresorptive agents such as denosumab and zoledronic acid should also be among their responsibilities. Finally, interpreting PSA and testos-terone level for a patient receiving ADT, calculating a PSA doubling time and its application to a clinical situation, and determining when to order imaging are important skills for these clinicians. They are often the first of the oncology

team to detect failure of a therapy and, thus, know when it should be switched for an alternative. Also, as a front line clinician the extender can be a lookout for patients who qualify for enrollment onto a clinical trial. In conclusion, the migration of the treatment of advanced and metastatic prostate cancer into a multidisciplinary domain, the availability of newer agents that are more user-friendly with regard to administration and followup, and the universal practice pattern for surveil-lance of these patients carve out a clear role for the APP trained in urologic oncology.

1. Caram ME, Borza T, Min HS et al: Early national dissemination of abiraterone and enzalutamide for advanced prostate cancer in Medicare Part D. J Oncol Pract 2017; 13: e694.

2. de Bono JS, Logothetis CJ, Molina A et al: Abi-raterone and increased survival in metastatic pros-tate cancer. N Engl J Med 2011; 364: 1995.

3. Ryan CJ, Smith MR, de Bono JS et al: Abiraterone in metastatic prostate cancer without previous che-motherapy. N Engl J Med 2013; 368: 138.

4. Fizazi K, Tran N, Fein LE et al: LATITUDE: a phase III, double-blind, randomized trial of andro-gen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate can-cer. J Clin Oncol, suppl., 2017; 35: abstract LBA3.

5. James ND, de Bono JS, Spears MR et al: Abi-raterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 2017; 377: 338.

6. Scher HI, Fizazi K, Saad F et al: Increased survival with enzalutamide in prostate cancer after chemo-therapy. N Engl J Med 2012; 367: 1187.

7. Beer TM, Armstrong AJ, Rathkopf DE et al: Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424.

8. Smith MR, Saad F, Chowdhury S et al: Apalu-tamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 2018; 378: 1408.

Course #005IC▼ Continued from page 6



C O U R S E # 0 4 3 I C

Novel Agents and Concepts in the Management of Hormone Naïve and Castration-Resistant Prostate CancerJudd W. Moul, MD, FACS, Course Director; Lawrence I. Karsh, MD, FACS and Christopher Sweeney, MBBS, Faculty

The management of advanced pros-tate cancer continues to evolve and the AUA2018 version of our course showcased important new work from the last year. Using a case based format and relying on the audience response system to poll our attendees, we had an intense 2-hour session. Probably the biggest news covered was the FDA (Food and Drug Administration) approval of apalutamide on Valentine’s Day 2018, making it the first therapeu-tic agent approved for nonmetastatic castration resistant prostate cancer (M0 CRPC).1 Furthermore, this agent was also the first to receive FDA approval on the end point of metastasis-free sur-vival (MFS). Also, updated data from the CHAARTED trial confirmed the benefit of up-front docetaxel for high volume, newly diagnosed M1 prostate cancer but did not confirm this benefit for low volume M1 disease.2

Newly Diagnosed Hormone Sensi-tive M1 Prostate Cancer

Several years ago hormone naïve/hor-mone sensitive newly diagnosed meta-static (M1) prostate cancer became hot news with the release of the CHAART-ED trial data in 2015 and the STAM-PEDE trial results in 2016 showing a benefit of up-front docetaxel chemo-therapy in new M1 disease.3,4 Primary androgen deprivation therapy (ADT) had been the only treatment for men with new M1 disease for more than three-quarters of a century. In the last few years CHAARTED and STAM-PEDE taught us that adding 6 cycles of docetaxel within 4 months of starting hormone therapy/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.3 However, the initial publica-tion hazard ratio generally supported a benefit of docetaxel for low volume M1 disease as well. The STAMPEDE trial confirmed the benefit of docetaxel and generally supported the use of che-motherapy for all men with new M1 disease.4 Median overall survival (OS) was 65 months for men randomized to receive docetaxel vs 43 months for men randomized to standard of care ADT alone. In 2018 Kyriakopoulos et al reported longer term followup from CHAARTED confirming the benefit of docetaxel for high volume disease but not supporting up-front chemotherapy for low volume disease.2

In 2017 the LATITUDE trial showed that abiraterone added to ADT for men with new M1 disease resulted in a similar survival benefit as docetaxel.5 We have now had a year to absorb and ponder these data, yet we do not have any level I head-to-head comparison between docetaxel and abiraterone or data to suggest that patients receive both agents. However, with less support for the use of docetaxel for low volume M1 disease, will urologists treating men with low volume M1 disease now forgo refer-ral to medical oncology in favor of giv-ing abiraterone? Will urologists lobby to have their new patients with high volume M1 disease receive docetaxel and abiraterone even though this combo is yet to be supported by phase III data? Are 6 cycles of docetaxel easier on patients than longer term use of oral abiraterone or vice versa? In any case, we debated the pros and cons of both drugs in the setting of new M1 prostate

cancer and presented case scenarios for both.

Hormone Sensitive Biochemically Recurrent M0 Prostate Cancer

In the area of hormone naïve advanced prostate cancer, we also briefly cov-ered the use of ADT for biochemi-cally recurrent/prostate specific antigen (PSA) recurrent prostate cancer.6 While the timing (early vs later), method (intermittent vs continuous) and agent (luteinizing hormone-releasing hormone [LHRH] agonist, antagonist etc) remain debated, we also addressed a number of interesting ongoing clinical trials that may shed some light. In particular, the EMBARK trial is now closed to enrollment for patients with high risk PSA recurrent disease. These men were randomized to LHRH alone, enzalu-tamide alone or LHRH plus enzalu-tamide. We anticipate that the eventual results will help put to rest some of the controversies. In particular, is there a role for enzalutamide alone in earlier advanced prostate cancer and is this “modern era combined androgen block-ade” (ie enzalutamide or apalutamide plus LHRH) more effective than mono-therapy?

Oligometastatic Prostate Cancer

An emerging concept in advanced prostate cancer is the idea of offer-ing definitive local therapy, such as radical prostatectomy, to men who have limited metastatic disease.7-9 While this would almost seem heretical to classi-cally trained urological oncologists, this idea of taking an aggressive treatment stance for men who have oligometastatic disease is developing, particularly in the era of presumed better imaging for early





metastases. We discussed a number of ongoing clinical trials addressing local therapy in the setting of oligometastatic disease (see Appendix). The HORRAD trial, one of the key trials, was also presented at AUA2018 (PD10 Prostate Cancer: Advanced Podium, Friday, May 18, 2018). It was a multicenter, randomized controlled trial of men with bone metastatic M1 prostate cancer comparing ADT alone (in 226) to ADT + radiation therapy (RT) (70 Gy) (in 216). Men with a PSA less than 20 ng/ml or men more than 80 years old were excluded from study. The primary end point was overall survival. At a median followup of 47 months there was no significant differ-ence (45 months for ADT + external beam RT and 43 months for ADT alone). However, this study was not mainly in patients with oligometastatic disease and, in fact, the concept of oligo-metastatic disease was not even on the radar when the trial started in 2004. In an exploratory nonplanned subgroup analysis of 74 men with fewer than 5 osseous metastases, there was a survival benefit of local radiotherapy to the pros-tate in the face of bony M1 disease.

Castration Resistant Prostate Cancer

Since 2010, 6 new agents have been approved by the FDA for M1 CRPC, including sipuleucel-T, cabazitaxel, abi-raterone acetate, denosumab, enzalu-tamide and radium-223.10 Except for cabazitaxel, all of these agents are commonly available for urologists and oncologists to prescribe. Some of the new concepts related to the agents that urologists may use for CRPC are dis-cussed.

