AUA. Prostate Cancer AUA 2013 ANNUAL MEETING HIGHLIGHTS ANNUAL MEETING HIGHLIGHTS Prostate Cancer

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1 October 2013 AUA 2013 ANNUAL MEETING HIGHLIGHTS Prostate Cancer Course #26PG Teaching Your Referring Physicians How to Interpret PSA Results and How to Find the Truth Beyond the Screening Controversy Course #38IC Managing Metastatic Prostate Cancer in Your Urology Practice: Coding and Science Course #47IC Detection of Prostate Cancer and Castration Resistant Prostate Cancer: AUA Guidelines Course #89IC Sequencing Novel Agents in Advanced Prostate Cancer 2013: Case-Based Key Knowledge for Urologists Plenary Sessions Critical Discussion: Managing Progressive Prostate Cancer: How, Who and When Take Home Message: Prostate Cancer AUANews Editor Gopal H. Badlani, MD AUA 2013 ANNUAL MEETING HIGHLIGHTS Prostate Cancer Publisher American Urological Association 1000 Corporate Boulevard Linthicum, MD Copyright 2013 by American Urological Association None of the contents may be reproduced in any form without prior written permission of the publisher. The opinions expressed in this publication are those of the speakers and do not necessarily reflect the opinions or recommendations of their affiliated institutions, the publisher, the American Urological Association or any other persons. Some articles in this publication may discuss unapproved or off-label uses of products. Any procedures, medications or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients conditions and of possible contraindications or dangers in use, review of any applicable manufacturers product information and comparison with the recommendations of the authorities. This CME activity is supported through educational grants from the following companies: it C red C ME

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3 AUANews AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 1 CME INFORMATION 2013 AUA Annual Meeting Highlights: Prostate Cancer Method of Participation To receive CME credit/hours of participation, participants must read the overview of courses 26PG, 38IC, 47IC and 89IC, complete the online posttest, passing with a score of at least 80%, and submit the evaluation and the credit request form by visiting prostatecancer13. Media Used This CME activity consists of a printed overview of the content presented at a live course at the 2013 AUA Annual Meeting and an online posttest and evaluation. Hardware/Software Requirements A PC-compatible computer running Windows XP or later, a Macintosh computer running OS X 10.1 or later, or a Linux computer running Mozilla Firefox 3.0 or later. Processor speed of 800 MHz (1 GHz preferred). A minimum of 128 MB of RAM (more preferred). A modem speed of at least 56k (broadband preferred). Internet browser should be one of the following: Internet Explorer 8.0 or later, Firefox 3.0 or later, Chrome 4.0 or later, or Safari 4.0 or later. Software requirement: Adobe Acrobat Reader 9 or newer. Estimated time to complete this activity: 1.25 hours Release Date: October 2013 Expiration Date: October 31, 2014 Evidence-Based Content It is the policy of the AUA to ensure that the content contained in this CME activity is valid, fair, balanced, scientifically rigorous, and free of commercial bias. AUA Disclosure Policy All persons in a position to control the content of an educational activity (i.e., activity planners, presenters, authors) participating in an educational activity provided by the AUA are required to disclose to the provider any relevant financial relationships with any commercial interest. The AUA must determine if the individual s relationships may influence the educational content, and resolve any conflicts of interest prior to the commencement of the educational activity. The intent of this disclosure is not to prevent individuals with relevant financial relationships from participating, but rather to provide learners information with which they can make their own judgments. Disclaimer The opinions and recommendations expressed by faculty, authors and other experts whose input is included in this program are their own and do not necessarily represent the viewpoint of the AUA. Course #26PG Teaching Your Referring Physicians How to Interpret PSA Results and How to Find the Truth Beyond the Screening Controversy Faculty Ian M. Thompson, Jr., MD, Course Co-Director Director, Cancer Therapy and Research Center The University of Texas Health Science Center at San Antonio San Antonio, TX Disclosures: SWOG: Leadership Position, Scientific Study or Trial Matthew R. Cooperberg, MD, MPH, Course Co-Director Assistant Professor of Urology UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA Disclosures: Takeda: Meeting Participant or Lecturer Peter R. Carroll, MD Professor and Chair University of California, San Francisco San Francisco, CA Disclosures: NIH: Scientific Study or Trial Ruth Etzioni, PhD Fred Hutchinson Cancer Research Center Seattle, WA Disclosures: Nothing to disclose David F. Penson, MD, MPH Professor of Urologic Surgery Vanderbilt University Nashville, TN Disclosures: Nothing to disclose Learning Objectives At the conclusion of this CME activity participants should be able to: critique the evidence and arguments for and against PSA based screening for prostate cancer: describe the outcomes of the 2 large randomized trials in PSA testing and how trial design and confounders influenced these outcomes describe the fall in prostate cancer mortality in the US since the inception of PSA testing and how modeling of these trends shows that about half of this fall is due to prostate cancer screening describe the patient who is most likely to benefit from PSA testing; and apply risk calculators, novel biomarkers, and other contemporary strategies in evaluating men with elevated PSA interpret conclusions about PSA based prostate cancer screening for referring primary providers Continued on page 2

4 2 AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS CME Information Continued from page 1 Course #38IC Managing Metastatic Prostate Cancer in Your Urology Practice: Coding and Science Faculty K. C. Balaji, MD, Course Director Chief of Urology/Professor, Urology & Cancer Biology Wake Forest University School of Medicine Winston-Salem, NC Disclosures: Sanofi Aventis: Meeting Participant or Lecturer Ronald L. Davis, III, MD Associate Professor of Urology Wake Forest University Baptist Health Winston-Salem, NC Disclosures: Nothing to Disclose Learning Objectives At the conclusion of this CME activity participants should be able to: select correct agents for use in management of patients with metastatic prostate cancer describe risks and benefits of the agent to patients with metastatic prostate cancer identify coding and administrative issues associated with use of the novel agents in urology office practice Course #47IC Detection of Prostate Cancer and Castration Resistant Prostate Cancer: AUA Guidelines Faculty H. Ballentine Carter, MD, Course Co-Director Professor of Urology/Oncology Johns Hopkins School of Medicine Baltimore, MD Disclosures: Nothing to disclose Michael S. Cookson, MD, Course Co-Director Rodes and Patricia Hart Professor of Urologic Surgery Vanderbilt University Nashville, TN Disclosures: Photocure: Meeting Participant or Lecturer Peter C. Albertsen, MD Urologist University of Connecticut Health Center Farmington, CT Disclosures: National Cancer Institute: Consultant or Advisor, Meeting Participant or Lecturer Adam S. Kibel, MD Brigham and Women s Hospital Boston, MA Disclosures: Dendreon: Consultant or Advisor, Meeting Participant or Lecturer Bruce J. Roth, MD Professor of Medicine Division of Oncology Siteman Cancer Center Washington University in St. Louis St. Louis, MO Disclosures: Oncogenix: Scientific Study or Trial Learning Objectives At the conclusion of this CME activity participants should be able to: analyze the latest evidence on the detection of prostate cancer and castration resistant prostate cancer as outlined in the AUA guidelines improve diagnostic and therapeutic decision making processes by illustrating the application of these guidelines in urologic practice acquire in-depth knowledge on the process by which evidence is used to develop scientifically rigorous, yet actionable, guidelines Course #89IC Sequencing Novel Agents in Advanced Prostate Cancer 2013: Case-Based Key Knowledge for Urologists Faculty Judd W. Moul, MD, FACS, Course Director James H. Semans Professor of Surgery Director, Duke Prostate Center Duke Health System-Urology Division Durham, NC Disclosures: Astra Zeneca: Scientific Study or Trial Phillip G. Febbo, MD Professor of Medicine and Urology University of California, San Francisco San Francisco, CA Disclosures: Janssen: Meeting Participant or Lecturer J. Kellogg Parsons, MD Associate Professor of Surgery Moores UC San Diego Comprehensive Cancer Center La Jolla, CA Disclosures: AMS: Meeting Participant or Lecturer Learning Objectives At the conclusion of this CME activity participants should be able to: diagnose castrate resistant prostate cancer (CRPC) and have a working knowledge of treatments and the proper order for administration manage CRPC with systemic agents by learning the proper candidates for treatment and be able to counsel patients on the pros and cons of therapy analyze the mechanism of action and risks/benefits of using systemic agents in the treatment of CRPC describe the bone targeted, radiopharmaceutical agent radium-223 and its sequencing review the new generation antiandrogen agent, enzalutamide, and its sequencing Statement of Need Urologists and other health care providers of prostate cancer treatment need to be aware of the latest developments and research in diagnosing and therapy, including the latest PSA screening guidelines, prognosis and management of localized and advanced prostate cancer. There is no clear right answer for the typical patient diagnosed with Continued on page 3

