1. Predicting toxicity after androgen deprivation: skeletal adverse events Fred Saad MD FRCS

2. BMD changes after orchidectomy 0 0.2 0.4 0.6 0.8 1 1.2 1.4 2 4 6 8 10 12 14 Time After Orchidectomy (yr) BMD (g/cm 2 ) Stepan et al. JCEM 1989;69:523 Normal Range early “rapid” bone loss 4-8% per yr

4. FRAX

5. Treatment options

6. Predicting bone metastases

7. Rising PSA in Non-Metastatic CRPC: PSA Levels Smith MR, et al. J Clin Oncol 2005;23:2918-2925. 0.5 1 1.5 2.0 2.5 3.0 Proportion of patients with bone metastases or death Years since random assignment PSA >24.0 ng/mL PSA 7.7-24.0 ng/mL PSA <7.7 ng/mL 0.8 0.6 0.4 0.2 0 1.0

8. Rising PSA in Non-Metastatic CRPC: PSA Doubling Time (PSADT) Smith MR, et al. J Clin Oncol 2005;23:2918-2925 . 0.5 1 1.5 2.0 2.5 3.0 Years since random assignment PSADT <6.3 months PSADT 6.3-18.8 months PSADT >18.8 months 0.8 0.6 0.4 0.2 0 1.0 Proportion of patients with bone metastases or death

9. # Bone Lesions and Risk for SRE > 3 Bone Lesions Versus ≤ 3 Bone Lesions Shirina N, et al. Presented at ASCO 2006. Poster 8529. In favor of less lesions In favor of more lesions Lung cancer and other solid tumors 1.54 Hazard ratio 0 0.5 1 1.5 2 1.41 1.51 Prostate cancer Breast cancer

12. Bone Markers

13. Prognostic Implications of Bone Markers: Relative Risks in Prostate Cancer P value <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.003 <0.001 0.001 3.82 3.03 All SRE First SRE NTX ≥100 nmol/mmol creatinine BAP ≥146 IU/L NTX 50–100 nmol/mmol creatinine Brown J et al. J Natl Cancer Inst . 2005;97:59. Death 4.31 2.65 3.25 3.05 4.59 3.10 3.19 0.1 1 10 Relative Risk (vs lowest marker category) NTX, N-telopeptide of type I collagen; BAP, bone-specific alkaline phosphatase

14. Normalization of NTX Levels vs Clinical Outcomes Among Patients With High NTX at Baseline 0 0.5 1.0 1.5 2.0 First SRE 0.61 38% .0411 Death 0.41 59% < .0001 In favor of normalized NTX In favor of persistently elevated NTX Saad et al. Sem Urol Oncol 2010 Lipton et al. Cancer 2009 Risk reduction P value

15. NTX Normalization Correlated With Improved Survival Versus Persistently Elevated NTX Proportion deceased, % patients Time on study, months (starting at month 3) 100 80 60 40 20 0 3 9 12 15 18 21 24 27 6 RR = 0.410 P < .001 E  E E  N

16. Survival Benefit by Percentage Reduction From Baseline NTX High NTX, NTX >64 nmol/mmol creatinine Relative Risk of Death 0 0.25 0.50 0.75 1.00 1.25 Median baseline NTX (125 nmol/mmol creatinine) 5 15 25 Patients with NTX decrease ≤ corresponding x-axis value 35 45 65 85 95 – 3 17 37 57 77 97 NTX Decrease From Baseline* (%) (Decrease vs Baseline) No change NTX correlated with risk of death *Calculated as ([Baseline NTX minus 3-month NTX] / baseline NTX) × 100.  

17. Survival by Percentage Change From Baseline NTX in Placebo Group *Calculated as ([Baseline NTX minus 3-month NTX] / baseline NTX) × 100. All patients in this analysis had baseline NTX > 64 nmol/mmol creatinine. Relative Risk of Death 95 85 65 45 35 25 15 5 3.00 2.75 2.50 2.25 2.00 1.75 1.50 1.25 1.00 0.75 0.50 0.25 0.00 -222 -202 -182 -162 -142 -122 -102 -82 -62 -42 -22 -2 18 38 58 78 98 Median baseline NTX (145 nmol/mmol creatinine NTX Decrease From Baseline* (%) (Increase vs Baseline) (Decrease vs BL) No change NTX  correlated with  risk of death Saad F et al . Presented at: AUA Annual Meeting; May 2008; Orlando, FL. Abstract 519.

18. Treatment options