Denosumab

Denosumab is prescribed at a dose of 120 mg (trade name XGEVA®) subcu-taneously monthly to prevent skeletal related events in men with M1 CRPC with bone metastases. The FDA also approved a 60 mg dose (trade name Prolia®) subcutaneously twice a year to

prevent bone loss (osteopenia and osteo-porosis) in men without bone metasta-ses who are on gonadotropin-releasing hormone (GnRH) analogue therapy for prostate cancer. We reminded urolo-gists to be mindful of using supportive agents including vitamin D and calcium supplements, and monitoring for osteo-penia and osteoporosis with annual dual energy x-ray absorptiometry scanning.11

Sipuleucel-T

Sipuleucel-T is a novel immunotherapy approved by the FDA in 2010 for asymptomatic or minimally symptom-atic M1 CRPC.12,13 The ideal patient for sipuleucel-T should have documented clinical metastases and a rising PSA while on continuous hormonal thera-py. The patient should 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 advan-tage to sipuleucel-T.14 Specifically, the estimated 3-year survival in this group of treated patients was 62.6% compared to 41.6% for men randomized to the control arm of the study. Sartor et al presented intriguing data at AUA2017 to suggest that this agent may be more effective in African American men. At the course in 2018 we reminded attend-ees that this agent should be used early in the course of M1 CRPC.

Abiraterone

Abiraterone is a 17-lyase and 17-hydro-lase inhibitor that blocks key pathways in the steroidal synthesis pathways lead-ing to androgen production. Low dose prednisone (5 to 10 mg daily is a physiological dose) is recommended to be administered with abiraterone to help limit overproduction of aldosterone and limit the side effects of hyperten-sion, hypokalemia and fluid retention. The FDA approved indication for abi-raterone is before or after docetaxel chemotherapy in men with M1 CRPC based on evidence from the Cougar-AA-301 and 302 clinical trials. The dose

for abiraterone is 1,000 mg orally once daily in the fasted state along with low dose steroid (5 mg prednisone orally twice daily). The final analyses of both trials were reviewed, showing clinically meaningful end points of OS and radio-graphic progression-free survival (Cou-gar 302) benefits.15 Abiraterone is also available in a 500 mg oral dose which allows for 2 rather than 4 pills per day which might help with compliance for some men. Abiraterone was FDA approved for use in men with newly diagnosed hor-mone sensitive M1 prostate cancer on February 7, 2018. Approval was based on LATITUDE (NCT01715285), a placebo controlled international clinical trial that randomized 1,199 patients with metastatic high risk disease. Patients received 1,000 mg abiraterone acetate orally once daily with 5 mg predni-sone once daily (in 597) or matching placebos orally once daily (in 602).16 Patients in both arms received a GnRH analogue or underwent bilateral orchi-ectomy. The major efficacy end point was overall survival. Median OS was not estimable and 34.7 months in the abiraterone acetate and placebos arms, respectively (HR 0.621; 95% CI 0.509, 0.756; p <0.0001). Median duration of abiraterone use was 24 months.

Enzalutamide

Enzalutamide, a next generation andro-gen receptor antagonist, was FDA approved in 2012 to treat men with disease that progressed after docetaxel based chemotherapy based on level I evidence from the AFFIRM trial. It received an expanded approval in 2014 for use before chemotherapy in the PREVAIL trial.17 Enzalutamide is taken orally at a dose of 160 mg daily with or without food and unlike abiraterone, it does not require 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. Presented at ASCO GU on February





8, 2018 and published in The New Eng-land Journal of Medicine on June 28, 2018, PROSPER is a phase III, randomized, double-blind, placebo controlled study of enzalutamide in men with M0 CRPC. It demonstrated an approximate 2-year MFS benefit over placebo showing that MFS is a meaningful end point.18 As of July 13, 2018 enzalutamide is now the second FDA approved drug for M0 CRPC.

Apalutamide

As previously noted, apalutamide, with a mechanism of action similar to enzalu-tamide, was the first drug for M0 CRPC approved by the FDA, which occurred on February 14, 2018. The data from the SPARTAN trial were presented at ASCO GU 2018 back-to-back with the similarly designed PROSPER as previ-ously noted, showing that apalutamide delayed MFS by 2 years.1 Overall the drug was very well tolerated. Unique side effects included maculopapular rash in 24% of patients but only 5% were grade 3-4. The rash usually resolved with topical lotions, drug holiday and temporary dose reduction. Approxi-mately 4% of patients required sys-temic corticosteroids. In addition, 8% of patients had decreases in thyroid hormone (considered chemical hypo-thyroidism) and there were no grade 3-4 adverse events The FDA did not mandate thyroid testing in the approval label. Seizure was reported in 2 patients (0.2%).

Comparing and Sequencing the Oral Agent Options

While all 3 novel oral hormonal agents (abiraterone, enzalutamide, apalu-tamide) are active in advanced pros-tate cancer, their benefit is not nec-essarily synergistic or cumulative. In other words, patients will likely have an initial robust response to any of the 3 agents. However, switching men to one of the other agents will likely not result in a sustained response and the response to the second/third agent may be more short-lived. Furthermore, now

that apalutamide and enzalutamide are FDA approved for M0 CRPC, how will urologists decide between them? Finally, while delaying metastases and the tran-sition from M0 to M1 CRPC for an average of 2 years with apalutamide or enzalutamide is important for patients, is use before documented metastases truly helping our patients to live longer and better? Both PROSPER (enzalutamide) and SPARTAN (apalutamide) showed trends toward an overall survival benefit when used for M0 CRPC. However, the OS data are not yet mature or prov-en for either drug. Some clinicians may still choose to hold novel therapy until M1 disease develops or use abiraterone (as it is or soon will be generic and pos-sibly less expensive), despite the fact that it is not FDA approved for M0 CRPC. Another topic of interest related to use of abiraterone and enzalutamide/apalutamide is molecular profiling. The discovery of the AR-V7 splice variant of the androgen receptor offers an intrigu-ing glimpse of the future of personalized medicine.19 Specifically, the response to abiraterone or enzalutamide was less robust in men who harbored this variant in circulating tumor cells. On February 26, 2018 Genomic Health, Inc. (Red-wood City, California) received FDA approval for Oncotype DX® AR-V7 Nucleus Detect™ test, a commercially available assay for AR-V7. It carries a relatively high price tag and is not yet covered by most payers.

Radium-223

Radium-223 is a parenteral radiophar-maceutical that can be ordered by urolo-gists, it is usually given in a nuclear med-icine or radiation oncology department setting but many large group practices have incorporated it into their centers. It is an alpha-emitting liquid radiation product that received FDA approval in May 2013 based on results from the ALSYMPCA trial.20 Radium-223 is indicated for the treatment of patients with symptomatic M1 CRPC with bone metastases and no known visceral meta-static disease. The dose regimen is 50 kBq (1.35 microcurie) per kg body

weight, given at 4-week intervals in 6 injections. Urologists may be familiar with ear-lier generation beta radiopharmaceuti-cals such as samarium and strontium. However, radium-223 is different. It is a large molecule alpha particle and does not penetrate the bone marrow to the degree of older agents. In other words, radium-223 is much less likely to cause serious bone marrow toxicity. In addi-tion, the use of radium-223 was associ-ated with an overall survival benefit whereas the older beta-emitting radio-pharmaceuticals were never proven to extend survival. For radium-223 to be associated with improved survival at least 4 monthly cycles must be adminis-tered. The big news in 2018 and discussed at the course was that radium-223 should not be used in patients currently being treated with abiraterone/prednisone. The phase III ERA223 trial compared abiraterone/prednisone plus radium-223 vs abiraterone/prednisone plus placebo in patients with asymptomatic or mildly symptomatic chemotherapy naïve meta-static castration resistant prostate cancer. The study was unblinded in late 2017. Bayer, the manufacturer of radium-223, reported that the unblinding followed the recommendation of an indepen-dent data monitoring committee that observed an imbalance with more frac-tures and deaths in patients receiving radium-223 and abiraterone/prednisone vs abiraterone alone. The big ques-tion is what about prior treatment with abiraterone and subsequent use of radi-um-223? Opinions vary among experts in the field and this was a hot topic of conversation at this year’s course.

