2. Natural History of Prostate Cancer Local therapy Androgen deprivation therapy (ADT) Therapies after ADT Death ADT mCRPC post- docetaxel mCRPC symptomatic mCRPC mildly symptomatic mCRPC asymptomatic (failed ADT) Hormone sensitive ADT + Docetaxel in high volume disease?

3. Definition of CRPC 2014

4. Definition of CRPC 2013

5. EAU Guidelines – 2014 edition

7. Mod. da Nelson et al, J Clin Oncol 2012 Il processo di progressione tumorale nel CaP Autoproduzione di Testosterone TARGET: CYP17 Attivazione di AR aspecifica Totalmente dipendente da testosterone circolante ADT Androgeno indipendente AR indipendente

8. Enzalutamide Reduced Risk of Death by 29% Enzalutamid e 87 2 Placeb o 84 5 863 835 850 781 824 744 797 701 745 644 566 484 395 328 244 213 128 102 33 27 2 2 0 0 Duration of Overall Survival (Months) Survival (%) 60 50 40 30 20 10 0 90 80 70 100 0369121518212427303336 Enzalutamide Placebo Hazard Ratio: 0.706 (95% CI: 0.60,0.84) P<0.0001 Patients at Risk Patients still alive at data cut off Enzalutamide: 72%; Placebo: 63% Enzalutamide: 241 deaths Placebo: 299 deaths Beer et al, N Engl J Med. 2014; 371(5):424-33 Placebo: 30.2 (95% CI 28.0, NYR) Enzalutamide: 32.4 (95% CI 30.1, NYR) Median Follow-up 22 Months

9. Final OS Analysis Median follow-up of 49.2 months Abiraterone treatment effect more pronounced when adjusting for 44% of prednisone patients who received subsequent abiraterone (HR = 0.74) Ryan C et al. ESMO 2014; Abstract 7530 (oral presentation)

10. Current Treatment Paradigm is Evolving Local therapy Androgen deprivation therapy (ADT) Therapies after ADT Death ADT supportive care (eg denosumab/bisphosphonates) mCRPC post- docetaxel mCRPC symptomatic mCRPC mildly symptomatic mCRPC asymptomatic (failed ADT) Hormone sensitive Sipuleucel-T Enzalutamide Abiraterone Docetaxel Cabazitaxel Radium 223 Enzalutamide ADT + Docetaxel in high volume disease?