6th Annual Interdisciplinary Prostate Cancer Congress

1. 6th Annual Interdisciplinary Prostate Cancer Congress Meeting in a Box

2. Screening for Prostate Cancer – The PSA Controversy Leonard G. Gomella, MD

3. US Preventive Services Task Force (USPSTF) Screening Recommendations • Per the 2012 USPSTF, no healthy man should undergo PSA screening unless symptoms of prostate cancer present • Full implications have yet to be realized • Defined prostate screening as • grade D • recommendation against the service. They had moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. Topic assigned by HHS Agency for Healthcare Research & Quality • Task Force: • General physicians • Nurses • Health psychologists • Epidemiologists • Statisticians Task Force set up by congressional mandate in 1984 Grade the quality of evidence-based research HHS=US Health & Human Services Department; PSA=prostate-specific antigen. Moyer VA, Ann Intern Med. 2012;157:120-34.

4. National Comprehensive Cancer Network (NCCN) Screening Guidelines • NCCN panelists note the variability in prostate tumor behavior • Key point is discussion between patient and provider about the risks and benefits of early detection of and treatments for prostate cancer • Goal is to evaluate aggressiveness of the cancer • Once a patient age 40 starts having risk and benefit discussion about baseline digital rectal exam (DRE) and absolute PSA values • May annually follow up with DRE and repeat PSA in patients with elevated PSA (≥1.0 ng/mL), African Americans, men taking 5-alpha-reductase inhibitors • Testing and biopsy decisions should be individualized for men > age 75 years • Further timing of follow-ups and DRE and PSA testing dependent on age, and life expectancy • Trying to determine need for TRUS-guided biopsy, and may also use PSA density, percent-free PSA, and PSA velocity to determine need for biopsy or if cancer is present PSA=prostate-specific antigen; DRE=digital rectal examination; TRUS=transrectal ultrasound. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer Early Detection, V2.2012. Accessed Sep 9, 2013.

5. American Cancer Society (ACS) Screening Guidelines • ACS supports informed discussion between healthcare provider and asymptomatic men about screening for prostate cancer • Average risk: annually beginning age 50 years with 10+ year life expectancy • Age 45 if high risk: High risk includes African-American men or those with first-degree relative with prostate cancer <65 years of age • Age 40 if very high risk: Very high risk includes multiple family members with prostate cancer at early age • Include information about uncertainties, risks, and potential benefits • If testing performed, PSA with or without DRE • 2009 guidelines reaffirmed in 2013 Wolf AM, et al. CA Cancer J Clin. 2010;118:244-50.

6. American Urological Association (AUA) Screening Guidelines • Recommendations based on age and risk • Average risk: • < Age 40, not recommended • Age 40-54: do not recommend routine screening • Age 55-69: informed shared decision making about screening risk and potential benefits • Age 70+ or patients with <10-15 years life expectancy: do not recommend routine screening • Alternatively, can individualize based on baseline PSA • High risk: <55 with positive family history or African-American race; decisions should be individualized • If decision to screen, frequency should be 2+ years instead of annual • Panel believes this will reduce overdiagnoses and false-positives while maintaining the majority of the benefits Carter HB et al. J Urol. 2013;190:419-26

7. PSA-Based Prostate Screening Potential Benefits Risks and Limitations Potential for overdiagnosis and overtreatment in patients with clinically insignificant cancer Decrease in quality of life, complications, and cost Various physiological and pathological factors can cause a rise in PSA, often temporal If PSA detectable, no matter how low, prostate cancer still a possibility2 Can take time for effect of population-based PSA screening to become significant3 Though increase in survival of prostate cancer patients, not able to directly link it to PSA-based screening • Earlier diagnosis: • Allows finding cancer at earlier stage, before it is symptomatic, while it is likely localized • 70% decrease in metastatic disease at diagnosis1 • Relative survival has increased to close to 100% since PSA screening became highly utilized1 • From 1975-1979, 10-year survival was 55.7% • In 2000, 10-year survival was 98.4% • US death rates have decreased about 4% per year 1. Howlader N et al. SEER Cancer Statistics Review, 1975-2010, National Cancer Institute. http://seer.cancer.gov/csr/1975_2010/. Accessed Sept 2, 2013. 2. Thompson IM et al. N Engl J Med. 2004;350:2239-46. 3. Loeb S et al. J ClinOncol. 2011;29:464-7.