Summary

The management of advanced prostate cancer continues to evolve in excit-ing and sometimes unexpected ways, and 2018 has brought further options to our patients, including abiraterone in newly diagnosed, hormone sensitive M1 prostate cancer, and apalutamide and enzalutamide for M0 CRPC. Fur-thermore, the AR-V7 molecular assay





became widely available, ushering in a new era in personalized medicine. How-ever, many questions remain including comparative assessment of apalutamide vs enzalutamide and sequential use of abiraterone and radium-223. Appendix. Current Clinical Trials Addressing Oligometastatic Prostate Cancer1. STAMPEDE trial -M1 • ADT versus ADT + RT to the

prostate (600 patients)2. HORRAD trial (Netherlands) -M1b 3. TRoMbone trial (UK) - benefit of

radical prostatectomy, especially in low volume disease - Low volume M1

• Usual treatment versus usual treat-ment + radical prostatectomy end point: 5-year OS

4. NCT01751438 (North America) - multicenter, randomized. Target 120 patients

• M1 (imaging), castration sensitive prostate cancer

• Systemic therapy versus systemic therapy + local radiation or sur-gery


2. Kyriakopoulos CE, Chen YH, Carducci MA et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term sur-vival analysis of the randomized phase III E3805 CHAARTED Trial. J Clin Oncol 2018; 36: 1080.

3. Sweeney CJ, Chen YH, Carducci M et al: Chemo-hormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737.

4. 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 con-trolled trial. Lancet 2016; 387: 1163.


6. 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.

7. Moul JW: Yes or no to local therapy for oligo-metastatic prostate cancer? Nat Rev Urol 2018; 15: 399.

8. Heidenreich A, Pfister D and Porres D: Cyto-reductive radical prostatectomy in patients with prostate cancer and low volume skeletal metasta-ses: results of a feasibility and case-control study. J Urol 2015; 193: 832.

9. Muldermans JL, Romak LB, Kwon ED et al: Stereotactic body radiation therapy for oligometa-static prostate cancer. Int J Radiat Oncol Biol Phys 2016; 95: 696.

10. Lowrance WT, Roth BJ, Kirkby E et al: Cas-tration-resistant prostate cancer: AUA guideline

amendment 2015. J Urol 2016; 195: 1444.11. Miller K, Steger GG, Niepel D et al: Harnessing

the potential of therapeutic agents to safeguard bone health in prostate cancer. Prostate Cancer Prostatic Dis 2018; doi: 10.1038/s41391-018-0060-y.

12. Slovin SF: Sipuleucel-T: when and for whom to recommend it. Oncology (Williston Park) 2017; 31: 900.

13. Bilen MA, Hess KR, Subudhi SK et al: Clinical predictors of survival in patients with castration-resistant prostate cancer receiving sipuleucel-T cellular immunotherapy. Cancer Chemother Phar-macol 2017; 80: 583.

14. Schellhammer PF, Chodak G, Whitmore JB et al: Lower baseline prostate-specific antigen is associ-ated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology 2013; 81: 1297.

15. 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.

16. Fizazi K, Tran N, Fein L et al: Abiraterone plus prednisone in metastatic, castration-sensitive pros-tate cancer. N Engl J Med 2017; 377: 352.


18. Hussain M, Fizazi K, Saad F et al: Enzalutamide in men with nonmetastatic, castration-resistant pros-tate cancer. N Engl J Med 2018; 378: 2465.

19. Antonarakis ES, Lu C, Wang H et al: AR-V7 and resistance to enzalutamide and abiraterone in pros-tate cancer. N Engl J Med 2014; 371: 1028.

20. Parker C, Nilsson S, Heinrich D et al: Alpha emit-ter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213.

C O U R S E # 0 5 8 I C

Management of Common Dilemmas in Prostate Cancer Diagnosis, Staging and TreatmentGerald L. Andriole, Jr., MD, Course Director; Anthony D'Amico, MD, PhD, Adam Kibel, MD and Oliver Sartor, MD, Faculty; Eric H. Kim, MD, Highlight Coauthor

During the last decade the management of advanced and metastatic prostate can-cer (PCa) has dramatically evolved due to advances in imaging, the develop-ment of new therapeutics and the pub-lication of a number of landmark trials demonstrating survival benefit with new treatment paradigms. We will focus on imaging and the newest evidence in the treatment of advanced and castration resistant prostate cancer (CRPC) with an emphasis on clinical management. The evidence supporting local therapy (eg surgery or radiation) for metastatic PCa also continues to develop, particu-

larly oligometastatic PCa, but is beyond the scope of this summary.

Imaging

Recent technological improvements in multiparametric magnetic resonance imaging (mpMRI) and positron emission tomography/computerized tomography (PET/CT) have led to drastic increas-es in their use in patients with PCa. Undoubtedly, mpMRI has changed the diagnostic model for PCa while PET/CT imaging appears to be gaining an ever expanding role in the evaluation of high risk patients at presentation

or with biochemical recurrence (BCR) after local therapy. Although the value of mpMRI is not debatable in the initial diagnosis of PCa, pre-biopsy risk dis-crimination as well as biopsy targeting, the value of mpMRI in advanced PCa is limited. The pretreatment identification of enlarged pelvic lymph nodes or extra-prostatic extension on mpMRI may be beneficial for patient counseling. How-ever, these findings on mpMRI alone are unlikely to change clinical decision making before local therapy.1 Similarly, mpMRI findings in the setting of BCR must be confirmed with histopathology





and coupled with imaging of distant sites before consideration of salvage local treatment. Bone imaging is indicated in the ini-tial staging of unfavorable intermedi-ate, high and very high risk PCa.2 The National Comprehensive Cancer Network® guideline recommends initial conventional 99mtechnetium MDP bone scan, with 18F-sodium fluoride (NaF) PET/CT imaging used for further eval-uation of equivocal findings. Although more expensive, the improved test per-formance of NaF PET/CT over conven-tional bone scan for the evaluation of PCa bone metastases is unquestionable, with sensitivity and specificity of 100% and 100% with NaF PET/CT vs 92% and 82% for conventional bone scan, respectively.3 11C-choline and 18F-fluciclovine (FACBC) PET/CT have been approved by the FDA (Food and Drug Adminis-tration) for localization of disease recur-rence or metastases in the evaluation of BCR. For both modalities the test performance depends heavily on pretest probability, which is based on conven-tional clinical parameters such as pros-tate specific antigen (PSA), PSA velocity and Gleason score. For instance, in the case of 11C-choline, the detection rate increases from 19% to 46% to 82% for PSA thresholds of 0.2 to 1 ng/ml, 1 to 3 ng/ml and greater than 3 ng/ml.4 For this reason 11C-choline is not recommended if PSA is less than 2 ng/ml. In the case of FACBC, the detection rate increases from 59% to 75% to 85% for PSA thresholds of 0.8 to 2 ng/ml, 2 to 6 ng/ml and greater than 6 ng/ml.5 Although positive predictive values for local, lymph node and bone recurrence are high for both modalities, FACBC seems to be outperforming 11C-choline with 100%, 91%, 100% vs 91%, 82%, 83%, respectively.6 Importantly, patho-logical confirmation of disease recur-rence should be performed if feasible, given the not insignificant rate of false-positive results. Prostate specific membrane antigen (PSMA) targeted agents, including

18F-DCFPyL and 68Ga-PSMA, seem to further improve detection rates over FACBC PET/CT. However, definitive comparative studies are not available. These small molecule ligands target the extracellular domain of PSMA, which is highly expressed in PCa cells, particu-larly when tumors become castration resistant. As a result, early studies dem-onstrate higher sensitivity with PSMA targeted agents, even at PSA values as low as 0.2 ng/ml.7-9 Based on this early evidence PSMA will likely become the preferred imaging modality for BCR and may prove to be clinically useful for initial staging of newly diagnosed PCa.

