1. 2012 GU Cancers Symposium San Francisco, CA February 2-4, 2012 Jerry M. Maniate MD, M.Ed, FRCPC Assistant Professor, Department of Medicine University of Toronto Dr. H. James Watt Hematology/Oncology Clinic Service of Hematology/Oncology Director of Medical Education St. Joseph’s Health Centre

2. Objectives In the next 30 minutes...

3. Outline Prostate Cancer Bone Targeted Therapy Renal Cell Cancer

4. Highlights of GUCA Symposium 2500 attendees 284 Prostate cancer abstracts 136 Renal cell carcinoma abstracts

5. Novel Targets & Novel Agents

6. MDV3100 Specific inhibitor of androgen receptor No known effect on androgen production Preclinical: anti-proliferative activity on prostate cancer cells that harbour amplification of AR Scher, Lancet 2010; 375: 1437 Scher, JCO, March 1, 2006

7. MDV3100 Progression measured as rising PSA Improved OS post-docetaxel Median OS: 18.4 mths vs. Not hormone resistant but rather castrate resistant due to drive of AR signaling Scher, Lancet 2010; 375: 1437 Scher, JCO, March 1, 2006

8. Post-chemotherapy: failed docetaxel MDV3100 160 mg po OD MDV3100 PlaceboPlacebo Primary EP: Overall Survival Primary EP: Overall Survival AFFIRM Study. Scher HI et al. JCO 30, 2012 (suppl 5; abstract LBA1) Secondary EP: Radiographic PFS Time to first SRE Time to PSA progression Circulating tumour cell count conversion rate Secondary EP: Radiographic PFS Time to first SRE Time to PSA progression Circulating tumour cell count conversion rate

9. AFFIRM Study N = 1199 pts (800 vs. 399) Balanced demographics / disease characteristics 520 death events reached Independent Drug Monitoring Committee (IDMC) concluded that the trial be stopped, unblinded and that the patients on placebo be offered the test agent

10. Post-chemotherapy: failed docetaxel MDV3100 160 mg po OD MDV3100 PlaceboPlacebo AFFIRM Study. Scher HI et al. JCO 30, 2012 (suppl 5; abstract LBA1) 18.4 mths 13.6 mths p<0.001 Median OS PFS Time to PSA progression Safety TO FOLLOW

11. AFFIRM Study Survival benefit observed across subgroups vs. placebo Median duration of Tx: 8.3 vs. 3.0 mths Tumour response on imaging No difference in adverse events No myelosuppression 0.6% had seizures (5 pts: 2 with brain mets, 2 had lidocaine for biopsies)

12. PREVAIL Study Asymptomatic or minimally symptomatic men with metastatic PrCa who are chemotherapy naive

13. Bone Targeted Therapy

14. Radium-223 Chloride ALSYMPCA Study

15. Radium-223 acts as a calcium mimic Integrated into bone Alpha emitter that provides localized effect Induces dsDNA breaks in adjacent tumour cells Short penetration Phase 2: Nilsson, Lancet Onco GUCA 2012, Abstract 8

16. ALSYMPCA Study Phase 3: post-docetaxel and docetaxel ineligible BSC ± Radium-223 6 injections at 4-wk intervals N = 541 (radium) vs. 268 (placebo) No cytotoxic chemotherapy Primary EP: OS Secondary EP: QoL, safety

17. ALSYMPCA Study Planned interim analysis at 320 deaths Balanced baseline characteristics Results: OS: 14.0 mths vs. 11 mths (stat sig) No routine imaging unlike DEN & Zometa studies

18. ALSYMPCA Study SRE: include spinal cord compression, pathologic fractures Reduced risk for SCC with Radium-223 vs. placebo A/E: Modest increase in neutropenia but only 2% Very well tolerated

19. Bone Protection in MetCRPC Can we prolong bone metastases free survival? Fracture prevention? Should we place patients on bone protective agent? Zoledronate vs. Denosumab? What is the optimal scheduling? Individualization of options?

20. Bone Protection in MetCRPC Considerations for individualization: Poor dentition Convenience: IV vs. SC Renal dysfunction Side effects Cost and co-payments Are these agents necessary when other agents are being used?

21. Renal Cell Carcinoma

22. RCC in the Vulnerable Patient Comorbidity Scores

23. RCC & Comorbidity Scores Accounting for comorbidities is important for clinical prognosis SEER Registry (1995- 2007 data) 1155 people with T1a N0 M0, well-differentiated At 10 years: 4% mortality for RCC causes 51% from non-RCC causes

24. Competing Risks What diseases did the patient have before the cancer diagnosis? Which ones are relevant?

25. Charlson Comorbidity Index Developed by fitting a statistical model to evaluate predictors of mortality

26. As CCI score increases, the mortality rate increases

27. Charlson Comorbidity Index 203 older pts with cancer Little or no correlation between comorbidty (CCI or Cumulative Illness Rating Scale - Geriatrics) and functional status (ECOG or ADLs) An assessment of comorbid medical conditions can provide information that is independent of patient’s functional status. Thus need to assess both. J Clin Oncol. 1998;16(4):1582