5 AUANews AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 3 CME Information Continued from page 2 prostate cancer, but as the population ages, there is a continued need to educate urologists on the treatment options available. Target Audience Urologists, urologists in training and nonphysician providers involved in urology. Accreditation The American Urological Association (AUA) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Credit Designation The American Urological Association designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credit. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This enduring material credit is valid only for content reformatted from courses 26IC, 38IC, 47IC and 89IC. The AUA takes responsibility for the content, quality, and scientific integrity of this CME activity. Planners Gopal Badlani, MD Professor and Vice Chair, Department of Urology AUA Secretary Wake Forest Baptist Medical Center Winston-Salem, NC Disclosures: Lithotripsy Group: Piedmont Stone & Physician Discovery: Investment Interest; Allergan: Other Elspeth M. McDougall, MD, FRCSC, MHPE Professor of Urologic Sciences Chair, AUA Education Council University of British Columbia Vancouver, British Columbia, Canada Disclosures: Nothing to disclose Commercial Support This activity is supported by educational grants from Abbvie, Algeta US, Amgen, Astellas Scientific and Medical Affairs, Inc., Bayer Healthcare, Janssen Biotech, Inc., Medivation, and Millennium: The Takeda Oncology Company. Off-label or Unapproved Use of Drugs or Devices It is the policy of the AUA to require the disclosure of all references to off-label or unapproved uses of drugs or devices prior to the presentation of educational content. The audience is advised that this continuing medical education activity may contain reference(s) to off-label or unapproved uses of drugs or devices. Please consult the prescribing information for full disclosure of approved uses. Copyright 2013 by the American Urological Association AUA Privacy and Confidentiality Policy Access the AUA Privacy and Confidentiality Policy online at cme/onlineeduconf.cfm. the AUA Office of Education with any questions at cme@auanet.org.

6 4 AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS COURSE #26PG Teaching Your Referring Physicians How to Interpret PSA Results and How to Find the Truth Beyond the Screening Controversy Ian M. Thompson, Jr., MD and Matthew R. Cooperberg, MD, MPH, Course Co-Directors; Peter R. Carroll, MD, Ruth Etzioni, PhD and David F. Penson, MD, Faculty Nearly 30,000 men in the United States are expected to die of prostate cancer in While this figure is exceeded only by lung cancer in terms of the cancer mortality burden among men, it represents a greater than 40% decrease in age adjusted mortality since prostate specific antigen (PSA) based screening started in earnest in the 1990s. 1 The best available estimates from validated statistical models suggest that 45% to 70% of this observed decrease can be attributed to screening, 2 and that improvements in the treatment of high risk cancer explain 22% to 33%. 3 Despite this remarkable success, largely unprecedented in cancer epidemiology, last year the U.S. Preventive Services Task Force (USPSTF), author of by far the most influential guidelines among primary care practitioners (PCPs), 4 recommended that all routine prostate cancer screening in this country stop. 5 How could this have happened? The answer is multifactorial, but ultimately largely reflects inadequate appreciation by PCPs and cancer specialists of the dramatic prognostic heterogeneity of prostate cancer 6 as well as the widespread failure to target interventions to the men most likely to benefit. Screening should be targeted to men with a long life expectancy, and immediate treatment reserved for those men found to harbor higher risk cancers. 7, 8 However, PCPs tend to screen older men much more consistently than younger men, 9 and screen without much regard for comorbidity or life expectancy. 10 Urologists and radiation oncologists, for their part, consistently overtreat low risk prostate cancers 11 and conversely tend to underuse aggressive local treatments for high risk disease, particularly among older men. 12 Moreover, too often quality of life outcomes do not meet patient expectations, which leads to low satisfaction and high levels of bother and regret. 13, 14 The question about the utility of screening comes down to weighing the relative harms and benefits. While little serious argument exists that the over diagnosis and subsequent overtreatment of low risk prostate cancer are significant public health problems, the USPSTF recommendation substantially overstates the harms of screening and underappreciates the mortality benefits. With respect to harms, just one example is the repeated reference to a 0.5% perioperative mortality rate for radical prostatectomy and high rates of other complications. 5 These figures are drawn from studies of men undergoing open prostatectomy in the 1990s, predominantly by low volume surgeons, and ignore many more recent studies indicating much more favorable outcomes. The evidence for mortality benefits comes from 3 large randomized controlled trials, only 2 of which were considered by the USPSTF. The ERSPC (European Randomized Study of Screening for Prostate Cancer) randomized more than 182,000 men in 7 European countries to screening every 2 to 4 years, and demonstrated a 21% to 29% relative reduction in prostate cancer mortality risk. 15 The absolute (as opposed to relative) mortality reduction was relatively low at 11 years of followup at 1.07 deaths avoided per 1,000 men randomized. However, if the trial results are projected forward throughout the participants anticipated life span, the absolute mortality reduction increases, and the numbers needed to screen and diagnose to save a single life decrease precipitously. 16 The prostate arm of the PLCO (Prostate, Lung, Colorectal and Ovarian) Cancer Screening Trial has been incorrectly characterized by the USPSTF and others as providing evidence that screening provides no benefit. The PLCO trial randomized nearly 77,000 men in the U.S. to annual PSA screening for 6 years vs usual care. The trial showed no mortality differences between the 2 arms. However, usual care in the United States in the 1990s, when the trial was accruing, included a high intensity of PSA screening, and in fact 85% of men in the usual care arm were screened with PSA at least once before and/or during the study. 17 Furthermore, only 30% to 40% of the men with increased PSA were actually followed for prostate biopsy. 18 Thus, the investigators concluded that there is no benefit for annual screening rather than opportunistic screening, but it is not informative with respect to the overall mortality impact of screening. 19 Finally, the Göteborg randomized trial, frequently described as a subset of the ERSPC, was in fact conceived separately from the ERSPC, and only about half the men in the trial were represented in the ERSPC. 20 This trial stands apart from the others in that the median age of screening (56 years) was quite young and the PSA thresholds used for biopsy referral were relatively low. Furthermore, most men were identified with low risk disease or treated at least initially with observation. This study demonstrated a 44% reduction in prostate cancer mortality at 14 years of followup with mortality curves continuing to diverge beyond 14 years. This trial was not considered by the USPSTF in its evidence review. It is increasingly clear that accepting the USPSTF recommendation for the indiscriminate cessation of PSA screening will have major consequences in Continued on page 5

7 AUANews AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 5 Course #26PG Continued from page 4 terms of metastatic disease developing in soaring numbers of men, 21 as well as progressive pain and disability, and ultimately prostate cancer mortality. However, it is equally clear that the current rates of overtreatment, with attendant cost morbidity, are no longer acceptable in the eyes of many PCPs and health policy makers as well as a growing segment of the urological community. Therefore, the way forward must be a smarter approach to screening, which could potentially realize even greater gains in mortality reduction while substantially reducing overtreatment. Evidence from the PCPT (Prostate Cancer Prevention Trial) clearly demonstrated that dichotomizing PSA does not guarantee that men with levels below any given threshold do not harbor occult disease. Rather, PSA is a continuous variable, with the likelihood of cancer and high grade cancer decreasing but not disappearing at lower values. 22 Furthermore, PSA should not be interpreted in a vacuum. Other parameters such as age, family history or biopsy history, and physical examination findings substantially affect the risk of cancer and high grade cancer. 23 Multiple well validated, online risk calculators now exist which can be used easily in clinical practices whose patients are similar to those with whom the calculator was validated to integrate these parameters (for the calculator based on the PCPT see These results can also be translated into easily interpreted pictograms (see figure). Faced with such a straightforward decision aid, well informed men will likely find it easier to make a decision for or against subsequent biopsy. However, a man who has not had a PSA test does not have the opportunity to evaluate his individual risk. Moreover, the reassurance associated with a low PSA for the majority of men screened is frequently undervalued in the literature. 24, 25 Indeed, multiple lines of evidence suggest that the best approach may be earlier, less frequent screening for many men Finally, it is critical that the diagnosis of prostate cancer be decoupled from a reflexive decision for immediate treatment. A growing body of literature supports the safety of active surveillance for low risk prostate cancer, at least in the short term to intermediate term, 29 and surveillance is increasingly recognized as a preferred initial strategy for low risk disease. 30 Urologists, radiation oncologists and others treating prostate cancer must adapt their counseling and management to reflect the indolent natural history of most such tumors. Quite simply, if we do not reduce overtreatment, we will lose screening. What is the road forward for PSA screening in 2013? A major priority must be to correct overtreatment, but in the meantime, urologists have the opportunity to engage at the local level through education and advocacy. Prostate cancer knowledge and screening practices tend to be vary greatly among primary care providers. 4 It is likely that some PCPs will stop screening altogether in response to the USPSTF guideline. For many others the USPSTF guideline, together with the recent release of other guidelines which conflict to various degrees in their recommendations, has only increased confusion. Ultimately all screening decisions remain local, at least at this point. Urologists have the opportunity to regain the role of experts on this question, and should seek to build trust with their local PCPs as purveyors of balanced, data driven education on this question. It is also clear that the USPSTF structure and process are fundamentally flawed when it comes to issues of cancer. The panel membership reflects little expertise or publication record experience in any area of oncology, and explicitly excludes specialists from the arenas of clinical medicine and biostatistics. The review process ultimately suffers from insufficient accountability and transparency. At its 2012 annual meeting the American Medical Association adopted Resolution 517, which expressed concern regarding the USPSTF recommendations on mammography and PSA screening, and recommended procedural reform to allow for meaningful input by specialists and other stakeholders. A bill currently before Congress, the USPSTF Transparency and Accountability Act (H.R. 5998), would increase the transparency of the panel s processes and require it to include specialists in its deliberations. The bill has begun to garner bipartisan support. Urologists interested in this issue should contact their U.S. representatives and encourage their patients (particularly veterans) to do the same. Requests that the USPSTF reconsider its position can also be submitted directly via a Topic Reconsideration Form, available Continued on page 6

