1. Advances in the Management of Skeletal Related Events/Bone Metastases in Prostate Cancer Robert Dreicer, M.D., M.S., FACP, FASCO Chair Dept of Solid Tumor Oncology Taussig Cancer Institute Cleveland Clinic Professor of Medicine Cleveland Clinic Lerner College of Medicine

2. Locally Advanced Disease Rising PSA Hormone Naive Rising PSA Castrate Metastases Castrate Resistant Asymptomatic Metastases Castrate Resistant Symptomatic Organ Confined Metastatic Disease (De novo) Clinical States In Prostate Cancer (circa Winter 2014) Metastases Castrate Resistant Post Docetaxel Metastases Castrate Resistant Post Cabazitaxel Sipuleucel-T Abiraterone Cabazitaxel Denosumab Enzalutamide Radium 223 Modified from Scher H, et al. Urology 2000

3. Bone Issues in Prostate Cancer A major bone tropic neoplasm Bone issues vary along the disease spectrum Impact of ADT  Osteoporosis  Increase in osteoporotic related fx Prevention/delay of bone metastases Castration resistant metastatic disease  SRE (SSE) prevention

4. Bone Events Defined Skeletal Related Event (SRE)  Radiation to bone  Pathologic fracture  Surgery to bone  Spinal cord compression  Hypercalcemia of malignancy Symptomatic Skeletal Event (SSE)  EBRT to relieve skeletal symptoms  New symptomatic pathologic bone fracture  Occurrence of spinal cord compression  Tumor-related orthopedic surgical intervention

5. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study 1904 men with metastatic CRPC were randomized to receive denosumab (human monoclonal antibody against RANKL) or zolendronic acid The primary endpoint was time to first on-study SRE (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority The same outcome was further assessed for superiority as a secondary endpoint Fizazi K, et al. Lancet. 2011 377:813-22

7. COU-AA-301: Abiraterone Acetate Improves Overall Survival in mCRPC HR = 0.646 (0.54-0.77) P< 0.0001 Placebo: 10.9 months (95%CI: 10.2, 12.0) 0 100200 300 400 500 600700 0 20 40 60 80 100 Survival (%) Days from Randomization Abiraterone acetate: 14.8 months (95%CI: 14.1, 15.4) 2 Prior Chemo OS: 1 Prior Chemo OS 14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo de Bono J et al: N Engl J Med 364:1995- 2005, 2011

8. Ryan CJ, et al. N Engl J Med 2013;368:138-48

9. Logothetis CJ, et al. Lancet Oncol 2012; 13: 1210–17

10. Scher H, et al. n engl j med 367:1187 2012

11. Impact of Enzalutamide, an androgen receptor signaling inhibitor, on time to first skeletal related event (SRE) and pain in the phase 3 AFFIRM Study Median time to first SRE for enzalumatide treated patients: 16.7 months versus 13.3 months for patients receiving placebo (hazard ratio [HR] = 0.69; P =.0001) 9 Pain palliation: as > 30% reduction in mean pain score at week 13 versus baseline without a > 30% increase in analgesic use was achieved by 45% of patients on enzalutamide compared with only 7% of patients in the placebo group (P =.0079) Fizazi K, et al. ESMO 2012 Abstract 896O

12. Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post- docetaxel or unfit for docetaxel Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post- docetaxel or unfit for docetaxel Total ALP: < 220 U/L vs ≥ 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No Total ALP: < 220 U/L vs ≥ 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No RANDOMISEDRANDOMISED 2:1 Radium-223 (50 kBq/kg) + Best standard of care Placebo (saline) + Best standard of care N = 922 TREATMENT 6 injections at 4-week intervals STRATIFICATION PATIENTS ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design

13. Parker C, et al. N Engl J Med 2013;369:213-23

15. Questions  Does the addition of “standard” bone targeted agents to next generation therapies “add”, “synergize” or “add nothing” to more effective therapies ?  Does the introduction of more potent agents earlier mitigate the effect of older agents?  Pharmacoeconomics Bone targeted agent with drugs that already impact on SRE?