8. Implications for Patient Care • PSA-based screening not appropriate for overall population • Prostate cancer screening makes sense in certain populations after informed discussion between patient and provider • Patients at high risk for the disease • Patients at high risk for death or morbidity from the disease • Patients in good health with life expectancy > 10-15 years • Can be difficult deciding treatment versus observation for an individual patient • Advise patients to seek a second opinion, especially with clinician experienced with both active surveillance and active treatment

9. Active Surveillance—Current Status and Future Directions E. David Crawford, MD

10. Watchful Waiting vs Active Surveillance / Active Monitoring

11. National Comprehensive Cancer Network (NCCN) Guidelines on Active Surveillance National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer, V4.2013. Accessed Sep 1, 2013.

12. Summary of Active Surveillance Studies CSS=cancer-specific survival; mo=months; OS=overall survival; p=pathologic; RP=radical prostatectomy.

13. Active Surveillance: Current Approach • Offered to all men with Gleason 6, PSA ≤10 (accepted by most) • PSA kinetics a guide only • Confirmatory biopsy within 1 year, targeting anterior/anterolateral horn • Repeat biopsy every 3-5 years (age, risk tolerance, PSA) to age 80 years • MP-MRI for PSA doubling time < 3 years or volume increase or 3+ minor element 4 • Treat if significant Gleason 4 or unequivocal lesion > 1 cm on MRI

14. New Endocrine Options for Advanced Prostate Cancer Robert Dreicer, MD, MS, FACP, FASCO

15. Abiraterone Phase III Trials: COU-AA-301 andCOU-AA-302 Primary endpoint: OS (N=1195) 2:1 Abiraterone 1000mg qd+ prednisone bid • 301 eligibility criteria: • Progressive mCRPC pts who failed a docetaxel regimen ± another chemotherapy • 302 eligibility criteria: • Progressive chemo-naïve mCRPC, asymptomatic or mildly symptomatic RANDOMI ZE Placebo qd+ prednisone bid 1:1 (N=1088) Co-primary endpoints: OS + rPFS by central review 1. de Bono et al. N Engl J Med. 2011;364:1995-2005. 2. Ryan CJ, et al. N Engl J Med. 2013;368:138-48.

16. Enzalutamide Phase III AFFIRM Trial • Median OS: 18.4 mo enzalutamide, 13.6 mo placebo (P < 0.0001) • Adverse events: Enzalutamide group reported 45% of patients with any ≥ grade 3 adverse event vs 53% with placebo • 3% of enzalutamide group and 4% of placebo group had an adverse event that led to death • Highest reported ≥ grade 3 adverse event was fatigue, with 6% of the enzalutamide group and 7% of placebo reporting (N=1199) 2:1 Enzalutamide 160 mg qd RANDOMI ZE • Eligibility criteria: • CRPC pts who progressed during or after treatment with a docetaxel-based regimen Primary endpoint: OS Placebo qd mOS=median overall survival. Scher HI et al. N Engl J Med. 2012;367:1187-97.

17. Second-Line Hormonal Therapy: Remaining Issues • Optimal timing • Role of combination therapy • When to stop androgen biosynthesis inhibitors • Major issue in the pre-chemotherapy setting • Optimal dose of steroids for androgen biosynthesis inhibitors • Issues of divergent practice urology vs oncology

18. Endocrine Agents in Development • Lyase inhibitors • Orteronel (TAK 700) • TOK-001 (galeterone) • CFG920 • VT-464 • EN3356 • Antiandrogens • ODM-201 • ARN-509 • AZD-3514 • EZN-4176 • TOK-001 (galeterone)