8 6 AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS Course #26PG Continued from page 6 at org/uspstf_topicrcnsdr. 1. Siegel R, Naishadham D and Jemal A: Cancer statistics, CA Cancer J Clin 2013; 63: Etzioni R, Tsodikov A, Mariotto A et al: Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control 2008; 19: Etzioni R, Gulati R, Tsodikov A et al: The prostate cancer conundrum revisited: treatment changes and prostate cancer mortality declines. Cancer 2012; 118: Tasian GE, Cooperberg MR, Cowan JE et al: Prostate specific antigen screening for prostate cancer: knowledge of, attitudes towards, and utilization among primary care physicians. Urol Oncol 2012; 30: Moyer VA on behalf of the U.S. Preventive Services Task Force: Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157: Esserman L, Shieh Y and Thompson I: Rethinking screening for breast cancer and prostate cancer. JAMA 2009; 302: Lu-Yao GL, Albertsen PC, Moore DF et al: Outcomes of localized prostate cancer following conservative management. JAMA 2009; 302: Wilt TJ, Brawer MK, Jones KM et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: Drazer MW, Huo D, Schonberg MA et al: Population-based patterns and predictors of prostatespecific antigen screening among older men in the United States. J Clin Oncol 2011; 29: Walter LC, Bertenthal D, Lindquist K et al: PSA screening among elderly men with limited life expectancies. JAMA 2006; 296: Cooperberg MR, Broering JM and Carroll PR: Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 2010; 28: Bechis SK, Carroll PR and Cooperberg MR: Impact of age at diagnosis on prostate cancer treatment and survival. J Clin Oncol 2011; 29: Barry MJ, Gallagher PM, Skinner JS et al: Adverse effects of robotic-assisted laparoscopic versus open retropubic radical prostatectomy among a nationwide random sample of Medicare-age men. J Clin Oncol 2012; 30: Schroeck FR, Krupski TL, Sun L et al: Satisfaction and regret after open retropubic or robot-assisted laparoscopic radical prostatectomy. Eur Urol 2008; 54: Schröder FH, Hugosson J, Roobol MJ et al: Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366: Gulati R, Mariotto AB, Chen S et al: Long-term projections of the harm-benefit trade-off in prostate cancer screening are more favorable than previous short-term estimates. J Clin Epidemiol 2011; 64: Pinsky PF, Blacka A, Kramer BS et al: Assessing contamination and compliance in the prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Clin Trials 2010; 7: Grubb RL 3rd, Pinsky PF, Greenlee RT et al: Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomized trial. BJU Int 2008; 102: Andriole GL, Crawford ED, Grubb RL 3rd et al: Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012; 104: Hugosson J, Carlsson S, Aus G et al: Mortality results from the Göteborg randomised populationbased prostate-cancer screening trial. Lancet Oncol 2010; 11: Scosyrev E, Wu G, Mohile S et al: Prostate-specific antigen screening for prostate cancer and the risk of overt metastatic disease at presentation: analysis of trends over time. Cancer 2012; 118: Thompson IM, Pauler DK, Goodman PJ et al: Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med 2004; 350: Thompson IM, Ankerst DP, Chi C et al: Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst 2006; 98: Cantor SB, Volk RJ, Cass AR et al: Psychological benefits of prostate cancer screening: the role of reassurance. Health Expect 2002; 5: Detsky AS: A piece of my mind. Underestimating the value of reassurance. JAMA 2012; 307: Ross KS, Carter HB, Pearson JD et al: Comparative efficiency of prostate-specific antigen screening strategies for prostate cancer detection. JAMA 2000; 284: Gulati R, Gore JL and Etzioni R: Comparative effectiveness of alternative prostate-specific antigenbased prostate cancer screening strategies: model estimates of potential benefits and harms. Ann Intern Med 2013; 158: Vickers AJ, Ulmert D, Sjoberg DD et al: Strategy for detection of prostate cancer based on relation between prostate specific antigen at age and long term risk of metastasis: case-control study. BMJ 2013; 346: f Cooperberg MR, Carroll PR and Klotz L: Active surveillance for prostate cancer: progress and promise. J Clin Oncol 2011; 29: Ganz PA, Barry JM, Burke W et al: National Institutes of Health State-of-the-Science Conference: role of active surveillance in the management of men with localized prostate cancer. Ann Intern Med 2012; 156: 591. COURSE #38IC Managing Metastatic Prostate Cancer in Your Urology Practice: Coding and Science K. C. Balaji, MD, Course Director and Ronald L. Davis, III, MD, Faculty During the last decade several prospective randomized phase III clinical trials demonstrated improvement in overall survival in patients with castration resistant prostate cancer (CRPC) with a variety of agents, including chemotherapy drugs, vaccines, novel androgen receptor (AR) antagonists and radionuclides used concurrently with androgen deprivation therapy (ADT). 1 These results are in sharp contrast to prior decades of clinical trials using a variety of agents that failed to demonstrate unequivocal improvement in survival in patients with metastatic prostate cancer. In addition, supplemental bone targeting agents have been shown to improve bone health in patients with nonmetastatic prostate cancer undergoing ADT. These newer drugs provide for a multidisciplinary approach to treating patients with advanced prostate cancer. In particular, several of the newer medications can be offered and administered in an office setting, and facilitate longer continuity of care for patients with existing providers including urologists. We discuss novel agents for CRPC that can be prescribed and managed primarily by urologists as part of a multidisciplinary approach. Sipuleucel-T (Provenge ) was the first cancer vaccine approved for human use. In patients with asymptomatic or minimally symptomatic CRPC with or without prior docetaxel chemotherapy, 3 doses of intravenous sipuleucel-t every 2 weeks resulted in improvement in median survival by 4.1 months compared to placebo. 2 The infusions can be given in the office. Three leukapheresis procedures at weeks 0, 2 and 4 can be arranged Continued on page 7