Castration Resistant Prostate Cancer

The efficacy of next generation androgen deprivation therapy (ADT), abiraterone and enzalutamide, and the subsequent FDA approval of their use in the post-chemotherapy and pre-chemotherapy settings, have drastically changed the management of metastatic CRPC.10-13 To date no study has prospectively compared the sequencing of abiraterone and enzalutamide, but retrospective studies suggest that even though cross-resistance between agents is high, out-comes favor abiraterone followed by enzalutamide.14,15

Technological advances in molecular diagnostics have allowed for the identifi-cation of gene variants in the DNA from circulating tumor cells. One potentially impactful variant in the case of metastat-ic CRPC is the androgen receptor slice variant AR-V7, which has been shown to predict resistance to abiraterone and enzalutamide as well as improve sur-vival with up-front chemotherapy.16,17 However, at this time some patients harboring the AR-V7 mutation have still demonstrated responses to next genera-tion ADT and, so, treatment decisions cannot be based solely on the presence of this variant.18

Finally, the role of therapy in the nonmetastatic CRPC setting is also continuing to change, as apalutamide has demonstrated improved metastasis-

free survival compared to placebo,19 and enzalutamide has demonstrated improved progression-free survival com-pared to bicalutamide.20 Importantly, future studies are needed to inform cli-nicians if initiation of these therapies for nonmetastatic CRPC improves overall survival in addition to prolonging the time to metastases.

Hormone Naïve Metastatic Pros-tate Cancer

The combination of up-front docetaxel and conventional ADT for hormone naïve metastatic PCa has demonstrated a significant survival benefit over con-ventional ADT alone in 2 landmark trials. In both studies the median overall survival improved from approximately 45 months in the control arm to 60 months in the study arm.21,22 Subse-quent analysis of the CHAARTED trial found that the survival benefit in the study appears to be confined to those patients with high volume disease, defined as visceral metastases or 4+ bone metastases with at least 1 outside of the axial skeleton.23 More recently, 2 studies have dem-onstrated a significant survival benefit with the addition of abiraterone to con-ventional ADT in patients with newly diagnosed hormone naïve metastatic PCa. The improvements are substantial with the median overall survival not reached by the abiraterone arm in either study.24,25 The design of the STAM-PEDE trial allows for direct comparison of the abiraterone + ADT and the docetaxel + ADT arms, which showed no difference in survival.26 The results from the final arm of the STAMPEDE trial, which includes treatment with abi-raterone + enzalutamide + conventional ADT, will provide further clarity in our approach to hormone naïve metastatic PCa. As our diagnostic technologies improve, new therapeutics become approved for use and the evidence of ongoing trials becomes available, our management of advanced and CRPC will continue to evolve. There are sev-





eral important takeaways at this time. 1) The indications for PET/CT are expanding, and will likely continue to expand as PSMA PET/CT and PET/MRI are approved for use. 2) AR-V7 is likely the first of many molecular profil-ing tests that will alter clinical manage-ment. 3) Earlier use of next generation ADT in nonmetastatic CRPC appears to be beneficial. 4) Earlier use of che-motherapy and next generation ADT in metastatic hormone naïve PCa appears to be beneficial.

1. Weaver JK, Kim EH, Vetter JM et al: Prostate magnetic resonance imaging provides limited incremental value over the Memorial Sloan Ket-tering Cancer Center preradical prostatectomy nomogram. Urology 2018; 113: 119.

2. Mohler JL, Lee RJ, Antonarakis ES et al: NCCN clinical practice guideline in oncology. Prostate cancer. Version 3.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed July 15, 2018.

3. Even-Sapir E, Metser U, Mishani E et al: The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med 2006; 47: 287.

4. Giovacchini G, Picchio M, Coradeschi E et al: Predictive factors of [11 C] choline PET/CT in patients with biochemical failure after radical pros-tatectomy. Eur J Nucl Med Mol Imaging 2010; 37: 301.

5. Bach-Gansmo T, Nanni C, Nieh PT et al: Mul-tisite experience of the safety, detection rate and diagnostic performance of fluciclovine (18F) posi-tron emission tomography/computerized tomogra-phy imaging in the staging of biochemically recur-rent prostate cancer. J Urol 2017; 197: 676.

6. Nanni C, Zanoni L, Pultrone C et al: 18F-FACBC (anti1-amino-3-18F-fluorocyclobutane-1-carboxylic acid) versus 11C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging 2016; 43: 1601.

7. Pfister D, Porres D, Heidenreich A et al: Detection of recurrent prostate cancer lesions before salvage lymphadenoectomy is more accurate with (68)Ga-PSMA-HBED-CC than with (18)F-fluoroethylcho-line PET/CT. Eur J Nucl Med Mol Imaging 2016; 43: 1410.

8. Morigi JJ, Stricker PD, van Leeuwen PJ et al: Pro-spective comparison of 18F-fluoromethylcholine versus 68Ga-PSMA PET/CT in prostate cancer patients who have rising PSA after curative treatment and are being considered for targeted therapy. J Nucl Med 2015; 56: 1185.

9. Afshar-Oromieh A, Avtzi E, Giesel FL et al: The diagnostic value of PET/CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the diag-nosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2015; 42: 197.

10. De Bono JS, Logothetis CJ, Molina A et al: Abi-raterone and increased survival in metastatic pros-tate cancer. N Engl J Med 2011; 364: 1995.


12. Ryan CJ, Smith MR, De Bono JS et al: Abi-raterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138.


14. Miyake H, Hara T, Tamura K et al: Compara-tive assessment of efficacies between 2 alterna-tive therapeutic sequences with novel androgen receptor-axis-targeted agents in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. Clin Genitourin Cancer 2017; 15: e591.

15. Maughan BL, Luber B, Nadal R et al: Comparing sequencing of abiraterone and enzalutamide in men with metastatic castration-resistant prostate cancer: a retrospective study. Prostate 2017; 77: 33.

16. Antonarakis ES, Lu C, Wang H et al: AR-V7 and resistance to enzalutamide and abiraterone in pros-tate cancer. N Engl J Med 2014; 371: 1028.

17. Scher HI, Lu D, Schreiber NA et al: Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol 2016; 2: 1441.

18. Bernemann C, Schnoeller TJ, Luedeke M et al: Expression of AR-V7 in circulating tumour cells does not preclude response to next generation androgen deprivation therapy in patients with cas-tration resistant prostate cancer. Eur Urol 2017; 71: 1.


20. Penson DF, Armstrong AJ, Concepcion R et al: Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol 2016; 34: 2098.

21. Sweeney CJ, Chen YH, Carducci M et al: Chemo-hormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737.

22. 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, multi-arm, multistage, platform randomised con-trolled trial. Lancet 2016; 387: 1163.

