This document summarizes recent developments in treating advanced prostate cancer. It discusses advances in hormonal therapy including intermittent therapy and new agents like abiraterone and MDV3100. It also discusses chemotherapy options for castration-resistant prostate cancer including docetaxel, cabazitaxel, and the use of zoledronate or denosumab to prevent bone complications.

1. ECLU May 2011

2. ECLU May 2011

3. New developments in the systemic treatment of advanced prostate cancer Ian F Tannock MD, PhD, DSc Princess Margaret Hospital and University of Toronto 3

7. The patient-based meta-analysis showed no significant benefit of MAB after 8000+ pts and 27 trials MAB is expensive, has increased toxicity and should not be used 7

8. Studies in animals show that intermittent ADT delays time to castrate-resistance Sato et al: J Steroid Biochem Molec Biol 1996;58:139-46 Several clinical trials now support the use of intermittent therapy for men with prostate cancer who have an excellent response to initial therapy 8

9. Randomized trials of intermittent vs continuous hormonal therapy 9 Trial N Setting Treatment Result De Leval: Clin Prost Cancer 2002 68 T3-4, N+, M+ goserelin+ flutamide  Time to CRPC Miller ASCO 2007 335 N+, M+ goserelin + bicalutamide Similar time to CRPC better QoL Thun AUA 2007 167  PSA after RP leuprolide Similar time to CRPC better QoL Calais da Silva Europ Urol 2009 626 T3-4, N+, M+ triptorelin + cyproterone Similar time to CRPC & survival, better QoL Klotz (NCIC PR7) ASCO GU 2011 1386  PSA after RP/RT LHRH agonist Similar time to CRPC & survival, better QoL

10. Time to Progression (Miller et al, 2007) Intermittent: median 16.6 months P = 0.17 Continous: median 11.5 months 10

15. There is increasing evidence that ADT raises insulin levels and may increase diabetes and cardiovascular disease >73,000 men age>65 treated for localized Ca prostate 1992-1999, observed through 2001 >1 in 3 received ADT (Keating et al, J Clin Oncol 2006;24:4448-56) Other recent series have confirmed these effects 15 Events per 1000 person-years Diabetes CHF MI Sudden death No treatment 20.9 61.3 10.9 9.0 LHRH agonist 29.0 72.3 13.6 12.9 Orchiectomy 24.5 63.3 13.2 12.5

20. Abiraterone acetate: Attard et al, JCO 2008 ;26: 4563; de Bono et al, ESMO 2010 ECLU May 2011 20

21. 21

28. The ASCENT2 study: Docetaxel plus high-dose calcitriol (DN-101) versus docetaxel (plus prednisone) for progressive CRPC (Scher et al, ASCO 2010) Study recruited 953 men. A placebo-controlled phase II study had suggested that DN-101 increases survival Trial was stopped early after an interim analysis showed more deaths in the DN-101 arm 28 DN-101 Control P-value Median survival (months) 16.8 19.9 0.019 (0.002 by logrank) Deaths due to prostate cancer 142 108 Deaths due to other cause 32 30 Dose modifications for docetaxel 229 160

29. Docetaxel + prednisone +/- bevacizumab for CRPC (Kelly et al, ASCO, 2010) Increase in OS and PFS are virtually identical to overview of 3 breast cancer trials – considered positive because primary endpoint was PFS 29 Endpoint DP + B (N=524) DP (N=526) HR P-value OS (mos) 22.6 21.5 0.91 0.18 PFS (mos) 9.9 7.5 0.77 <0.0001 PSA-RR 69.5% 57.9% 0.0002 Toxicity 

32. The TROPIC study: cabazitaxel or mitoxantrone with prednisone for metastatic CRPC previously treated with docetaxel (De Bono et al, ASCO 2010) Time (months) Proportion of OS (%) The study met its primary objective (  survival) N=755 Should Mr Eriksson receive 2 nd -line chemotherapy? 32 0 6 12 18 24 30 MP CBZP Median OS (months) 12.7 15.1 Hazard ratio 0.72 95% CI 0.61–0.84 P -value <.0001 Censored MP CBZP Combined median follow-up: 13.7 months 100 80 60 40 20 0

33. Important secondary results of the cabazitaxel trial Concerning! Major impairment to quality of life 33 Efficacy MP CBZP p-value Comment Tumor response (%) 4.4 14.4 0.0005 PSA response (%) 17.8 39.2 0.0002 MP consistent with other studies Pain response (%) 7.8 9.2 0.63 Disappointing ! Toxicity MP CBZP Comment Toxic death 7 (1.9%) 18 (4.9%) Neutropenic sepsis 1.3% 7.5% Diarrhea (≥ grade III) 0.3% 6.2% Neuropathy (%) ?????

38. On his next visit to clinic, Mr Eriksson is failing, but his wife brings a newspaper article about Sipuleucil-T a type of immunotherapy. “What does this treatment involve” she asks, “and could it be used to save my husband’s life?” Men with CRPC undergo leukophoresis Patient’s antigen-presenting cells (APC) cultured in presence of prostatic acid phosphatase (PAP) linked to G-CSF Ship to central facility Ship to patient’s treatment facility Infuse into patient Process is repeated 3 times at 2-week intervals 38

39. Sipuleucel-T Estimated cost = $93,000 39

41. Thanks to our international fellows who stimulate my ideas (but are not responsible for them).....and have done much of the work Especially: Dominik Berthold Bostjan Seruga & Saroj Niraula 41

42. ECLU May 2011

43. ECLU May 2011

44. ECLU May 2011