9 AUANews AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 7 Course #38IC Continued from page 6 at a local blood bank, the sample mailed to the manufacturer s central processing facility and infused to patients 3 days later. Patients may need to be premedicated with acetaminophen and an antihistamine. The infusion lasts for about 60 minutes and patients are observed for 30 minutes. Side effects that occur more than twofold compared to placebo include chills, fever, hypertension and groin pain. Abiraterone (Zytiga ) is an oral antiandrogen that inhibits the CYP17A1 enzyme involved in steroid synthesis. Oral abiraterone improved progression radiographic progression-free survival by 8.2 months and overall survival compared to placebo in patients with CRPC before chemotherapy 3 and overall survival in patients who have undergone chemotherapy by 3.9 months. 4 Abiraterone is currently the only novel antiandrogen that is approved for patients with CRPC before chemotherapy. Patients with CRPC with a prostate specific antigen (PSA) progression of more than 2 ng/ml, radiographic bone or soft tissue progression who are minimally symptomatic, or with an ECOG (Eastern Cooperative Oncology Group) performance status of 2 or less can be administered 1 gm (250 mg tablets 4) once a day at least 1 to 2 hours after a meal along with 5 mg prednisone by mouth twice a day. Adverse events of note include fluid retention or edema, hypokalemia, hypertension, cardiac disorder, alanine aminotransferase or aspartate transaminase increase. In general, the incidence of grade 3-4 toxicities was less than 5% higher in the abiraterone and prednisone groups compared to prednisone alone. A complete metabolic panel evaluation once every 4 to 6 weeks may be a reasonable strategy to monitor side effects while patients are on abiraterone. Enzalutamide (Xtandi ) is a secondgeneration AR antagonist that binds and prevents the translocation of AR to the nucleus. 5 Enzalutamide is currently approved for use in patients with CRPC who have progression after docetaxel chemotherapy. Because of a favorable toxicity profile, enzalutamide can be prescribed to patients without restrictions based on performance status. A phase III randomized study demonstrated that enzalutamide improved survival by 4.8 months compared to placebo. In addition, enzalutamide showed significant improvement in secondary end points, including time to PSA progression and radiographic progressionfree survival. 6 Enzalutamide is administered as 160 mg orally (40 mg tablets 4) once a day. Seizures were reported in 0.9% of patients. Unlike abiraterone, patients treated with enzalutamide do not need to be prescribed prednisone and the side effects profile does not require additional or specific tests related to the medication. The U.S. Food and Drug Administration recently approved radium-223 dichloride (Xofigo ), an intravenously administered radionuclide, for the treatment of patients with CRPC, symptomatic bone metastases and no known visceral metastatic disease. 7 Radium-223 dichloride is an alpha particle-emitting radiotherapeutic drug that mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover such as bone metastases. The approval was based on a doubleblind, placebo controlled, randomized phase III trial in patients with metastatic CRPC who had symptomatic bone metastases and no known visceral metastatic disease. The study demonstrated improvement in overall survival by 3.8 months in the treatment arm vs placebo and treatment also delayed time to first skeletal related event (SRE). The recommended dose and schedule for radium-223 dichloride are 50 kbq/kg (1.35 µci/kg) administered by slow intravenous injection over 1 minute every 4 weeks for 6 doses. The most common (at least 10%) adverse reactions in patients receiving radium-223 dichloride were nausea, diarrhea, vomiting and peripheral edema. The most common (at least 10%) hematologic laboratory abnormalities were anemia, decreased white cell count or thrombocytopenia. Of patients treated with radium-223 dichloride 2% experienced bone marrow failure or ongoing pancytopenia. Depending on local institutional arrangements patients could be referred to radiation oncology or nuclear physics departments for treatment. All patients with CRPC undergoing treatment with novel agents as previously discussed or chemotherapy should remain on continuous ADT, which places them at increased risk for osteopenia or osteoporosis. Efforts to preserve or improve bone health by supplementation with oral calcium and vitamin D is common clinical practice, although direct evidence of benefit is lacking. 8 Newer bone targeted agents have been studied in patients with prostate cancer undergoing ADT. Denosumab, a RANK (receptor activator of nuclear factor κb) ligand inhibitor, was evaluated in phase III randomized studies in patients on ADT for nonmetastatic androgen sensitive or castration resistant prostate cancer. Denosumab 60 mg (Prolia ) administered subcutaneously once in 6 months in patients with prostate cancer on ADT (presumably androgen sensitive) demonstrated a 4.8% to 6.7% change in difference in bone mineral density in favor of denosumab compared to placebo at 24 months. 9 Vertebral fractures occurred in 3.9% of the placebo group vs 1.5% of the treatment arm at 36 months. In another large study addressing the prevention of fractures in postmenopausal women with osteoporosis (FREE- DOM trial), 60 mg denosumab subcutaneously every 6 months increased the time before and decreased the incidence of vertebral fractures. 10 While these studies did not primarily address survival or SREs, the subcutaneous administration of 60 mg Prolia once in 6 months may be a cost-effective strategy in patients on ADT. Alternatively zoledronic acid (Reclast ), a bisphosphonate that inhibits osteoclastic activity, administered as a 4 mg intravenous infusion annually, has also been shown to improve bone mineral density by 2.1% to 7.1% in Continued on page 8

10 8 AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS Course #38IC Continued from page 7 patients with nonmetastatic prostate cancer receiving ADT. 11 Another large phase III, double-blind, randomized trial comparing intravenous 4 mg and 4 or 8 mg zoledronic acid (Zometa ) in patients with lung cancer and other solid tumors demonstrated that zoledronic acid decreased SREs (4 mg arm 38% and 4/8 mg arm 35% vs placebo 44%). 12 In 2 large phase III studies 120 mg subcutaneous denosumab (XGEVA ) were given every 4 weeks to patients with nonmetastatic CRPC. Compared to placebo, denosumab significantly increased bone metastasis-free survival by a median of 4.2 months and time to first bone metastasis by 3.7 months. 13 In another head-to-head comparison study with zoledronic acid, denosumab significantly increased time to first bone metastasis to 20.7 months compared to 17.1 months in the zoledronic acid arm. 14 Osteonecrosis of the jaw occurred in 2% to 5% of patients treated with denosumab and dental clearance is recommended before the initiation of treatment. While none of the bone preserving strategies has demonstrated significant differences in overall survival, the options may need to be discussed with patients undergoing ADT for nonmetastatic androgen sensitive or castration resistant prostate cancer. The benefits of a marginal decrease in SRE and a delay COURSE #47IC in time to first bone metastasis or SRE by about 4 months need to be weighed against the risks and costs of treatment, which are not negligible. In summary, in addition to the chemotherapeutic agents docetaxel and cabazitaxel, several classes of novel agents have shown improvement in overall survival and are currently approved for use in patients with CRPC. These agents are studied in arbitrary settings before or after chemotherapy. While the sequence of administration of these agents remains to be refined, abiraterone and radium-223 dichloride are approved for use before and after chemotherapy, and enzalutamide is approved for use after chemotherapy. The data on bone targeted agents are generated in patients with nonmetastatic prostate cancer undergoing ADT, but are often extrapolated in the clinical setting to patients with metastatic disease. Familiarity with the indications and side effect profiles of these novel agents will allow for a continuing and active role of urologists in the treatment of patients with CRPC. 1. Loblaw DA, Walker-Dilks C, Winquist E et al: Systemic therapy in men with metastatic castrationresistant prostate cancer: a systematic review. Clin Oncol 2013; 25: Kantoff PW, Higano CS, Shore ND et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: Ryan CJ, Smith MR, de Bono JS et al: Abiraterone Detection of Prostate Cancer and Castration Resistant Prostate Cancer: AUA Guidelines in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: de Bono JS, Logothetis CJ, Molina A et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: Tran C, Ouk S, Clegg NJ et al: Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009; 324: Scher HI, Fizazi K, Saad F et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: Parker C, Nilsson S, Heinrich D et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: Datta M and Schwartz GG: Calcium and vitamin D supplementation during androgen deprivation therapy for prostate cancer: a critical review. Oncologist 2012; 17: Smith MR, Saad F, Egerdie B et al: Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer. J Urol 2009; 182: Adami S, Libanati C, Boonen S et al: Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial. J Bone Joint Surg Am 2012; 94: Michaelson MD, Kaufman DS, Lee H et al: Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonistinduced bone loss in men with prostate cancer. J Clin Oncol 2007; 25: Rosen LS, Gordon D, Tchekmedyian S et al: Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial--the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003; 21: Smith MR, Saad F, Coleman R et al: Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379: Fizazi K, Carducci M, Smith M et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377: 813. H. Ballentine Carter, MD and Michael S. Cookson, MD, MMHC, Course Co-Directors; Peter C. Albertsen, MD, Adam S. Kibel, MD and Bruce J. Roth, MD, Faculty In response to the rapidly changing field of prostate cancer screening and treatment, the AUA combined 2 of its new guidelines into a single instructional course designed to update clinicians on the latest changes in evidence-based recommendations for the detection of prostate cancer (DPC) and the management of castration resistant disease (CRPC). Detection of Prostate Cancer Most prostate cancers are detected through prostate specific antigen (PSA) based screening of asymptomatic men. The publication of 2 randomized prostate cancer screening trials (PLCO [Prostate, Lung, Colorectal and Ovarian] Cancer Screening Trial and ERSPC [European Randomized Study of Screening for Prostate Cancer]) provided insight into the balance of benefits and harms of PSA based prostate cancer detection, justifying the development of an AUA guideline. 1-4 While digital rectal examination and biomarkers other than PSA are used for prostate cancer detection, a systematic Continued on page 9