23. Kyriakopoulos CE, Chen YH, Carducci MA et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term sur-vival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol 2018; 36: 1080.

24. Fizazi K, Tran N, Fein L et al: Abiraterone plus prednisone in metastatic, castration-sensitive pros-tate cancer. N Engl J Med 2017; 377: 352.


26. Sydes MR, Spears MR, Mason MD et al: Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol 2018; 29: 1235.

C O U R S E # 0 6 3 I C

Prostate Cancer Update William J. Catalona, MD, Course Director; Douglas M. Dahl, MD, FACS, Stanley L. Liauw, MD, Stacy Loeb, MD, MSc, Robert B. Nadler, MD and Rus-sell Szmulewitz, MD, Faculty

This course highlights the important findings on prostate cancer (PCa) pub-lished during the last year.

Statistics and Epidemiology

During the prostate specific antigen (PSA) screening era there has been an 80% decrease in the proportion of patients with PCa with metastases at diagnosis and a greater than 53% decrease in PCa specific mortality. Five-year survival is approximately 99% for

patients presenting with local or regional disease and 29% for those with distant metastases.1,2 The incidence of PCa plummeted after the USPSTF (U.S. Preventive Ser-vices Task Force) issued a grade D recommendation against screening in 2012, and the rate of positive nodes and PCa mortality began to rise.3 In 2018 the USPSTF upgraded their recommen-dation to grade C for shared decision making for men 55 to 69 years old, but

not in men older than 70 or for other high risk men4 for whom stronger rec-ommendations should be considered.5 Modeling reanalysis of the PLCO (Prostate, Lung, Colorectal, and Ovari-an) cancer screening trial revealed a PCa mortality reduction comparable to that of the ERSPC trial.6 The Göteborg trial reported a 35% decrease in PCa mortal-ity, and men age 55 to 59 had a 53% decrease in mortality.7 The CAPS trial, testing 1-time PSA screening, reported





no mortality reduction but has substan-tial methodological limitations.8 Genetic testing for DNA repair gene mutations (BRCA1/2, ATM, Lynch syndrome) and for HOXB13 is encour-aged for patients with a positive family history and for those with metastases.9 Epidemiological studies suggest that vasectomy is associated with a small risk of low grade PCa that should not change practice.10 Statin11 and aspirin12 use are associated with reduced PCa mortality but have not been tested in randomized trials.

Biopsy

Magnetic resonance imaging (MRI) tar-geted biopsies diagnose more high grade tumors and transrectal ultrasound guid-ed biopsies diagnose more low grade tumors. Significant cancer is missed with MRI targeted biopsy alone and, thus, routine 12-core biopsy is also warrant-ed.13 MRI should be considered for patients with a prior negative biopsy.14 MRI has a low sensitivity in patients on active sur-veillance (AS).15 A 1.5 T MRI machine is safe for patients with implanted devices containing metal.16 PSA based tests such as PSA density and the Prostate Health Index improve the negative predictive value of MRI.17

Recent antibiotic treatment, foreign travel and being a health care worker are risk factors for post-biopsy infec-tions. Targeted prophylaxis based on rectal swab cultures, the local antibio-gram or use of transperineal biopsy are options to reduce post-biopsy infec-tions.18 Disinfecting biopsy needles with formalin or alcohol slightly decreases the risk of infection.19

The extent of biopsy core involve-ment is not highly predictive of pros-tatectomy pathology.20 The cribriform pattern of Gleason 4 cancer is less fre-quently detected on MRI.21

Predictive Markers, Staging and Imaging

The PCa intermediate risk group is

heterogeneous, with cribriform and intraductal being the most aggressive patterns. Genetic tests may help in dis-tinguishing aggressiveness.22 The new American Joint Committee on Cancer clinical staging system now incorpo-rates Gleason and PSA.23 New imaging tracers for staging include Na18F posi-tron emission tomography (PET)/com-puterized tomography, fluciclovine 18F/PET, PSMA-68Ga/PET and 18F-PSMA/PET.24,25

Active Surveillance

AS is gaining increasing acceptance, especially in the Veterans Affairs (VA) system.26 Compliance with AS biopsies is low and biennial biopsies may be sufficient.27 Any Gleason pattern 4 on biopsy is associated with more adverse pathology and biochemical failure.28, 29

Focal Therapy

Focal therapy has a high failure rate and should be considered investiga-tional.30 Most positive posttreatment biopsies occur in treated regions and MRI detects only a minority of these persistent cancers. Complications of partial gland ablation include incon-tinence and erectile dysfunction, and are more frequent in radiation failures, especially fistulas.31,32 Electroporation has a high positive repeat biopsy rate, especially with higher grade tumors.33 Photodynamic therapy decreases PSA but posttreatment positive biopsies are not uncommon.34

Prostatectomy

Retrospective studies report a higher risk of death with radiotherapy than with radical prostatectomy but are con-founded by biases.35 The PIVOT com-pared surgery with observation in a largely VA population and concluded that the results were equivalent between surgery and observation.36 However, all outcomes favored surgery and inter-mediate risk patients had a significant benefit from surgery. There is no dif-ference in recurrence-free survival with

standard vs extended node dissection, as metastases may occur in regions where nodes are not dissected and where radiation is not delivered.37 Treat-ment for oligometastatic disease reduces local recurrences and improves time to androgen deprivation therapy (ADT) but does not increase survival.38 Tes-tosterone (T) replacement is safe except in physiologically hypogonadal men.39 Orgasmic dysfunction is common after radical prostatectomy.40

Radiotherapy

Dose escalated radiotherapy improves PSA control but has not yet been shown to improve survival (followup is short and event rate is low).41 For intermediate risk disease dose escalation reduces PSA recurrence and metastases with mini-mally increased toxicity.42 In very high risk disease external beam radiothera-py with a brachytherapy boost yielded better local control than conventional radiotherapy.43 External beam radio-therapy with a brachytherapy boost is beneficial mainly to men with multiple risk factors but has more toxicity.44 Hypofractionated radiotherapy (4 to 5 weeks vs 8 to 9-week course) yields equivalent results for disease control or late toxicity with only a slight increase in acute gastrointestinal (GI) toxicity.43 Stereotactic body radiation is extreme hypofractionation (less than 5 days).45 Proton beam radiotherapy theoreti-cally provides better dosimetry with less genitourinary toxicity but more GI toxicity, and a marginal overall benefit at double the cost.46 Toxicity is compa-rable for stereotactic body radiation but the cost is less. Proton beam or brachy-therapy are not preferred for salvage treatment. Hydrogel spacers provide only a small benefit in GI toxicity.47

After prostatectomy, prospective trial results are pending comparing adjuvant radiotherapy vs early salvage thera-py.48,49 Hypofractionation is also effec-tive in the postoperative setting.50 ADT improves the results of salvage radio-therapy for patients with a high risk of metastases.51 There are no definitive





guidelines for duration of ADT with salvage radiotherapy, and most receive short-term ADT. Treating lymph nodes with salvage radiotherapy also has better results, but a greater dose is delivered to the rectum, small bowel and bladder.52

Advanced Disease

Intermittent ADT is associated with less risk of heart failure or fractures.53 Low T levels after ADT persist for more than 6 months54 and there is greater cardiovascular mortality among patients with longer T suppression.55 Early ADT in patients with biochemi-cal failure involves more sexual and menopausal side effects.56 ADT is not associated with an increased risk of Alzheimer’s disease.57

Metastasis-free duration is a strong surrogate for survival in drug stud-ies.58 Testing for the abnormal andro-gen receptor, AR-V7, is now available to predict response to ADT.59 ADT + abiraterone + prednisone is the standard of care for advanced castrate sensitive PCa.60 Abiraterone costs $10,000 to $12,000 per month but the response is the same with half the dose if taken with a low fat breakfast.61 Abiraterone failures have a brief response to enzalu-tamide.62

Docetaxel improves survival but ADT/Abi/prednisone may be better (more expensive with high co-pay insur-ance).63 Apalutamide (an androgen receptor antagonist) was recently FDA approved for nonmetastatic castration resistant

prostate cancer with rapid PSA doubling times, and greatly improves metastasis-free survival.64 The 177Lu-PSMA-617 conjugated antibody targets prostate specific membrane antigen on PCa cells (phase 2 study of its efficacy ongoing) and the PSA response rate was 60%.65

Conclusions

Advances have been made in PCa care. Hopefully, new guidelines incorporat-ing shared decision making about PSA screening will enhance benefits and decrease harms going forward. New bio-markers and imaging techniques offer promise for new and better treatment selection.