28. Charlson Comorbidity Index CAUTIONS: **Other measures may be more appropriate Nomograms are statistical models that can be used to predict outcomes, and are visual representations of the model Be careful of extrapolation to unusual values

29. Metastatic RCC When to treat? What are the deciding factors for when to start systemic therapy?

30. Metastatic RCC: Goal Delay as long as possible a patient from reaching a lethal tumour burden while maintaining QoL RCC is an inherently diverse disease with a diverse biology

31. Who can we observe? Good performance status Low volume Slow growing Asymptomatic

32. When should we start? Increased pace of disease New organ sites Symptoms from disease MD / patient anxiety

33. Therapy in mRCC Advantages: Reduction in tumour burden Delay worsening of disease Relatively convenient, oral therapy Disadvantages: Chronic therapy Chronic toxicity

34. Sunitinib in Elderly Pts with mRCC Pooled data analysis of 1059 pts 65% (689 pts): Sunitinib 50 mg/d (4wks on, 2wks off) 35% (370 pts): continuous OD dosing 1st line setting: 74% (783 pts) 2nd line setting: 26% (276 pts) Hutson TE et al. J Clin Oncol. 29: 2011 (suppl; abstract 4604)

35. Sunitinib in Elderly Pts with mRCC Median PFS: 9.0 vs. 10.9 mths (p=0.0830) Median OS: 23.3 vs. 23.7 mths (p=0.5441) No difference when age taken Overall tolerability is similar In younger pts: increased HFS, chest pain Hutson TE et al. J Clin Oncol. 29: 2011 (suppl; abstract 4604)

36. Ph.3 AXIS Trial for mRCC What is the effect of prior first-line treatment duration and axitinib dose titration on axitinib efficacy? Axitinib: potent and selective 2nd-gen VEGFR-I (VEGFR-1, -2, and -3) Rini BI et al. GUCA Symp 2012; abstract 354

37. Axitinib Potent and selective second-generation inhibitor of VEGFR-1, -2, and -3 If no toxicity > grade 2 and BP 2 wks ➜ increase axitinib to 7mg po BID and then to 10 mg po BID Rini BI et al. GUCA Symp 2012; abstract 354

38. AXIS Trial Axitinib 5 mg po BID Axitinib Sorafenib 400 mg po BID Sorafenib 6.7 mths 4.7 mths Median PFS Rini BI et al. GUCA Symp 2012; abstract 354 At least one total daily dose > 10mg 6.6 mths 8.3 mths At least one total daily dose ≤ 10mg N =132 pts N = 227 pts Second Line mRCC (clear cell) p<0.0001

39. AXIS Trial Second Line mRCC (clear cell) p<0.0001 Rini BI et al. GUCA Symp 2012; abstract 354 Prior Sunitinib ≥9mths Prior Sunitinib <9mths 6.3 mths 4.5 mths Axitinib 5 mg po BID Axitinib Sorafenib 400 mg po BID Sorafenib 6.7 mths 4.7 mths Median PFS N =195 pts (53.9%) N =194 pts (53.7%)

40. Foretinib Oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL and TIE-2 receptors Activating mutations and/or amplifications in MET in papillary RCC Choueiri TK et al. GUCA Symp 2012; abstract 355

41. Locally adv. or met papillary RCC Intermittent arm Foretinib 240 mg/d on day 1- 5 of every 14 days 37 pts Intermittent arm Foretinib 240 mg/d on day 1- 5 of every 14 days 37 pts Daily dose arm Foretinib 80 mg/d 37 pts Daily dose arm Foretinib 80 mg/d 37 pts ORR 13.5% PFS 9.3 mths 1-yr OS 70% Median OS not reached ORR 13.5% PFS 9.3 mths 1-yr OS 70% Median OS not reached Choueiri TK et al. GUCA Symp 2012; abstract 355

42. Locally adv. or met papillary RCC Intermittent arm Foretinib 240 mg/d on day 1- 5 of every 14 days 37 pts Intermittent arm Foretinib 240 mg/d on day 1- 5 of every 14 days 37 pts Daily dose arm Foretinib 80 mg/d 37 pts Daily dose arm Foretinib 80 mg/d 37 pts ORR 13.5% PFS 9.3 mths 1-yr OS 70% Median OS not reached ORR 13.5% PFS 9.3 mths 1-yr OS 70% Median OS not reached Choueiri TK et al. GUCA Symp 2012; abstract 355

43. Foretinib: Toxicity Grade 3/4: Fatigue 6.8% HTN 50% Diarrhea 6.8% Non-fatal pulmonary embolism: 11% No sig diff between the 2 cohorts in efficacy or safety

44. Summary Prostate Cancer Bone Targeted Therapy Renal Cell Cancer

45. Questions maniaj@stjoe.on.ca maniaj@stjoe.on.ca maniaj@stjoe.on.ca