11 AUANews AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 9 Course #47IC Continued from page 8 literature review revealed that there was not enough evidence to address the 4 a priori outcomes of interest (prostate cancer incidence/mortality, quality of life [QOL], diagnostic accuracy and harms of testing) for tests other than PSA, resulting in a PSA focused guideline on the detection of prostate cancer. The course covered the evidence review and interpretation that led to the guideline statements for the average risk, asymptomatic male in 4 age categories (less than 40 years, 40 to 54 years, 55 to 69 years and 70+ years). Emphasis was placed on the fact that the guideline panel did not go beyond the evidence (by assuming benefits in the absence of evidence) in formulating statements because the quality of the evidence was moderate for benefits and was high for harms. Three types of evidence-based statements were used in the DPC guideline based on the quality of the evidence and certainty of the results (standard, recommendation, option), and each statement was presented with the supporting evidence. Guideline Statement 1. Recommend against PSA screening in men younger than 40 years (Recommendation, Evidence Strength Grade C). In this age group there is a low prevalence of clinically detectable prostate cancer, 5 no evidence demonstrating benefit of screening, and the same harms of screening exist as in other age groups. Guideline Statement 2. Routine screening in men age 40 to 54 years at average risk is not recommended (Recommendation, Evidence Strength Grade C). For men age 40 to 54 years at higher risk (eg positive family history or African-American race), decisions regarding prostate cancer screening should be individualized. The 2 largest randomized trials did not address screening for this age group. 1-4 Although lower quality evidence demonstrates that a single PSA test before age 50 years can help risk stratify men for the presence of aggressive prostate cancer decades later, 6 this finding does not address whether the benefits of screening outweigh the harms of screening in these men. Because the prevalence of lethal prostate cancer in this age group is low, 7 lead times are longer in younger vs older men 8 and the side effects of treatment would be long lasting, the panel concluded that routine screening for this age group was not appropriate. Guideline Statement 3. Recommend shared decision making for men 55 to 69 years old who are considering PSA screening, and proceeding based on personal values and preferences. The highest level of evidence for the benefits of screening was in this age group (estimated 1 death averted per 1,000 men invited for screening over a decade and a relative risk reduction of 21%). 3 Given the modest reduction in cancer specific mortality, the potential for greater benefit with longer followup as well as the potential for harm (false-positive tests, prostate biopsy complications, over diagnosis and treatment related side effects), 9 the panel emphasized shared decision making as a prerequisite to PSA based screening. Guideline Statement 4. To reduce the harms of screening, a routine screening interval of 2 years or more may be preferred over annual screening in those men who have participated in shared decision making and decided on screening. Compared to annual screening, it is expected that screening intervals of 2 years will preserve the majority of the benefits, and reduce over diagnosis and false-positives (Option, Evidence Strength Grade C). While annual PSA testing has been the norm in the U.S., modeled simulations based on national and trial data 10 as well as evidence from randomized screening trials suggest that rescreening intervals longer than yearly will reduce harms but not benefits. 1-3 Guideline Statement 5. Screening as a routine is not recommended for men 70 years or older, or for any man with less than a 10 to 15-year life expectancy (Recommendation, Evidence Strength Grade C). Some men older than 70 years who are in excellent health may benefit from prostate cancer screening. The rationale for this statement is that 1) over diagnosis rates increase with age and are especially high among older men with low risk disease, 11 2) there was no reduction in prostate cancer death for men 70 years or older in a randomized screening trial, 3 and 3) competing risks of mortality in this age group make it less likely that a benefit from the treatment of localized disease will be realized Dr. Peter Albertsen Member, AUA Guideline Panel Dr. H. Ballentine Carter Chair, AUA Guideline Panel 1. Andriole GL, Crawford ED, Grubb RL 3rd et al: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009; 360: Schröder FH, Hugosson J, Roobol MJ et al: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009; 360: Schröder FH, Hugosson J, Roobol MJ et al: Prostatecancer mortality at 11 years of follow-up. N Engl J Med 2012; 366: Andriole GL, Crawford ED, Grubb RL 3rd et al: Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012; 104: Li J, Djenaba JA, Soman A et al: Recent trends in prostate cancer incidence by age, cancer stage, and grade, the United States, Prostate Cancer 2012; 2012: Lilja H, Cronin AM, Dahlin A et al: Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen at or before age 50. Cancer 2011; 117: Surveillance, Epidemiology and End Results: Fast Stats. Available at Accessed June 3, Savage CJ, Lilja H, Cronin AM et al: Empirical estimates of the lead time distribution for prostate cancer based on two independent representative cohorts of men not subject to prostate-specific antigen screening. Cancer Epidemiol Biomarkers Prev 2010; 19: Moyer VA and U.S. Preventive Services Task Force: Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157: Gulati R, Gore JL and Etzioni R: Comparative effectiveness of alternative prostate-specific antigenbased prostate cancer screening strategies: model estimates of potential benefits and harms. Ann Intern Med 2013; 158: Gulati R, Wever EM, Tsodikov A et al: What if I don t treat my PSA-detected prostate cancer? Answers from three natural history models. Cancer Epidemiol Biomarkers Prev 2011; 20: Wilt TJ, Brawer MK, Jones KM et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: Bill-Axelson A, Holmberg L, Ruutu M et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: Popiolek M, Rider JR, Andrén O et al: Natural history of early, localized prostate cancer: a final report from three decades of follow-up. Eur Urol 2013; 63: 428. Continued on page 10

12 10 AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS Course #47IC Continued from page 9 Castration Resistant Prostate Cancer While most patients with advanced prostate cancer respond initially to androgen deprivation therapy (ADT), they ultimately experience disease progression despite castration on average between 1 and 3 years after the initiation of therapy. Prostate cancer remains the second leading cause of cancer death in men in the United States with more than 28,000 deaths in 2012 alone. 1 The treatment of men with metastatic CRPC (mcrpc) has changed dramatically during the last decade. Before 2004, once primary ADT failed, treatments were administered solely for palliation. In landmark articles Tannock 2 and Petrylak 3 et al demonstrated that docetaxel improved survival for these patients with mcrpc. Following the approval of docetaxel and until the date for inclusion in the publication and presentation of the AUA CRPC guidelines, 4 additional agents (abiraterone, sipuleucel- T, cabazitaxel and enzalutamide) that show a survival benefit were approved by the U.S. Food and Drug Administration (FDA) on the basis of randomized clinical trials. 4-7 These agents have been tested in multiple disease states of CRPC to determine if or when patients might benefit from each treatment. After the AUA Annual meeting, on May 15, 2013 the FDA approved the use of radium-223 dichloride for the treatment of patients with mcrpc, symptomatic bone metastases and no known visceral metastatic disease. 8 This approval and others anticipated highlight the need for these guidelines to inform clinicians regarding changes in the management of this rapidly evolving disease state, and underscore the importance of periodic updating of these guidelines as new agents become available. The course highlighted the fact that the CRPC guidelines were developed using 6 index patients which were intended to represent the most common scenarios encountered in clinical practice. Accordingly, patients with CRPC were categorized based on the presence or absence of metastases, degree and severity of symptoms, overall performance status and whether they had received prior treatment with docetaxel. Guideline statements for each of the index patients were rated as standard, a recommendation, an option or an expert opinion based on the grading of the strength and quality of the evidence as well as the panel s assessment of the benefits and harms of treatment. The statements were also formatted into a user friendly algorithm, available in a pocket guide and web based format. A summary of the CRPC guideline statements for each index patient and respective statement was presented. Index patient 1 is asymptomatic with an increasing PSA and no radiographic evidence of metastases. Clinicians should recommend observation with continued ADT to those patients with nonmetastatic CRPC. Since all agents have potential side effects and no treatment has been shown to extend survival or demonstrate a clinically meaningful delay in the development of metastasis, we must first do no harm. Patients should be encouraged to enter clinical trials when available. Clinicians may also offer treatment with first-generation antiandrogens or first-generation androgen synthesis inhibitors to select patients. Clinicians should not offer systemic chemotherapy or immunotherapy to patients with nonmetastatic CRPC outside the context of a clinical trial. Index patient 2 is asymptomatic or has minimal symptoms, with metastases and no prior docetaxel. In this setting clinicians should offer abiraterone plus prednisone, docetaxel or sipuleucel-t. Clinicians may offer first-generation antiandrogen therapy, or first-generation androgen synthesis inhibitors or observation to index 2 patients who do not want or cannot have one of the standard therapies. 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, has a good performance status and has not previously received docetaxel. Clinicians should offer docetaxel chemotherapy and in this setting they may offer abiraterone plus prednisone. Clinicians may also offer ketoconazole plus steroid, mitoxantrone or radionuclide therapy to patients who do not want or cannot have one of the standard therapies. Clinicians should not offer treatment with estramustine or sipuleucel-t to these index 3 patients. Index patient 4 is symptomatic with metastases, a poor performance status and no prior docetaxel treatment. Clinicians may offer treatment with abiraterone plus prednisone to these patients. Clinicians may also offer treatment with ketoconazole plus steroid or radionuclide therapy to patients who are unable or unwilling to receive abiraterone plus prednisone. Clinicians may also offer docetaxel or mitoxantrone chemotherapy in select patients, specifically when performance status is directly related to the cancer. Clinicians should not offer sipuleucel-t to these patients. Index patient 5 is symptomatic with metastases, a good performance status and a history of docetaxel use. Clinicians should offer treatment with abiraterone plus prednisone, cabazitaxel or enzalutamide to these patients. If the patient received abiraterone plus prednisone before docetaxel chemotherapy, he should be offered cabazitaxel or enzalutamide. Clinicians may offer ketoconazole plus steroid to these patients if abiraterone plus prednisone, cabazitaxel or enzalutamide are unavailable. Clinicians may offer re-treatment with docetaxel to patients who were benefitting at the time of discontinuation (due to reversible side effects) of docetaxel chemotherapy. Index patient 6 is symptomatic, with metastases, a poor performance status and prior docetaxel treatment. The goal of palliation is to prevent and relieve suffering, and to support the best possible QOL for the patient and family. Palliative radiotherapy can be an option for controlling bone pain in some patients. Clinicians should offer palliative care to these patients. Alternatively, for selected patients clinicians may offer treat- Continued on page 11