The complete list of references for this summary can be obtained by contacting [email protected].

C O U R S E # 0 7 4 I C

AUA Castration-Resistant Prostate Cancer (CRPC) Guidelines Michael S. Cookson, MD, MMHC, Course Director; Adam S. Kibel, MD and David F. Jarrard, MD, Faculty

A better understanding of tumor biol-ogy and mechanisms of escape from conventional treatments has resulted in more effective therapies for men with advanced prostate cancer. In fact, the treatment of patients with newly diagnosed metastatic disease and castra-tion resistant prostate cancer (CRPC) continues to evolve, which is important for patients who suffer from the sec-ond leading cause of cancer death in men.1 Improved overall survival with 6 different therapeutic agents, coupled with the success of earlier use of some already approved agents and now a 7th approved therapy to delay the devel-opment of metastases, have resulted in updates of the AUA guidelines for CRPC. For the 6th 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 castra-

tion resistant disease. The treatment of men with metastatic CRPC (mCRPC) continues to evolve. Almost 15 years ago, once androgen deprivation therapy (ADT) failed, treat-ments for men with CRPC were only palliative. However, 2 landmark studies published in 2004 by Tannock2 and Pet-rylak3 et al demonstrated that docetax-el improved survival in patients with mCRPC compared to mitoxantrone. Subsequently, the field has evolved. In fact, 5 additional agents (abiraterone, sipuleucel-T, cabazitaxel, enzalutamide and radium-223) that have all shown a survival benefit have been approved by the U.S. FDA (Food and Drug Admin-istration) based on randomized clinical trials.4-9 These agents have been tested in multiple mCRPC disease states to determine the benefit from each treat-ment. Now these agents and others are being investigated in earlier stages of the disease, including the nonmetastatic

(M0) setting. At the AUA 2018 annual meeting we presented an update to AUA CRPC guidelines. One reason for the contin-ued update is the relatively rapid evolu-tion of the field. While new agents are undergoing clinical trials, other agents are moving up in the sequencing. This year we presented data from 2 land-mark trials in patients with nonmeta-static CRPC. For the first time, we have data demonstrating a significant delay in metastasis-free survival using agents directed at the androgen axis. Before the meeting both studies had been presented at ASCO GU. The first published study was the SPARTAN trial, a randomized trial comparing apalutamide vs placebo in patients with M0 CRPC at high risk for metastasis.10 The investigators reported a highly significant improve-ment in metastasis-free survival with use of apalutamide vs placebo in men at high risk for metastasis as determined





by a prostate specific antigen (PSA) dou-bling time of 10 months or less. This has resulted in the FDA approval of apalu-tamide for use in men with M0 CRPC. Results from PROSPER also demon-strated similar improvement in metasta-sis-free survival in men with M0 CRPC at high risk for metastasis with use of enzalutamide vs placebo.11 These 2 studies are considered practice changing in that for the first time we now have 2 agents proven to delay the develop-ment of metastases in men with a rap-idly rising PSA in the setting of normal conventional imaging (M0 CRPC). It is also the first time that an agent has been approved for men with CRPC based on this new primary end point. What is not known is the impact of these treatments on ultimate survival at this juncture in the disease spectrum, and this issue will require additional long-term followup. Enzalutamide before chemotherapy in men with asymptomatic or mildly symptomatic mCRPC was discussed in the context of the PREVAIL trial, a ran-domized trial of enzalutamide compared to placebo in men with mCRPC before docetaxel therapy.9 The study demon-strated significant improvement in the 2 co-primary end points of overall survival (HR 0.706, 95% CI 0.60-0.84, p <0.001) and radiographic progression-free sur-vival (HR 0.186, 95% CI 0.15-0.23) in patients treated with enzalutamide vs placebo. Previously, abiraterone plus prednisone was approved in the pre-chemotherapy setting (COU-302) as well.4 In addition, the use of an alpha emit-ting radionuclide therapy was discussed relative to the FDA approved use of radium-223 dichloride in men with mCRPC who are symptomatic from bone metastases and without visceral metastatic disease.8 These approvals and others anticipated in the not too distant future highlight the need for continuous periodic updating of the guidelines to inform clinicians regarding the rapidly evolving management of this disease. The CRPC guidelines were devel-oped using 6 index cases intended to

represent the most common scenarios encountered in clinical practice. Accord-ingly, cases with CRPC were catego-rized based on the presence or absence of metastases, degree and severity of symptoms, overall performance status and prior treatment with docetaxel che-motherapy. Guideline statements for each of the index cases were rated as a standard, a recommendation, an option or an expert opinion based on the grad-ing 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 an algorithm. A summary of the revised CRPC guideline statements for each index case along with clinical case scenarios were presented for illustration. Index patient 1 is asymptomatic with an increasing prostate specific antigen and no radiographic evidence of metas-tases. Currently apalutamide is FDA approved for patients with M0 CRPC based on data from the SPARTAN trial.10 However, based on previously presented data from the PROSPER trial it is highly anticipated that enzalutamide will soon be approved for these patients.11 Accordingly, the panel thought that clinicians should offer apalutamide or enzalutamide with continued ADT to patients with nonmetastatic CRPC at high risk for metastasis. Clinicians may also recommend observation with continued ADT to patients with nonmetastatic CRPC at high risk for metastasis who do not want or cannot have one of the standard therapies. Clinicians may offer treat-ment with a second-generation andro-gen synthesis inhibitor (ie abiraterone + prednisone) to select patients with M0 CRPC at high risk for metastasis who do not want or cannot have one of the standard therapies and are unwilling to accept observation. Currently chemo-therapy or immunotherapy should not be offered to patients with nonmetastatic CRPC outside 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. Clinicians may offer first-generation antiandrogen therapy, first-generation androgen synthesis inhibi-tors or observation to index 2 patients who do not want or cannot have stan-dard 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 abi-raterone + prednisone, enzalutamide or docetaxel chemotherapy in this setting. 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. Cli-nicians may offer treatment with abi-raterone + prednisone or enzalutamide to these patients and ketoconazole + steroid or radionuclide therapy to those who are unable or unwilling to receive abiraterone + prednisone or enzalu-tamide. 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 symptom-atic bone metastases and without known visceral disease, specifically when per-formance status is directly related to symptoms of bone metastases. Index patient 5 is symptomatic with metastases, a good performance status and a history of docetaxel use. Clini-cians should offer treatment with abi-raterone + prednisone, cabazitaxel or enzalutamide. If the patient received abiraterone + prednisone or enzalu-tamide before docetaxel chemotherapy, he should be offered cabazitaxel. Keto-





conazole + steroid may be offered if abiraterone + prednisone, cabazitaxel or enzalutamide is unavailable. Re-treat-ment with docetaxel may be suggested for patients who were benefitting at the time of docetaxel discontinuation (due to reversible side effects). Patients with symptomatic bone metastases and no visceral metastases should be offered 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 suf-fering, 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 cases clinicians may offer treat-ment 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 pre-ventive treatment (eg supplemental cal-cium, vitamin D) to reduce the risk of fractures and skeletal related events.12 Denosumab or zoledronic acid may

be selected as preventive treatment for skeletal related events in patients with mCRPC and bony metastases.13, 14