19. Evolving Approaches for Chemotherapy for Advanced Prostate Cancer Daniel P. Petrylak, MD

20. Docetaxel Hormone-Refractory Prostate Cancer • Docetaxel + prednisone remains the standard of care for first-line chemotherapy for metastatic disease • Investigating markers for drug resistance *Compared to mitoxantrone arm. d2=day 2 of cycle; HR=hazard ratio; mos=months; mOS=median overall survival; pred=prednisone; q=every. 1. Tannock et al. N Engl J Med. 2004;351:1502-12. 2. Berthold DR, et al. ASCO Prostate Cancer Symposium 2007; abstract 147. 3. Petrylak et al. New Engl J Med. 2004;351:1513-20.

21. Phase III Trials of Docetaxel Combinations • To date, no combination improves on docetaxel and prednisone

22. Phase III TROPIC Registration Study of Cabazitaxel vs Mitoxantrone in Docetaxel-Resistant Patients • mOS: 12.7 momitoxantrone+prednisone, 15.1 mocabazitaxel+prednisone (P<0.0001) • Adverse events: Cabazitaxel group reported 8% patients with ≥ grade 3 febrile neutropenia vs 1% in mitoxantrone • Diarrhea was reported in 6.2% of cabazitaxel group and 0.3% of mitoxantrone group • Leukopenia also higher in cabazitaxel group (68% to 42%) (N=755) • Eligibility criteria: • mCRPC pts who progressed during or after treatment with a docetaxel-based regimen • Stratification: • ECOG PS (0, 1 vs 2) • Measurable vs non-measurable disease Cabazitaxel q3w + prednisone/prednisolone qd * 10 cycles RANDOMI ZE Mitoxantroneq3w + prednisone/prednisolone qd * 10 cycles Primary endpoint: OS Secondary endpoints: PFS, response rate, safety de Bono et al. Lancet. 2010;376:1147-54.

23. Advances in Immunotherapy Susan F. Slovin, MD, PhD

24. Rationale for Immunologic Approaches in Prostate Cancer • Well-characterized cell surface molecules: PSA, PSMA, PAP, STEAP, PSCA, Globo H, GM2, MUC-1,2, Tn, TF, Lewisy • Biomarkers [PSA, CTCs] to study disease progression/response • Widely applicable to all disease states: • Biochemical relapse thru castration-resistant disease • Likely potentiated via combinatorial approaches: radiotherapy, chemotherapy, biologic agents (GM-CSF, IL-2) or checkpoint inhibitors (anti-CTLA-4, anti-PD-1), monoclonal antibody-chemo conjugates

25. Immunotherapies to Date… Successes (limited) Failures (many) G-Vax Protein Peptide DNA • Sipuleucel-T • Ipilimumab • PROSTVAC • Anti-PD-1

26. Brief Summary of Immunologic Trials in Prostate Cancer • Sipuleucel-T autologous immunotherapy: Median overall survival benefit 4.1 mo in phase III IMPACT trial (P = 0.03)1 • PROSTVAC-VF vaccine: Primary endpoint of PFS in phase II trial similar with control, but at 3 years median overall survival benefit 8.5 mo (P = 0.006)2 • Ipilimumab antibody to CTLA-4: 10 mg/kg with or without radiotherapy had benefit for patients with tumor-evaluable disease in phase II trial,3 • Ipilimumab is being further tested in 2 phase III trials: one in chemotherapy-naïve, the other in docetaxel-resistant cases 1. Kantoff PW et al. N Engl J Med. 2010;363:411-22.2. Kantoff PW et al. J ClinOncol. 2010;28:1099-105. 3. Slovin SF et al. Ann Oncol. 2013;24:1813-21.