13 AUANews AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 11 Course #47IC Continued from page 10 ment with abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid or radionuclide therapy. Clinicians should not offer systemic chemotherapy or immunotherapy to these patients. The guidelines also address bone health and state that clinicians should offer all patients with CRPC preventive treatment (eg supplemental calcium, vitamin D) to reduce the risk of fractures and skeletal related events. 9 Clinicians may choose denosumab or zoledronic acid when selecting a preventive treatment for skeletal related events in patients with mcrpc with bony metastases. 10, 11 Dr. Michael Cookson Dr. Adam Kibel Dr. Bruce Roth 1. Siegel R, Naishadham D and Jemal A: Cancer statistics, CA Cancer J Clin 2012; 62: 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: Petrylak DP, Tangen CM, Hussain MH et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: Ryan CJ, Smith MR, de Bono JS et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: Kantoff PW, Higano CS, Shore ND et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: de Bono JS, Oudard S, Ozguroglu M et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: Scher HI, Fizazi K, Saad F et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: National Cancer Institute: FDA Approval for Radium 223 Dichloride. Available at cancertopics/druginfo/fda-radium-223-dichloride. 9. Bischoff-Ferrari HA, Willett WC, Wong JB et al: Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005; 293: 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: Fizazi K, Carducci M, Smith M et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377: 813. COURSE #89IC Sequencing Novel Agents in Advanced Prostate Cancer 2013: Case-Based Key Knowledge for Urologists Judd W. Moul, MD, FACS, Course Director; Phillip G. Febbo, MD and J. Kellogg Parsons, MD, Faculty Since 2010 there has been unprecedented growth and change in the field of advanced prostate cancer with 6 new agents being approved by the U.S. Food and Drug Administration (FDA) and several more compounds pending approval as of the 2013 AUA Annual Meeting (see figure). While prostate cancer remains an integral part of urology, the field is changing. Certainly the last decade might be called the age of the robot. While robotics and early stage disease are still critically important, the emerging age might take urology back to our roots of comprehensive management of prostate cancer from early to late. When I was a resident in urology in the early 1980s, there were few medical oncologists who had an interest in prostate cancer and we, as urology residents, were well trained in the management of advanced prostate cancer. In those days we were well versed in managing spinal cord compression, and the use of orchiectomy/androgen deprivation therapy (ADT), oral antiandrogens and even diethylstilbestrol/ estramustine. In that era the NPCP (National Prostate Cancer Project) was a national multicenter cooperative group funded by the National Cancer Institute, focused on clinical trials for advanced prostate cancer, and was a urology run program. Giants in our field, including Continued on page 12

14 12 AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS Course #89IC Continued from page 11 Drs. Gerald Murphy, Dave McLeod, Paul Schellhammer and Joe Schmidt, were all urologists at the forefront of advanced disease. Many of the trials run by the NPCP in those days were systemic chemotherapy trials headed by urologists. We have built our field on the premise that urology is a surgical as well as a medical specialty, and this blending of disciplines is what has drawn many of us to the field since our specialty s inception. As more consolidation occurs in the academic and private sectors, more large groups are designating subspecialty care. It is critical for at least 1 partner to remain at the forefront of advanced prostate cancer and offer or assist in the offering of these new agents. Of the 6 new medications 5 (sipuleucel-t, abiraterone, enzalutamide, denosumab, radium-223) are squarely in the realm of urology, being oral agents or parenteral agents under our prescribing purview. Furthermore, many of us also embrace the multidisciplinary management of prostate cancer, and need to be familiar with these agents to help cement our expertise and relationship with our medical oncology colleagues and partners. It is critical for us to know these agents to be able to contribute to the best interest and care of our patients. At the 2013 AUA Annual Meeting this course drew a large and eager group of participants, and we used a case based and audience response system (ARS) learning format. In this overview I will also use these methods to summarize the new agents and proper sequencing. A 55-year-old otherwise healthy white male presented with back pain and was found to have a prostate specific antigen (PSA) of 165 ng/ml as well as Gleason 7, 8 and focal 9 disease on biopsy and a positive bone scan. With the grade D rating for prostate cancer screening proclaimed by the U.S. Preventive Services Task Force during the 2012 AUA Annual Meeting, we hope that this scenario of advanced disease at initial presentation will not reemerge. (We are happy to see that the AUA reaffirmed their support for PSA screening in men 55 to 69 years old in the latest 2013 AUA Best Practice Statement for PSA.) Because this patient had high risk M1 disease he was initiated on ADT with the pure gonadotropinreleasing hormone antagonist degarelix. Degarelix was FDA approved in December 2008 and has the advantage of lacking the testosterone surge or flare. Dr. J. Kellogg (Kelly) Parsons discussed this agent in detail and presented the latest clinical trial results. The patient had a good response and achieved a PSA nadir of 0.4 ng/ml 5 months after the initiation of ADT. While this is a good PSA nadir, a more ideal situation would be if the PSA nadir had gone to undetectable (less than 0.2 ng/ml). PSA in this patient started to increase and he was later started on denosumab (XGEVA, 120 mg subcutaneously monthly) to prevent the skeletal related events known to be common in the later course of advanced metastatic prostate cancer. This medication can be prescribed at the initial diagnosis of bony metastatic prostate cancer or can be withheld until the patient experiences castration resistant prostate cancer (CRPC), as was done with this patient. In the clinical trials of 120 mg denosumab the patients had CRPC but the FDA approved a broadened indication requiring bony metastases but not requiring the patient to have CRPC. Some clinicians believe we should only use this new agent for CRPC due to the cumulative risk of osteonecrosis of the jaw, while others believe that high risk cases with new M1 bony disease deserve consideration for denosumab. Since denosumab is a subcutaneous injection, and it does not affect renal function and does not require dose adjustment for renal insufficiency, it is becoming more popular for urologists to administer. Since the drug can cause hypocalcemia, urologists must check serum calcium levels before ordering denosumab, and must also ask patients to take vitamin D and calcium supplements while on 120 mg denosumab. Finally, XGEVA is not approved to treat men who do not have bony metastases. There is an FDA approved lower dose of denosumab (trade name Prolia ) to prevent bone loss (osteopenia and osteoporosis) in men without bone metastases who are taking luteinizing hormone-releasing hormone (LHRH) therapy for prostate cancer. This lower dose is 60 mg denosumab given subcutaneously twice yearly or every 6 months. This patient also received sipuleucel- T novel immunotherapy at this stage of asymptomatic CRPC. This patient specific agent involves 3 plasmapheresis procedures followed by administration of sipuleucel-t a few days later. The course of treatment is generally conducted over about 4 weeks. This is an ideal treatment for urologists and their staff to administer since patients are typically under the care of urologists during the course of the disease and the treatment has few side effects. The ideal patient for sipuleucel-t has documented clinical metastases and has an increasing PSA while on continuous hormonal therapy. He does not have bone or cancer pain requiring narcotic pain medications. He also must have a castrate testosterone level (less than 50 ng/dl) and meet the other on label indications. It is now estimated that more than 99% of insured patients in the U.S. will be covered for this treatment. Since this is an active immunotherapy, ideally patients should be treated early in the course of CRPC when their immune system is the most robust. It is important to select patients for sipuleucel-t who have a 3 to 6-month window or more before they will need chemotherapy or other therapeutics that might interfere with the immune system. Most recently the response to sipuleucel-t was examined based on PSA at the start of this novel treatment. In men who had PSA levels in the lowest quartile of IMPACT (Immunotherapy for Prostate Cancer Trial) (PSA less than 22 ng/ml), there was a more robust overall survival advantage to sipuleucel-t. Specifically the estimated 3-year sur- Continued on page 13

