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

3. Scope of the Problem

4. Incidence

5. Incidence > 30% will get ADT

6. Mortality

7. Mortality Almost all have bone mets

8. 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

9. Changes in BMD During GnRH Agonist Treatment Mittan et al. J Clin Endocrinol Metab. 2002;87:3656 . 12-month data. Lumbar spine Total hip P < .001

10. ADT Associated Bone Loss 1. Kanis. Osteoporosis . 1997:22; 2. Eastell et al. J Bone Miner Res. 2002;17(suppl 1):S165; 3. Lee et al. J Clin Endocrinol Metab . 2002;87:329; 4. Maillefert et al. J Urol . 1999;161:1219; 5. Gnant. Breast Cancer Res Treat. 2002;76(suppl 1):S31. Abstract 12; 6. Shapiro et al. J Clin Oncol. 2001;19:3306. Normal men 1 Early menopausal women 1 Late menopausal women 1 AI therapy in PMW 2 Androgen deprivation therapy agonist 4 AI therapy plus GnRH agonist 5 Ovarian failure secondary to chemotherapy 6 Bone marrow transplant 3

11. Prevalence of Osteoporosis at Baseline and Under ADT – Cross-sectional Data Overall prevalence of osteoporosis, osteopenia, and normal BMD according to ADT duration. *Patients had not received ADT at time of BMD measurement. Percentage of patients Androgen deprivation therapy duration (years) Morote et al., UROLOGY 69: 500–504, 2007.

12. Relationship Between BMD and Fracture Risk BMD T-score, SD units Fracture risk Osteoporosis Osteopenia 0 2 4 6 8 10 12 14 16 18 -4 -3 -2 -1 0 1 2

15. Higher Death Rate Observed at 36 Months in Patients With Vertebral Fracture at Study entry Smith, Saad et al. presented at ECCO 2009

16. Screening for bone loss in men: Who is at risk?

21. FRAX

22. Treatment options

23. Pamidronate IV q 3months Lumbar Spine Total Hip P≤ 0.005 for each comparison Smith MR et al. N Eng J Med. 2001;345:948. Final 12-month data -5 -4 -3 -2 -1 0 1 2 BMD Percent Change No pamidronate Pamidronate

24. Z oledronic Acid IV q 3 months Lumbar spine Total hip P <0.001 for each comparison Smith MR et al. J Urol. 2003;169:2008. -4 -2 0 2 4 6 8 BMD Percent Change Placebo Zoledronic acid Final 12-month data

25. Z oledronic Acid IV q 12 Months Lumbar spine Total hip P <0.005 for each comparison Michaelson MD et al. J Clin Oncol. 2006;25:1038. -6 -4 -2 0 2 4 6 BMD Percent Change Placebo Zoledronic acid Final 12-month data

26. Alendronate PO weekly Lumbar spine Total hip P <0.04 for each comparison except P =0.08 for total hip on placebo Greenspan SL et al. Ann Intern Med. 2007;146:416. -3 -2 -1 0 1 2 3 4 5 BMD Percent Change Placebo Alendronate Final 12-month data

28. Denosumab Fracture Prevention Study R A N D O M I Z E Denosumab q6 months for 3 years Current androgen deprivation therapy for prostate cancer; Age >70 or T score <-1.0 (n=1,468) Placebo q6 months for 3 years Primary end point : change in lumbar spine BMD Key secondary end point : new vertebral fractures Smith MR et al. N Engl J Med. 2009;361:745.

29. Denosumab Increased BMD at All Skeletal Sites 10 8 6 4 2 0 -2 -4 -6 0 1 3 6 12 24 36 Month Percent Change in BMD From Baseline C. Femoral Neck Denosumab Placebo Difference at 24 mo, 3.9 percentage points 10 8 6 4 2 0 -2 -4 -6 0 1 3 6 12 24 36 Month Percent Change in BMD From Baseline 8 6 4 2 0 -2 -4 -6 0 1 3 6 12 24 36 Month Percent Change in BMD From Baseline A. Lumbar Spine Denosumab Placebo Difference at 24 mo, 6.7 percentage points Denosumab Placebo Difference at 24 mo, 4.8 percentage points B. Total Hip 8 6 4 2 0 -2 -4 -6 0 1 3 6 12 24 36 Month Percent Change in BMD From Baseline Denosumab Placebo Difference at 24 mo, 5.5 percentage points D. Distal Third of Radius Smith MR et al. N Engl J Med. 2009;361:745.