The treatment of CRPC is undergo-ing an evolution with multiple new agents on the horizon, from immune modulators to vaccines to novel antian-drogens. In addition, use of approved agents is being clinically trialed in ear-lier disease stages of the disease state. The potential benefits beyond delaying the development of metastases in the M0 CRPC disease state, as well as the impact on subsequent therapies and quality of life, are just a few of the antici-pated questions to be answered. In addi-tion, the use of genetic testing appears to be gaining attention in men with CRPC, particularly in areas where there is an actionable therapeutic associated with the mutation. It is anticipated that the AUA CRPC guidelines will be modified again in the near future, coinciding with the completion of ongoing trials. The goal remains to keep clinicians abreast of this rapidly changing CRPC land-scape.

1. Siegel RL, Miller KD and Jemal A: Cancer Statis-tics, 2018. CA Cancer J Clin 2018; 68: 7.

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 mito-xantrone 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 che-motherapy. N Engl J Med 2013; 368: 138.

5. Kantoff PW, Higano CS, Shore ND et al: Sipu-leucel-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 pro-gressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: 1147.


8. National Cancer Institute: FDA Approval for Radium 223 Dichloride. Available at www.cancer.gov/cancertopics/druginfo/fda-radium-223-dichlo-ride.



11. Hussain M, Fizazi K, Saad F et al: PROSPER: a phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol, suppl., 2018; 36: abstract 3.

12. Bischoff-Ferrari HA, Willett WC, Wong JB et al: Fracture prevention with vitamin D supplementa-tion: a meta-analysis of randomized controlled trials. JAMA 2005; 293: 2257.

13. 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.

14. 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 randomized, double-blind study. Lancet 2011; 377: 813.

C O U R S E # 0 7 8 I C

Management of Prostate Cancer: A Case Based Approach with Emphasis on Integrating New Molec-ular Diagnostics into Clinical PracticeEric A. Klein, MD, Course Director; Andrew J. Stephenson, MD, Faculty

Precision medicine is a concept defined by the idea that medical decision mak-ing, be it a decision to treat or not to treat, or choosing a specific drug or therapy, is based on the molecular char-acteristics of the disease or tumor. The theme of our postgraduate course this year was that the era of precision medi-cine in prostate cancer has continued to mature. The ability to characterize

an individual’s risk of prostate cancer based on germline genetics (future risk of disease), the likelihood that he has an aggressive prostate cancer at the moment of consultation (current risk of disease, how aggressive the known can-cer is, whether the cancer has progressed biologically while on active surveillance, the likely benefit of adjuvant radiothera-py 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 and gene expression based tests. These efforts at better bio-logical 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. The USPSTF (U.S. Preventive Ser-vices Task Force) recently upgraded its recommendation for prostate specific antigen (PSA) screening from “D” to “C” for men 55 to 69 years old, rec-ognizing the long-term result of the ERSPC (European Randomized Study of Screening for Prostate Cancer) and the widespread adoption of active sur-veillance, the latter of which has reduced the harms of over diagnosis and over-treatment. There are several next gen-eration biomarkers on the market that have better diagnostic accuracy than PSA and can further reduce unnecessary biopsies by about 30% to 35% (fig. 1). We reviewed data on a new assay called IsoPSA™ that measures multiple cancer specific isoforms of PSA in the serum based on structure rather than concen-tration. A validation study confirmed the high sensitivity and specificity of the assay demonstrated in the initial study, and if widely adopted could reduce unneeded biopsy by almost 50% (fig. 2).1 As the power of DNA sequencing advances, the ability to identify genes in germline DNA (ie DNA that an individual is born with) has expanded. While not all men with prostate cancer should undergo germline DNA testing, the consensus is that men with known syndromes should be tested, including those with familial breast cancer/ovar-ian cancer syndrome (BRCA families), Lynch syndrome and known mutations

in the HOXB13 gene. There are several commercially available gene panels for testing but it is important that the results be interpreted and put into context with the help of a certified genetic counselor. Emerging discussion centers around whether patients with many first-degree relatives and those who present with high grade (Gleason 8 or greater) or metastatic disease also be tested. Data on this issue are maturing. Increasing data demonstrate that prostate cancers in men who have germline BRCA muta-tions behave more aggressively, respond less well to androgen deprivation and androgen receptor blockade, but may be more sensitive to inhibition by a class of drugs known as PARP (poly[ADP-ribose] polymerase) inhibitors. Studies of the 3ßHSD gene have demonstrated an inherited muta-tion that prevents its degradation, allowing dihy-drotestosterone to accumulate in the prostate at higher levels than in wild-type men.2 Sev-eral studies have shown that men who inherit this mutation respond less well to andro-gen deprivation and are likely best treated with com-bined blockade including a lutein-

izing hormone-releasing hormone ago-nist/antagonist plus an androgen recep-tor blocker. The use of active surveillance con-tinues to grow nationally, aided in part by the demonstrated utility of magnetic resonance imaging (MRI) to reduce under sampling and genomic tests to help assign biological risk. These tech-nologies provide complementary infor-mation about the suitability for active surveillance (see Appendix). Accumulat-ed experience and data demonstrate that MRI improves the likelihood of finding Gleason 7 or higher cancer, although it is limited by the fact that MRI does not identify smaller tumors even if they are high grade, and generally requires a second biopsy to confirm clinical suspicion of high grade disease. MRI




Figure 1. Figure 2.

Appendix.



is further limited by its operator depen-dence. Genomics has the advantage of providing a direct estimate of biological potential but is limited by tumor het-erogeneity. When used wisely these technologies can help correctly identify or exclude men using hard biological criteria.

All of this work demonstrates that recent advances in genomic and bio-marker science (including IsoPSA and MRI) can be usefully applied to the treatment of men at risk for and diag-nosed with prostate cancer.

1. Klein EA, Chait A, Hafron JM et al: The single-parameter, structure-based IsoPSA assay demon-

strates improved diagnostic accuracy for detection of any prostate cancer and high-grade prostate cancer compared to a concentration-based assay of total prostate-specific antigen: a preliminary report. Eur Urol 2017; 72: 942.

2. Hearn JW, AbuAli G, Reichard CA et al: SD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study. Lancet Oncol 2016; 17: 1435.