15 AUANews AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 13 Course #89IC Continued from page 12 vival in this group of patients was 62.6% for those treated with sipuleucel-t compared to 41.6% for controls. Since most patients with CRPC who have these lower PSA values are in the care of urologists, these latest data place the use of sipuleucel-t squarely with urology practices if they choose to administer this therapy to their patients. Later our patient had progression and was treated with systemic docetaxel at 75 mg/m 2 intravenously every 3 weeks. Docetaxel (former trade name Taxotere ) is now a generic medication in the U.S. Docetaxel was FDA approved in 2004, and between 2004 and 2010 was the only chemotherapy agent proven to extend survival in advanced prostate cancer. Our patient received 7 cycles of docetaxel before disease progressed. Dr. Phillip Febbo discussed chemotherapy options. Our patient had further progression and was treated with abiraterone. The current FDA approved indication for abiraterone is before or after the patient has progression on docetaxel based systemic chemotherapy. Abiraterone had not yet been FDA approved pre-chemotherapy when this patient was treated. However, in late 2012 the drug, which is also is active in the pre-chemotherapy setting, was officially FDA approved to be used in patients with CRPC before systemic chemotherapy. For most patients treated in 2013 the popular sequencing of novel agents would place the use of abiraterone before systemic chemotherapy. The dose of abiraterone is 1,000 mg orally once daily along with a low dose steroid (5 mg prednisone orally, twice daily). Abiraterone is a 17-lyase and 17-hydrolase inhibitor, and blocks key pathways in the steroid synthesis pathways leading to androgen production. Low dose prednisone (7.5 to 10 mg daily is a physiological dose) is recommended to be administered with abiraterone to help limit the overproduction of aldosterone, and the side effects of hypertension, hypokalemia and fluid retention. For urologists and urology residents taking board and recertification examinations, this mechanism of action is critical knowledge, especially now that abiraterone is approved in the pre-chemotherapy setting where we are in an ideal position to prescribe it. After the patient started to have progression on abiraterone, he was offered cabazitaxel, another novel systemic chemotherapy (Jevtana ). This novel agent was FDA approved in June 2010 for men in whom disease progressed after docetaxel. At the time it was the only agent to prolong survival in men who had progression on docetaxel. Now there are 3 novel agents (abiraterone, cabazitaxel and enzalutamide) that are FDA approved in the post-docetaxel disease state. Enzalutamide is another novel oral hormonal therapy agent approved by the FDA in 2012 to treat men who have progression after docetaxel based chemotherapy. This drug, taken at a dose of 160 mg daily, is a novel oral antiandrogen that is more potent than prior generation agents such as flutamide, nilutamide and bicalutamide. While the drug is currently only FDA approved in the post-chemotherapy clinical setting (as of August 2013), it also has activity in earlier stage disease and will likely be approved for use before chemotherapy sometime in the next 6 to 12 months. At that time it will be more commonly prescribed by urologists. Unlike abiraterone, enzalutamide does not have to be given with low dose prednisone. However, enzalutamide does have an approximate 1% risk of seizures associated with its use. Dr. Febbo also discussed using abiraterone followed by enzalutamide. While both novel oral hormonal agents are active in advanced prostate cancer, their benefit is not necessarily synergistic or cumulative. In other words, patients will likely have an initial robust response to either agent, but then switching to the other agent will not likely result in a sustained response and the response to the second used agent may be more short-lived. Once both agents (abiraterone and enzalutamide) are FDA approved in the pre-chemotherapy CRPC setting, urologists will have an important sequencing choice in determining which of these 2 agents to use first. At that time, cost considerations will likely come into play. As of mid 2013 the full retail cost of enzalutamide was approximately $7,400 per month and the cost of abiraterone was approximately $6,100 per month. The latest novel agent covered in the course was radium-223. This new agent is a parenteral radiopharmaceutical that can be ordered by urologists and is provided in a nuclear medicine or radiation oncology department setting. The product is an alpha-emitting liquid radiation product that has been given the trade name Xofigo. It received FDA approval shortly after the 2013 AUA Annual Meeting and is now in the supply chain at many major centers. Radium-223 is an alpha particle-emitting radioactive therapeutic agent indicated for the treatment of patients with CRPC, symptomatic bone metastases and no known visceral metastatic disease. The dose regimen of radium-223 is 50 kbq (1.35 µci) per kg body weight, given at 4-week intervals for 6 injections. Urologists may have been familiar with earlier generation radiopharmaceuticals such as strontium, but radium-223 is different. Radium-223 is alpha particle based and does not affect the bone marrow to the degree of older agents. In other words, radium-223 is much less likely to cause serious bone marrow toxicity with low white blood cell counts. In addition, the use of radium-223 is associated with an overall survival benefit whereas the older radiopharmaceuticals were never proven to extend survival. Since radium-223 has a unique mechanism of action, there might be a cumulative or synergistic effect when combined with other novel agents such as abiraterone or enzalutamide. However, this benefit has yet to be proven. In addition to the case, we also used an ARS to gauge the audience knowledge and to emphasize key teaching points. QUESTION 1. After initiation of degarelix therapy, castrate levels of testosterone are generally achieved within: A) 24 hours B) 3 days Continued on page 14

16 14 AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS Course #89IC Continued from page 13 C) 7 days D) 28 days ANSWER: B. Degarelix is a pure LHRH antagonist developed by Ferring Pharmaceuticals, Inc. and FDA approved in December Unlike other LHRH agonists, there is no initial testosterone surge or flare with degarelix and this may provide a clinical advantage. More than 95% of patients achieve castrate testosterone levels within 3 days. QUESTION 2. Which of the following is not true of abiraterone? A) a potential side effect is hypokalemia B) it is an oral medication C) it is superior to leuprolide for extending overall survival in men with metastatic prostate cancer D) it inhibits androgen synthesis ANSWER: C. Answers A, B and D are all correct. However, answer C is incorrect. There are no randomized trials in patients with metastatic prostate cancer comparing abiraterone to traditional LHRH agonists such as leuprolide. QUESTION 3. Enzalutamide has demonstrated improved overall survival compared to placebo in which of the following scenarios? A) metastatic CRPC after chemotherapy B) metastatic CRPC before chemotherapy C) high risk localized prostate cancer D) A and B ANSWER: A. Enzalutamide is currently only FDA approved and proven to extend overall survival for men with CRPC who have progression after docetaxel based chemotherapy. However, the drug is active in earlier stages of prostate cancer and may be proven to extend survival in CRPC before chemotherapy. As of this writing (August 2013) the only correct answer is A. QUESTION 4: How is radium-223 different from samarium and strontium treatment? A) it primarily targets bone metastases B) it has no bone marrow toxicity C) it has been proven to improve overall survival D) it improves symptoms related to bone metastases ANSWER: C. Radium-223 is the only radiopharmaceutical that has been proven to extend survival. The agent has much less bone marrow toxicity but it does have some, so answer B is incorrect. All these agents target bone metastases and all improve symptoms so A and D are not the best answers. QUESTION 5: Cabazitaxel is a novel taxane that: A) improves overall survival in men with metastatic CRPC after docetaxel B) has a high risk of neuropathy C) improves cancer related pain D) can be given safely with abiraterone ANSWER: A. The drug does not have a high risk of neuropathy so answer B is incorrect. The practical point is that even if neuropathy developed with docetaxel, cabazitaxel could be tried safely. Answer C is incorrect because we have little data from the pivotal phase III trial (the TROPIC trial) regarding pain relief. Answer D is incorrect because clinical trials have not been completed to know whether it is safe to administer cabazitaxel with abiraterone. QUESTION 6: In counseling patients about treatment with sipuleucel-t, they should be informed that: A) there is often a strong reaction to the infusion of the vaccine B) there is unlikely to be an impact on PSA C) they are likely to have nausea during treatment D) there are infectious risks to the vaccine similar to those of a blood transfusion ANSWER: B. Sipuleucel-T does not decrease PSA so the correct answer is B. Most patients have a very mild reaction or no reaction to the treatment so answer A is incorrect. It is also rare to have nausea so answer C is incorrect. The risk of infection is lower than with a blood transfusion since the patients own blood is used to make the product, so answer D is incorrect. Crawford ED, Tombal B, Miller K et al: A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol 2011; 186: 889. de Bono JS, Logothetis CJ, Molina A et al: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: de Bono JS, Oudard S, Ozguroglu M et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: Fizazi K, Carducci M, Smith M et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377: 813. Fizazi K, Scher HI, Molina A et al: Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13: 983. George D and Moul JW: Emerging treatment options for patients with castration-resistant prostate cancer. Prostate 2012; 72: 338. Kantoff PW, Higano CS, Shore ND et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411. Klotz L, Boccon-Gibod L, Shore ND et al: The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallelgroup phase III study in patients with prostate cancer. BJU Int 2008; 102: Parker C, Nilsson S, Heinrich D et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213. Petrylak DP, Tangen CM, Hussain MH et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: Scher HI, Beer TM, Higano CS et al: Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010; 375: Scher HI, Fizazi K, Saad F et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: Small EJ, Schellhammer PF, Higano CS et al: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-t (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 24: Smith MR, Saad F, Coleman R et al: Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379: 39. 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.