30. Denosumab Decreased New Vertebral Fractures 0 2 4 6 New Vertebral Fracture (%) Placebo Denosumab P =0.004 P =0.004 P =0.006 1.9 0.3 3.3 1.0 3.9 1.5 12 24 36 Month No. of Patients 13 2 22 7 26 10 Smith MR et al. N Engl J Med. 2009;361:745.

31. Predicting bone metastases

32. 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

33. 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

34. Denosumab to prevent metastases R A N D O M I Z E Denosumab monthly Rising PSA despite ADT No bone metastases PSA >8 PSADT <10 months (n~1500) Placebo monthly Primary End Point : Bone metastasis-free survival 4 Month delay in time to first metastases Smith et al. AUA 2011

35. Consequences of Bone Metastases Disease Bone metastases Fracture Hypercalcaemia Surgery to bone Radiation to bone SREs Spinal cord compression Loss of autonomy Consequences Significant morbidity Bone pain Decreased survival Increased healthcare costs and resources Ultimate consequence Reduced quality of life SREs = Skeletal-related events

36. Pathologic Fractures Negatively Affect Survival Saad F, et al. Cancer. 2007;110(8):1860-1867. Hazard ratio 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 De creased mortality Increased mortality .0 4 P value 29 % Risk increase 1.29 < .01 52 % 1.52 Prostate cancer Breast cancer

37. Evaluating Risk and Value of Bone Markers

38. In PC, %PABS Inversely Correlates with Survival Noguchi M, et al. Br J Cancer . 2003;88:195-201. 0.8 0.6 0.4 0.2 0 Survival Probability 0 10 20 30 40 50 60 70 80 90 Time (months) Less than 4.6% Greater than 4.6% Log rank p = 0.011 Less than 4.6% Greater than 4.6% 32 24 27 20 20 13 13 9 4 4 2 1 1.0

39. # 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

43. Bone Markers

44. 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

45. SRE vs BAP Level Cook et al. Clin Cancer Res. 2006 Jun 3361-7.

46. Survival vs BAP Levels Cook et al. Clin Cancer Res. 2006 Jun 1;12 :3361-7.

47. SRE vs Baseline NTX Level Cook et al. Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3361-7.

48. Survival vs Baseline NTX Cook et al. Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3361-7.

49. 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

50. 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

51. 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.  

52. 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.

53. A Phase 2 Study of Denosumab in Subjects With High NTx on IV Bisphosphonates BrCa PrCa MM Bone Met UNTx>50mmol despite ivBp Denosumab 180 mg SC Q4W Denosumab 180 mg SC Q12W Bisphosphonate IV Q4W 25 weeks on treatment Optional 2-Year Extension/ Follow-up Up to 32 weeks off treatment Fizazi K, et al. J Clin Oncol . 2009 Feb 23. [Epub ahead of print].

54. Patients With Reduced uNTx Levels Fizazi K, et al. J Clin Oncol . 2009 Feb 23. [Epub ahead of print].

55. Treatment options

56. Zoledronic Acid and SREs Saad F, et al. J Natl Cancer Inst . 2004;96:879-882 P = .028 38 26 17 4 6 2 0 49 33 25 8 7 4 1 0 10 20 30 40 50 60 Any SRE Radiation to Bone Fractures Spinal Cord Compression Change in Antineoplastic Therapy Surgery to Bone HCM Zoledronic acid 4 mg (n = 214) Placebo (n = 208) Patients With SRE, %

58. Cumulative expected Bone Complications (n) per 100 patients Months since randomization Placebo Zoledronic acid 4 mg P = 0.002 20 40 60 100 120 80 0 3 6 9 12 15 21 18 24 27 Risk of Developing a Bone Complication Reduced by 35% Saad F, et al. J Natl Cancer Inst . 2004;96:879-882

59. Survival Median, months P value ZOL 4 mg 18.2 .103 Placebo 15.6 ZOL 4 mg 214 162 113 56 10 Placebo 208 148 94 40 5 Saad F, et al. J Natl Cancer Inst . 2004;96:879-882

60. Denosumab to prevent skeletal-related events R A N D O M I Z E Denosumab monthly Castrate-resistant Bone metastases No prior bisphosphonate (n~1800) Zoledronic acid monthly Primary End Point : Skeletal-related events

61. Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) Primary endpoint

62. Secondary endpoints

63. Overall Disease Progression Secondary endpoints