27. Conclusions on Immunologic Approaches in Prostate Cancer • Not every immunotherapy fits a specific disease and vice versa • Appropriateness of immune therapy for all clinical states of disease but clinical judgment prevails (ie, potential delay in impact of immune therapy) • Combinatorial approaches: checkpoint inhibitors alone/together/chemo/RT/vaccines/cytokines • Monoclonal antibody-chemo conjugates

28. Novel Therapies and Bone-Targeted Therapy Daniel P. Petrylak, MD

29. Skeletal-Related Events in Cancer • The skeleton is the most common site of metastasis • SRE: fracture, spinal cord compression, radiation or surgery to bone, and hypercalcemia SRE=skeletal-related event. Coleman. Cancer. 1997;80:1588-94. Bubendorf, et al. Hum Pathol. 2000;31:578-83. Saad, et al. Cancer. 2007;110:1860. Coleman. Oncologist. 2004;9:14-27.

30. Phase III Trial of Denosumab vs Zoledronic Acid in Castration-Resistant Prostate Cancer • Supplemental calcium and vitamin D were strongly recommended • Primary endpoint: (noninferiority) time to first on-study SRE • Secondary endpoint: superiority (N=1901) Zoledronicacid 4 mg IV + placebo scq4wk • Eligibility criteria: • Hormone-refractory (castration-resistant) • ≥1 bone metastasis • Stratification: • Previous SRE • PSA concentration • Chemotherapy for prostate cancer within 6 wks RANDOMI ZE Denosumab120 mg sc+ placebo IV q4wk IV=intravenous; SC=subcutaneous. Fizazi et al. Lancet. 2011;377:813-22.

31. Phase III Trial of DenosumabvsZoledronicAcid Results *P=0.0002 non-inferiority. CI=confidence interval; CTCAE=common terminology criteria for adverse events; gr=grade; NR=not reported; TTP=time to progression. Fizazi et al. Lancet. 2011;377:813-22.

32. FDA-Approved Bone-Targeting Radionuclides for the Treatment of Bone Metastases 1. Xofigo [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2013. 2. Quadramet [package insert]. Princeton, NJ: EUSA Pharma (USA), Inc.; 2009. 3. Metastron[package insert]. Arlington Heights, IL: Medi-Physics, Inc.; 1998.

33. Bone-Targeting Radionuclides for Patients with Prostate Cancer Bone Metastases ALP=alkaline phosphatase; EBR=external beam irradiation; PDS=pain descriptor scale (nonlinear); RT=radiotherapy; VAS=100-mm pain intensity visual analog scale (linear). Sartor et al. Urology. 2004;63:940-5. Nilsson et al. Lancet Oncol. 2007;8:587-94. Porter et al. Int J RadiatOncolBiol Phys. 1993;25:805-13.

34. Cabozantinib in Bone Metastatic Prostate Cancer • Phase II Trial1 • Cabozantinib administered 100 mg daily • 67% of patients (total N=171) showed bone scan response after retrospective review • Reduction in bone markers • Other benefits: • Pain improvement and narcotics reduction • PFS benefit seen regardless of docetaxel pretreatment or naïve • PSA changes discordant with other measures of antitumor activity • 2nd trial to attempt lower starting doses to limit adverse events2 • Primary outcome was week 6 bone scan response • For N=24 at 40 mg, 1 complete response, 15 partial responses, 8 stable disease with tolerable adverse event profile • Phase IIIs ongoing 1. Smith DC et al. J ClinOncol. 2013;31:412-19. 2. Lee RJ et al. Clin Cancer Res. 2013;19:3088-94.

35. Conclusions on Novel Therapies and Bone-Targeted Therapies • Alpha-emitting isotope therapy improves survival in men with CRPC • Minimal toxicity • Combination studies with hormonal/chemotherapeutic agents are underway • New agents are targeting bone and have promising activity

36. Can We Combine Novel Agents in the Management of Advanced Prostate Cancer? Robert Dreicer, MD, MS, FACP, FASCO

37. Combination Therapy in Metastatic Castration-Resistant Prostate Cancer: Current Status • Testosterone suppression • + second-line hormonal therapy • + sipuleucel-T • + docetaxel, + bone-targeted agents • + radiotherapy

38. Brief Summary of Abiraterone + Enzalutamide Trials in Prostate Cancer • Phase II MDV3100 in bone metastatic CRPC (NCT01650194) • N=60, prior chemotherapy allowed • Proposed Intergroup 3-arm phase III metastatic CRPC • Enzalutamide + abiraterone + prednisone • Enzalutamide monotherapy • Abiraterone + prednisone CRPC=castration-resistant prostate cancer; Ph=phase.