17 AUANews AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS 15 Plenary Sessions Continued PLENARY from page 14 SESSIONS Critical Discussion: Managing Progressive Prostate Cancer: How, Who and When Options for Progressive Prostate Cancer Expand, as do Questions Joel B. Nelson, MD, Discussant; James D. Brooks, MD and Robert E. Reiter, MD, Presenters (Reprinted from AUA Daily News, Tuesday, p 34) There have been a number of medical advances in the last few years to delay the progression of prostate cancer. In fact, the old days of a patient getting his affairs in order when advanced disease developed are coming to an end, said Joel B. Nelson, MD, professor and Chair of the Department of Urology at the University of Pittsburgh School of Medicine, and Co-Director of the University of Pittsburgh Cancer Institute Prostate Cancer Program. Dr. Nelson is one of three experts who will examine which patients need to be treated, how to treat them and when they need to be treated during a Critical Discussion today titled Managing Progressive Prostate Cancer: How, Who and When. The 20-minute presentation is part of Plenary I in Hall A of the San Diego Convention Center. Dr. Nelson has planned an interactive presentation in which he will introduce various situations and ask the two speakers for their comments and insight. He will be joined in the discussion by Robert E. Reiter, MD, professor of Urology and Molecular Biology, and Director of the Prostate Cancer Program at UCLA s Jonsson Cancer Center, and James D. Brooks, MD, professor of Urology and a member of the Stanford Cancer Institute at the Stanford School of Medicine. Dr. Nelson will begin the session by describing the spectrum of progressive disease and use study data to show the variability in what can occur when progressive disease develops after primary treatment. Critical decisions, such as when the urologist should consider starting hormonal therapy for a patient who has had definitive local therapy, will be discussed. Another critical decision is whether hormonal therapy should be used continuously or in an intermittent fashion. The panel will review the National Cancer Institute of Canada s PR.7 Trial, the results of which were published last Take Home Message: Prostate Cancer year. This study of intermittent hormonal therapy in patients with progressive disease showed that intermittent androgen deprivation therapy was noninferior to continuous therapy with respect to overall survival and that some quality of life factors improved with intermittent therapy. The panel will discuss when the urologist should consider switching a patient to another form of therapy after the disease becomes castration resistant. Dr. Nelson will address working with medical oncologists to better manage progressive prostate cancer. His own practice focuses primarily on open radical prostatectomy for clinically localized disease, and he also has an academic interest in advanced and progressive disease. Drs. Reiter and Brooks are urologic oncologists, each with a significant focus on prostate cancer. They are among the few professors of urology who still do basic science research as part of their practice, Dr. Nelson said. Dr. Paul H. Smith, III and Dr. Jay D. Raman, Hershey, Pennsylvania, provided the audience with highlights of the AUA meeting on prostate cancer. The abstract numbers are indicated in parentheses. (Reprinted from AUANews 2013; Vol. 18, No. 7, pp 7-8) Prostate cancer had a robust presence at the 2013 AUA Annual Meeting with more than 500 abstracts presented in 27 poster or podium sessions. Accompanying these presentations were well constructed plenary sessions as well as 3 new clinical guidelines including the Early Detection of Prostate Cancer. Epidemiology and Natural History Active surveillance (AS) regimens continued to be underused in the United States in the last decade (220). Such observations are contrasted by findings from a Swedish population based study emphasizing that more than 50% of patients with low risk disease are successfully maintained on AS (661). In addition, at a 10-year median followup only 54% of patients on AS experienced disease progression with less than 1% cancer specific mortality (CSM) (223). In 3,013 patients the metabolic syndrome was associated with prostate cancer (OR 1.44) as well as high grade histology (OR 1.58) at prostate needle biopsy (PNBx) (341). Detection and Screening At a median followup of 12.8 years the Rotterdam section of the ERSPC (European Randomized Study of Screening for Prostate Cancer) reported a 32% risk reduction in CSM among screened men 55 to 69 years old but no benefit in men 70 years old or older (1932). The grade D recommendation assigned to prostate specific antigen (PSA) screening by the U.S. Preventive Services Task Force has translated to a decrease in the number of men screened as determined by patients presenting with an increased PSA or those undergoing PNBx (1253, Continued on page 16

18 16 AUA 2013 SAN DIEGO, CA ANNUAL MEETING HIGHLIGHTS Plenary Sessions Continued from page ). The prolonged impact of PNBx on erectile function and urinary symptoms (1927) and the increased risk of infectious complications with repeat biopsies (1244, 1246) highlight the need to improve biopsy accuracy. Novel techniques such as magnetic resonance imaging (MRI)/transrectal ultrasound fusion may be valuable given their ability to improve the detection of high grade tumors while reducing the number of cores needed for diagnosis (2218, 2219). Markers Epigenetic field effects can aid in the diagnosis of prostate cancer at PNBx. In particular, variations in the methylation patterns of the EVX1 and FGF1 genes in tumor negative biopsy tissue differentiate between patients with and without prostate cancer (negative predictive value 0.909, AUC 0.774) (2132). In patients with adverse pathological features at prostatectomy genomic classifier systems are able to identify patients at greatest risk for disease progression and disease specific mortality (2130, 2229, 2230, 2243). Such tools can help tailor individual patient followup regimens as well as the decision making process regarding adjuvant therapy. Staging Preoperative MRI may aid surgical planning before prostatectomy. In a series of 353 patients undergoing robotic assisted laparoscopic prostatectomy (RALP), preoperative MRI had a positive and negative predictive value of 59% and 80%, respectively, for the detection of extraprostatic extension (239). Furthermore, a nomogram combining MRI findings with biopsy data (percent ipsilateral positive cores) improved the detection of side specific extracapsular extension (AUC 0.871) (237). Classification of pt3a cancers into focal vs established demonstrated prognostic significance when evaluating 10-year disease-free survival after prostatectomy (367). Localized Disease Of approximately 5,500 patients undergoing minimally invasive radical prostatectomy those undergoing laparoscopic radical prostatectomy had a higher rate of overall complications as well as high grade (Clavien III/IV) complications than those undergoing RALP (676). In a SEER (Surveillance, Epidemiology and End Results)-Medicare based study of nearly 10,000 patients undergoing prostatectomy incisional hernias were significantly more common after minimally invasive radical prostatectomy (HR 3.2) (1347). Two reports addressed the therapeutic impact of nodal yield at prostatectomy, and neither extended lymphadenectomy during robotic prostatectomy (359) nor higher overall nodal yield (358) impacted the risk of biochemical recurrence (BCR). Advanced Disease A report on 1,088 chemotherapy naïve patients with metastatic castration resistant prostate cancer (CRPC) randomized to abiraterone acetate or placebo indicated delayed time to disease progression in the abiraterone acetate cohort (713). The alpha-emitting radiopharmaceutical radium-223 dichloride was shown to reduce pain and opiate use as well as improve quality of life in patients with CRPC and bone metastases (714). Between 1992 and 2007 the use of chemotherapy in men with metastatic prostate cancer increased from 12% to 31% (779). However, accompanying this greater use of chemotherapy was a 50% hospital readmission rate from therapy, highlighting the morbidity associated with metastatic prostate cancer and resultant treatment. In a retrospective review of 292 patients with pt3n+m0 prostate cancer, adjuvant hormone therapy improved BCRfree survival vs adjuvant radiotherapy or observation alone, but had no impact on cancer specific survival or overall survival (718). The optimal timing to initiate salvage radiation therapy (SRT) for BCR after prostatectomy was addressed in a review of the SEARCH (Shared Equal Access Regional Cancer Hospital) database (719). A pre-srt PSA of 1 ng/ml or less vs greater than 1 ng/ml was associated with a lower failure rate, although there were no observed differences in failure rates among substratified pre-srt PSA values less than 1 ng/ml. Basic Research Several groups explored the impact of diet on prostate tumorigenesis. A low fat fish oil diet was associated with decreased pro-inflammatory eicosanoids and prostate cancer cell cycle progression score compared to Western diet in a cohort of men undergoing prostatectomy (313). A prostate cancer mouse xenograft model suggested that compared to other fat sources (olive oil, corn oil or other saturated fats), only fish oil was associated with slowed tumor growth and improved survival (316). A high fat diet resulted in larger tumor size and significant alterations in microrna expression, particularly mir-130a down-regulation, in a prostate cancer mouse xenograft model (314). Such microrna changes may underlie high fat diet induced prostate tumorigenesis. Overall the Annual Meeting highlighted the wealth of work being done to better understand the biology, therapy and natural history of prostate cancer. Such knowledge will be increasingly important given the changing landscape of prostate cancer detection.

19 Registration opens on December 5, Meeting begins on Friday, May 16!

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