P R E S E N TAT I O N

Urologic Care for the Advanced Practice Provider: 2018 Prostate Cancer Update: Clinical Guidelines & ManagementHeather Schultz, RN, MSN, NP-C and Kenneth Mitchell, MPAS, PA-C, Course Co-Directors, and Daniel Park, PA, MHA, Faculty

With major advancements in primary treatment options, screening guidelines, biomarkers to aid in prognostication and treatment planning and multipara-metric (mp) magnetic resonance imag-ing (MRI), our approach to caring for patients with prostate cancer (PCa) con-tinues to evolve. PCa screening and the latest USPSTF (U.S. Preventive Ser-vices Task Force) recommendations are topics about which practitioners need to be continuously updated as many patients receive questionable counsel-ing regarding prostate specific antigen (PSA) depending on who they have spoken with or what news article they have read. It is up to us, active members of the AUA, to provide clear, concise, data driven recommendations to help patients sort through the noise. The presentation opened with a brief overview of prostate cancer statistics in the United States and then moved to the latest guidelines for localized prostate cancer based on current AUA guide-lines. Also mentioned was the expand-ing use of biomarkers currently available along with the clinical use of mpMRI. In addition, focal therapy, in the form of cryotherapy and high intensity focused ultrasound (HIFU), was reviewed as a primary method of prostate cancer treatment. Lastly, a few ongoing clinical trials were discussed in addition to some

of the latest hot topics in the foreseeable future of prostate cancer treatment. PCa continues to be the most com-mon, noncutaneous malignancy in American men, representing an astound-ing 30% of all new cancer diagnoses. PCa is responsible for approximately 9% of all cancer related deaths and the lifetime risk of the disease is currently 1 in 7. Fortunately only 1 in 39 actually die of the disease. Interestingly, since the 2012 USPSTF recommendations were released, advising against screen-ing, there has been a significant drop in the incidence of PCa. In 2013 there were approximately 238,000 new cases of PCa. The latest 2018 projections from the American Cancer Society note that the number of new cases this year is esti-mated to be 165,000, which represents a 30% decrease in diagnosis since the 2012 PCa screening era. The question remains, are there truly fewer cases of PCa or are we just catching the disease later? Studies have indicated that there has been an estimated near tripling of bio-chemical recurrence and a quadrupling of nodal metastatic disease. Yes, there has been an overall drop in the number of new Gleason 6 (Grade Group 1) disease but, conversely, there has been a significant rise in the diagnosis of high grade PCa and biochemical recurrence

rates. The importance of risk stratifica-tion was discussed, and the agreement of the USPSTF and the AUA on screen-ing for men between 55 and 69 years old was solidified as this age group showed the greatest benefit from screen-ing. What remains critical is asking our-selves who should be screened and then, perhaps more importantly, who should be treated? Therefore, we turn to the myriad of biomarkers currently available to clini-cians today. We are fortunate to have such incredible genomic tools at our dis-posal but there are certainly limitations to these tests such as clinical utility. We must ask ourselves, “Does ordering this test truly effect clinical decision mak-ing processes and benefit the patient in the long term? Is it cost-effective? Do the results only validate that which we already assumed or do they make an impact on our treatment recommenda-tions?” If the answer is the latter, then these tests can become a good resource and help us reassure a subset of patients in our joint decision making regarding treatment. Since a biomarker is defined as “a biological feature that can be used to measure the presence or progress of disease or the effects of treatment,” then mpMRI can also be considered a bio-marker. In fact, we use biomarkers daily in our practice, with PSA, vital signs,





body mass index all biomarkers. But what makes MRI particularly impact-ful? It can change the way we practice. MRI is a game changer in the field of prostate cancer. MpMRI can help avoid the detection of clinically unimportant, indolent cancer that would likely never cause harm or impact a patient’s overall survival. Likewise, it can help detect clinically significant cancers that have been missed with traditional sextant biopsies, such as lesions in the anterior region. MRI can also help better clas-sify disease with targeted, 3-dimensional fusion biopsies that can better assess the volume of disease rather than rely on a random sampling of the gland. In a recent study published in The New England Journal of Medicine, mpMRI helped detect 50% more clinically sig-nificant cancer versus standard biopsies. Perhaps the time is coming when MRI can be used as a screening tool for PCa. However, multiple factors would cer-tainly need to be considered such as cost of the machine, radiologist expertise and insurance coverage. Nevertheless, MRI will likely have a greater role as other potential features are added, including magnetic resonance spectroscopy, MRI parameters in active surveillance, visual cues with focal therapy treatment plan-ning and preoperative risk assessment. The rationales associated with focal vs radical therapy were also present-ed. Research going back more than 2 decades indicates that the index lesion drives tumor biology in the prostate. That is, the majority of the tumor bulk is in direct correlation with the index lesion. Prostate cancer is typi-cally multifocal and bilateral, but the clinical characteristics of the disease are invariably defined by the index lesion. We have learned from years of radical treatments for other soft tissue cancers, including cancers of the breast and kidney, that radical surgery may not be required for select patients. Enter the era of focal therapy, namely cryother-apy and HIFU. Both modalities were explained, including ideal patient selec-tion for each, in addition to other focal

therapy options on the horizon, ie focal electroporation and vascular targeted photodynamic therapy. Many patients with PCa are Internet savvy and have done their due diligence with online research. On occasion, cli-nicians might have a newly diagnosed patient with PCa entering the office asking for HIFU treatment by name. Although approved by the U.S. Food and Drug Administration for prostate ablation, and not explicitly for PCa treatment, HIFU is an option clinicians should be aware of with the growing demand and market drivers evident from a simple Google search. The latest 2017 AUA guidelines state that there is a lack of robust evidence of the efficacy of HIFU and that it may not be curative, potentially warranting further treatment. However, if one has a patient in clinic who is risk averse and adamantly refuses surgery or radia-tion, HIFU is an option that should be discussed. There remain strict inclu-sion and exclusion criteria for potential HIFU cases, including gland size volu-metrics, clusters of intraprostatic calculi larger than 1 cm and other measures that need to be considered before deter-mining if a patient is a HIFU candidate. Case studies were discussed, including the use of contrast enhanced ultrasound indicating perfusion immediately before and after HIFU ablation, and the cor-relation with posttreatment re-staging histology. Pros and cons of focal thera-pies were addressed and the need for re-staging biopsies was emphasized. Finally, clinical trials were presented, including the first study of focal che-motherapy targeting the prostate gland directly. The study involved the use of paclitaxel placed in nanoparticles and injected precisely into 1 lobe of the prostate gland 1 month before prosta-tectomy. Preclinical studies have dem-onstrated tumor regression in mice, and the potential for PCa treatment via injection can be groundbreaking pend-ing final study results. There was also a brief discussion on photodynamic therapy, whereby a bacterium on the

ocean floor, when exposed to a certain spectrum of light, can produce enough energy to destroy tissue without thermal insult. We are certainly living in exciting times for innovative PCa treatment. What about patients with biochemical recurrent PCa who have had negative traditional imaging evaluation, includ-ing computerized tomography and bone scan? We are entering the new age of positron emission tomography (PET) imaging in prostate cancer. There are multiple types of PET scans available today including PET-Axumin®, pros-tate specific membrane antigen PET and 11C-acetate PET. These special scans can yield metabolic uptake and help aid targeted therapies for a select group of patients. We may ask how this affects long-term overall survival but it is still too early to determine. Nevertheless, PET scanning can open doors to poten-tial further treatment for men unwill-ing to remain on androgen deprivation therapy. Lastly, we discussed the University of Southern California’s PA Fellowship in Clinical Urology. As our nation faces a dramatic rise in our baby boomer population and a shortage of urologists to meet that demand, advanced practice providers (nurse practitioners, physician assistants) will be called upon to help assist the needs of this patient demo-graphic. Developing a formal program with standardized postgraduate training specifically designed for the vast array of urological diseases, including proce-dural training and robotic first assisting, can have a major impact on the quality and timing of urological care rendered. Doing so may provide our urologist col-leagues more time to spend with com-plex cases, as well as with their families.

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AUANEWSassets.auanet.org/.../pdfs/auanews/AUA18-CRPC-Highlights.pdfdiagnosed with CRPC have metastatic disease. Of those patients without metas-tases, 33% can expect to develop them