39. Combination and/or Sequential Therapy in CRPC: Challenges • Current reimbursement paradigm is slowly but inexorably coming to an end. • Compendium listing of drugs will be nice, but will increasingly miss the point. • In a world of Accountable Care Organizations, medical homes, and contracts for populations, we need to think about VALUE in addition to science/clinical results.

40. Radium-223 Combination Therapy • Excellent toxicity profile • Unique mechanism of action • Combination studies with androgen receptor-targeted agents • Issues of other bone-targeted therapy when combined with two potent agents that decrease SREs/impact survival • Combination with immunomodulatory agents

41. Near-Term Questions for Combination Therapy • Can more-potent androgen receptor-targeted therapy cure patients with minimal disease? • The adjuvant breast paradigm • Lyase inhibitor + next-generation androgen receptor antagonist • Locally-advanced prostate cancer status post combined modality therapy • Cost effective/value-based care questions

42. Emerging Biomarkers: Ready for Prime Time? Daniel P. Petrylak, MD

43. Potential DNA Biomarkers • APC = adenomatosis polyposis coli • Inactivated in various malignancies including prostate cancer by genetic and epigenetic mechanisms • GSTP1 = glutathione-S-transferase-P1/π • Believed to play a role in the protection of DNA from oxidative damage • RASSF1A = Rasassociation domain family 1 isoform A • Tumor suppressor • RARβ2 = retinoic acid receptor β2 • Tumor suppressor • MDR1 = multidrug resistance 1 • May play a role in anticancer drug resistance • CCND2 = cyclin D2 • Cell-cycle regulator

44. PSA Response to CRPC • While a ≥50% decrease from baseline has been accepted as clinically relevant response,1a ≥30% decrease has also been demonstrated as a surrogate threshold for predicting survival.2,3 • Record the percentage change from baseline (rise or fall) at 12 weeks, and separately, the maximal change (rise or fall) at any time using a waterfall plot.4 1. ScherHI, et al. J ClinOncol. 2011;29:3695-704. 2. Petrylak DP, et al. JNCI. 2006;98:516-21. 3. Armstrong AJ, et al. J Clin Oncol. 2007;25:3965-70. 4. ScherHI, et al. J ClinOncol. 2008;26:1148-59.

45. PSA Does Not Always Accurately Reflect Response to CRPC Therapy • Newer therapies, such as sipuleucel-T will improve survival without decreasing PSA levels. • For cytotoxic or hormonal therapies, early PSA responses, rises or declines, should not be used for clinical decision making.1 • Discordance between PSA change and clinical responses, such as pain response2 or progression/regression of bone metastases, have been reported.3 1. ScherHI, et al. J ClinOncol. 2008;26:1148-59. 2. Berthold DR, et al. Clin Cancer Res. 2008;14:2763-7. 3. Ryan CJ, et al. Clin Cancer Res. 2011;17:4854-61.

46. Other Biomarkers With Correlation to Outcomes in Prostate Cancer ADT=androgen-deprivation therapy; DHT=dihydroxytestosterone; LHRH=luteinizing hormone-releasing hormone 1. Perachino M, et al. BJUI. 2010;105:648-51. 2. Nishiyama T, et al. Cancer Res. 2004;10:7121-6. 3. de Bono JS, et al. Clin Cancer Res. 2008;14:6302-9.

47. Other Biomarkers With Correlation to Outcomes in Prostate Cancer (cont.) 1. Danila DC, et al. Eur Urol. 2011;60:897-904. 2. Mehra R, et al. Cancer Res. 2008;68:3584-90. 3. Attard G, et al. Oncogene. 2008;27:253-63. 4. Attard G, et al. Cancer Res. 2009;69:2912-8. 5. Guo Z, et al. Cancer Res. 2009;69:2305. 6. George DJ, et al. Clin Cancer Res. 2005;11:1815-20.