1. A Call to Action: Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer: Highlights From the Symposium Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC This program is supported by an educational donation from

2. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Overview  The Bone Microenvironment and the Prostate Cancer Patient: Key Concepts  Treatment-Related Bone Loss: Risk Assessment and Current and Emerging Approaches to Therapy  Prevention of Metastatic Disease: Are New Options on the Horizon?  Evolving Evidence for the Treatment of Bone Metastases in Prostate Cancer

3. The Bone Microenvironment and the Prostate Cancer Patient: Key Concepts

4. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Cancer Bone Disease Is Prevalent 1. Ferlay J, et al. IARC Globocon 2000. 2. Coleman RE. Cancer Treat Rev. 2001;27:165-176. 3. Coleman RE. Cancer. 1997;80:1588-1594. 4. Zekri J, et al. Int J Oncol. 2001;19:379-382. Myeloma Renal Melanoma Bladder Thyroid Lung Breast Prostate 5-Yr World Prevalence, Thousands [1] 144 480 533 1000 475 1394 3860 1555 Frequency of Bone Metastases in Cancers [2] 70-95 20-25 14-45 40 60 30-40 65-75 Median Survival, Mos [2-4] 6-54 12 6 6-9 48 6 - 7 19-25 12-53 More lytic More blastic

5. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Steps in Metastasis Primary malignant neoplasm New vessel formationInvasionEmbolism Bone metastases ExtravasationAdherence Endothelial cell Arrest in distant capillary bed in bone Multi cell aggregates (Lymphocytes, platelets) Tumor cell Proliferation Response to Microenvironment

6. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Osteoblastic  Prostate and breast  Bone formation mediated by osteoblasts Types of Cancer Bone Disease Osteolytic  Breast and myeloma  Bone destruction mediated by osteoclasts

7. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Bone Metastasis: Vicious Cycles Adapted from Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;15;350:1655-1664.

8. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Cellular Mechanisms of Bone Metastasis  Osteolytic  Osteoblastic  Mixed lytic-blastic

9. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Osteoclastic bone resorption New bone formation Hattner R, et al. Nature. 1965:206:489-490. Frost’s Contribution

10. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Imbalance Breast cancer, myeloma Osteoporosis Prostate cancer

11. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Bone Metastasis Models Osteolytic Osteoblastic ZR-75-1 MDA-MB-231

12. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer LuCaP Intrabial Model 250,000 cells in 10 uL

13. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Bone Metastasis Caused by MCF-7/Neu OsteolyticMixedOsteosclerotic Heart inoculation 04-68> 10

14. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Exposure to a Tumor Stroma Elicits Permanent Malignant Transformation BPH-1 CAFTD CAF BPH-1 Graft Culture + G418 Initiated cell Tumorigenic cell

15. Treatment-Related Bone Loss: Risk Assessment and Current and Emerging Approaches to Therapy

16. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer 4000 3000 2000 1000 35-39 ≥ 85 Hip Vertebrae MenWomen Incidence/1,000,000 Person-Yrs Age (Yrs) 0 Melton LJ, et al. J Bone Miner Res. 1992;7:1005-1010. Fracture Risk by Sex and Age

17. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer 0.0 1.0 2.0 3.0 Low BMI (20-25) Prior Fracture FH (Hip) Smoking Current Alcohol > 2/d Steroid Use Kanis JA, et al. Osteoporos Int. 2005;16:581-589. +BMD-BMD Response Rate Risk for Hip Fracture in Men and Women

18. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer WHO/FRAX Risk Assessment Available at: http://www.shef.ac.uk/FRAX/.

19. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer National Osteoporosis Foundation Fracture Prevention Guidelines for Men  Consider FDA-approved medical therapies based on the following –A vertebral or hip fracture –Femoral neck or spine T-score ≤ -2.5 –FRAX 10-yr probability of a hip fracture ≥ 3% or 10-yr probability of any major fracture ≥ 20%

20. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Major Causes of Fractures in Men  Alcohol abuse  Chronic glucocorticoid therapy  Hypogonadism

21. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Smith MR, et al. J Clin Oncol. 2005;23:7897-7903. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. 0.6 0.7 0.8 0.9 1.0 01234567 Yrs No GnRH agonist (n = 7774) GnRH agonist < 1 yr (n = 1368) GnRH agonist ≥ 1 yr (n = 2519) Proportion Without Fracture GnRH Agonists and Time to First Fracture

22. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer 0 3 6 9 12 15 18 Any FractureFracture Resulting in Hospitalization Frequency (%) +2.8%; P <.001 +6.8%; P <.001 ADT (n = 6650) No ADT (n = 20,035) 12.6 21 5.2 19.4 2.4 Shahinian VB, et al. N Engl J Med. 2005;352:154-164. Proportion of Patients With Fractures 1-5 Yrs After Cancer Diagnosis

23. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Total Hip P <.001 for each comparison Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661. Reproduced with permission of The Endocrine Society. 12-mo data Percent Change GnRH agonist Control -4 -3 -2 -5 0 1 2 Lumbar Spine GnRH Agonists Decrease Bone Mineral Density in Men With Prostate Cancer

24. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Total Hip P <.001 for each comparison Smith M, et al. J Urol. 2003;169:2008-2012. Final 12-mo data BMD Percent Change Zoledronic acid Placebo -3 -2 -4 0 2 5 7 1 4 3 6 Lumbar Spine Quarterly Zoledronic Acid Increases BMD During GnRH Agonist Therapy

25. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Lumbar SpineTotal Hip P <.005 for each comparison Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Final 12-mo data BMD Percent Change Zoledronic acid Placebo -4 -3 -2 -5 1 4 6 0 3 2 5 Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy

26. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Total Hip Greenspan SL, et al. Ann Intern Med. 2007;146:416-424. 12-mo data BMD Percent Change Alendronate Placebo -2 -3 1 5 0 3 2 4 Lumbar Spine Alendronate Increases Bone Mineral Density During GnRH Agonist Therapy

27. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Normal older men + Androgen deprivation therapy ~ 3 fold increase in fracture incidence Adapted from Mellstrom D, et al. J Bone Miner Res. 2008;23:1552-1560. Reproduced with permission of the American Society for Bone and Mineral Research. 0.20.40.60.81.0 20 40 60 80 100 120 Incidence/1000 Person-Yrs 0 0 1.2 fE2 (pg/mL) Low Free E2 Levels Are Associated With Greater Fracture Incidence

28. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer RANDOMIZERANDOMIZE Primary endpoint: new vertebral fractures Secondary endpoints: BMD, lipids, breast symptoms, hot flashes Current androgen deprivation therapy for prostate cancer; Older than 70 yrs of age or low BMD (N = 1382) Toremifene daily for 2 yrs Placebo daily for 2 yrs Toremifene Fracture Prevention Study

29. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Primary endpoints: BMD, new vertebral fractures Current androgen deprivation therapy for prostate cancer; Older than 70 yrs of age or T score > -1 (N = 1468) Denosumab every 6 mos for 3 yrs Placebo every 6 mos for 3 yrs RANDOMIZERANDOMIZE Denosumab Fracture Prevention Study

30. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Conclusions  Androgen deprivation therapy increases fracture risk in prostate cancer survivors  A variety of drugs increases bone mineral density during androgen deprivation therapy  Toremifene, a SERM, increases bone mineral density and decreases incidence of new vertebral fractures  Denosumab, a novel RANKL-targeted antibody, increases bone mineral density and decreases incidence of new vertebral fractures  Ongoing RCTs will evaluate denosumab for prevention of bone metastases and disease-related skeletal complications

31. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Practical Recommendations  Consider potential adverse effects in decisions about GnRH agonist therapy  Adopt strategies to reduce morbidity for men who require treatment –Education about risks –Screening for osteoporosis –Drug therapy for men at greatest risk

32. Prevention of Metastatic Disease: Are New Options on the Horizon?

33. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Castration-Resistant PC M0M+ AsymptomaticM+ Symptomatic M0M+ A continuum, but not equal in time 25-30 Mos 33 Time to Progression of Bone Disease In Prostate Cancer

34. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer TAP and BAP are serum-based assays NTP and DPD are urine-based assays 0123456 Fold Increase Above ULN (Mean ± SEM) Bone deposition markers Bone resorption markers HRPC, M+ Placebo Arm Baseline Nelson JB, et al. J Urol. 2003;169:1143-1149. Total Alkaline Phosphatase Bone Alkaline Phosphatase N-Telopeptides Deoxypyridinoline Bone Markers Are Seriously Awry in HRPC

35. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer TAP and BAP are serum-based assays NTP and DPD are urine-based assays Total Alkaline Phosphatase Bone Alkaline Phosphatase N-Telopeptides Deoxypyridinoline HRPC, M+ Placebo Arm Week 12 Nelson JB, et al. J Urol. 2003;169:1143-1149. After 12 wks on trial, placebo arm 0123456 Fold Increase Above ULN (Mean ± SEM) Bone deposition markers Bone resorption markers Bone Markers Are Seriously Awry in HRPC

36. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Mason MD, et al. J Natl Cancer Inst. 2007;99:765-776. Copyright © 2009 Oxford University Press. Eligible patients Randomly assigned (n = 508) Analyzed (n = 254) Placebo (n = 254)Active (n = 254) Stopped tablets early (n = 132) 5 yrs on trial, tablets (n = 122) Stopped tablets early (n = 156) 5 yrs on trial, tablets (n = 98) 10 yrs median follow-up, 47 symptomatic bone mets, 127 deaths 10 yrs median follow-up, 60 symptomatic bone mets, 130 deaths PR04: Clodronate in Nonmetastatic Patients; ADT Naive

37. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Dearnaley DP, et al. J Natl Cancer Inst. 2003;95:1300-1311. Copyright © 2009 Oxford University Press. Patients eligible for MRC PR05 Randomized (n = 311) Analyzed (n = 156)Analyzed (n = 155) Allocated to control group (n = 156) Received allocated intervention (n = 152) Did not receive allocated intervention (n = 4)  2 withdrew consent  1 second primary malignancy  1 dyspnea Allocated to active group (n = 155) Received allocated intervention (n = 150) Did not receive allocated intervention (n = 5)  2 died  2 withdrew consent  1 transient ischemic attack Lost to follow-up (n = 3)  1 reached primary endpoint first  2 stopped trial drug first Discontinuation of trial drug  Primary endpoint/any death (n = 92)  3 yrs (maximal time) on trial drug (n = 34)  Other (early) (n = 30) Lost to follow-up (n = 1)  1 reached primary endpoint first Discontinuation of trial drug  Primary endpoint/any death (n = 70)  3 yrs (maximal time) on trial drug (n = 32)  Other (early) (n = 53) Follow-Up Allocated Enrollment Analysis PR05: Clodronate in Bone Metastatic Patients on ADT

38. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Mason MD, et al. J Natl Cancer Inst. 2007;99:765-776. Study OS PR04 PR05 PCa death PR04 PR05 Symp bone mets/prog or PCa death PR04 PR05 HR (95% Cl) 1.01 (0.76-1.34) 0.80 (0.62-1.03) 1.11 (0.76-1.62) 0.77 (0.59-1.01) 1.22 (0.89-1.69) 0.79 (0.61-1.02) 0.50.81.01.252.0 Effect Size Favors ClodronateFavors Placebo Forest Plots: PR04 Compared With PR05

39. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.Saad F, et al. J Natl Cancer Inst. 2004;96:879-882. Initial 15-Mo StudyFollow-up 24-Mo Study Randomized (N = 643) Randomized N = 643 Zoledronic acid 4 mg (n = 214) Zoledronic acid 8/4 mg (n = 221) Placebo (n = 208) Zoledronic acid 4 mg (n = 214) Zoledronic acid 8/4 mg (n = 221) Placebo (n = 208) Efficacy analysis: 214 Safety analysis: 214 Efficacy analysis: 221 Safety analysis: 218 Efficacy analysis: 208 Safety analysis: 208 Efficacy analysis: 214 Safety analysis: 214 Efficacy analysis: 221 Safety analysis: 218 Efficacy analysis: 208 Safety analysis: 208 Discontinuations: 133 Withdrew consent: 41 Adverse event: 38 Death: 25 Unsatisfactory therapeutic effect: 19 Other: 10 Completed trial: n = 62 Completed trial: n = 65 Discontinuations: 159 Withdrew consent: 50 Adverse event: 44 Death: 40 Unsatisfactory therapeutic effect: 17 Other: 8 Discontinuations: 143 Withdrew consent: 35 Adverse event: 29 Death: 32 Unsatisfactory therapeutic effect: 34 Other: 13 Completed trial: n = 81 Discontinuations: 158 Withdrew consent: 44 Adverse event: 40 Death: 33 Unsatisfactory therapeutic effect: 25 Other: 16 Discontinuations: 173 Withdrew consent: 56 Adverse event: 46 Death: 42 Unsatisfactory therapeutic effect: 20 Other: 9 Discontinuations: 156 Withdrew consent: 40 Adverse event: 34 Death: 40 Unsatisfactory therapeutic effect: 36 Other: 15 Completed trial: n = 37 Completed trial: n = 36 Completed trial: n = 49 Completed 15-mo analysis: 82 Entered extension: 75 Completed 15-mo analysis: 61 Entered extension: 53 Completed 15-mo analysis: 65 Entered extension: 58 Zoledronic Acid Studies

40. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. Copyright © 2009 Oxford University Press (jnci.oxfordjournals.org). 0 10 20 30 50 70 80 90 100 110 % Without the Event 40 60 0 90 180270 360 450 540 Time After the Start of Study Drug (Days) Zol 4 mg Zol 8/4 mg Placebo Zol 4 mg: 214 163 113 92 70 5 0 Zol 8/4 mg: 221 155 102 68 46 4 0 Placebo: 208 149 103 69 43 1 0 Zoledronic Acid Studies Primary Endpoint: SRE

41. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Zoledronic Acid Study  Median time to disease progression: 84 days  No significant survival advantage Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. Copyright © 2009 Oxford University Press (jnci.oxfordjournals.org).

42. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Limitations of Zoledronic Acid Trial Design  Skeletal-related events broadly defined –Pathological bone fractures, spinal cord compression, surgery/radiation to bone, change in therapy to treat bone pain  Zoledronic acid is potent but nonspecific in its effects –Obvious effect on osteoporotic bone –Possible effect on prostate cancer bone metastases

43. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer  Long natural history of HRPC M0 to M+ progression –At 2 yrs, only 33% had developed bone metastases –Median time to first bone met not reached by 30 mos Zoledronic Acid to Delay Time to Bone Mets

44. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Death Begins to Compete With Endpoint Proportion of Patients With Event Yrs Since Random Assignment 0 0.2 0.4 0.6 0.8 1.0 00.51.01.52.02.53.0 Death Bone metastasis Bone metastasis or death HRPC, M0 N = 201 Placebo Arm

45. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. PSA and PSADT Best Define M0 to M+ Proportion of Patients With Bone Metastases or Died 0 0.2 0.4 0.6 0.8 1.0 0 Yrs Since Random Assignment 0.5 1.0 1.5 2.0 2.5 3.0 PSA < 7.7 ng/mL PSA 7.7-24.0 ng/mL PSA > 24.0 ng/mL A B Proportion of Patients With Bone Metastases or Died 0 0.2 0.4 0.6 0.8 1.0 0 Yrs Since Random Assignment 0.5 1.0 1.5 2.0 2.5 3.0 PSADT < 6.3 mos PSADT 6.3-18.8 mos PSADT > 18.8 mos

46. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer ET A RET B R ET-1 Metastasis Disease progression Angiogenesis Osteoblast stimulation Invasion Vasodilatation Apoptosis Clearance of ET-1 Dawson N, et al. ASCO 2008 GU Symposium. Abstract 7. Endothelin 1 Blockade

47. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Atrasentan Phase II M96-594: Atrasentan Phase II M96-594: Metastatic Hormone Refractory Prostate Cancer  288 patients with asymptomatic metastatic HRPC  Primary endpoint: time to disease progression –Clinical –Radiographic Open-label atrasentan extension Atrasentan 10 mg (n = 89) Placebo (n = 104) Atrasentan 2.5 mg (n = 95) Screening RandomizationDisease progression or study close Carducci MA, et al. J Clin Oncol. 2003;21:679-689.

48. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Carducci MA, et al. J Clin Oncol. 2003;21:679-689. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Days Since Randomization Probability of No Disease Progression 0.0 0.2 0.4 0.6 0.8 1.0 0100200300400 Placebo Atrasentan 2.5 mg (P =.035 vs placebo) Atrasentan 10 mg (P =.021 vs placebo) Study M96-594: Time to Disease Progression - Evaluable Population 500

49. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer *P <.01 compared with placebo * 0 10 20 30 40 50 Final Mean Change From Baseline (ng/mL + SE) Placebo Atrasentan 2.5 mg Atrasentan 10 mg Study M96-594: Change in Bone Alkaline Phosphatase - ITT Nelson JB, et al. J Urol. 2003;169:1143-1149.

50. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Days Since Randomization Probability of Not Progressing Phase III study M00-244: Time to Disease Progression - ITT Atrasentan Nelson JB, et al. Cancer. 2008;113:2478-2487. 2008 © American Cancer Society. Reproduced with permission of John Wiley & Sons, Inc. PlaceboAtrasentan Events, n (%)267 (56.3)227 (48.6) Median time to DP, days 671764 Stratified HR: 0.913 (95% CI: 0.766-1.092) Stratified P =.288 0.0 0.1 0.4 0.6 0.8 1.0 0180720108014401800 0.2 0.3 0.5 0.7 0.9 36054090012601620 Placebo

51. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Non-USPlaceboAtrasentan Median time to DP, days 667847 USPlaceboAtrasentan Median time to DP, days 671590 US N = 380 Days Since Study Start Probability of Not Progressing Non-US N = 561 Atrasentan Placebo Nelson JB, et al. Cancer. 2008;113:2478-2487. 2008 © American Cancer Society. Reproduced with permission of John Wiley & Sons, Inc. HR: 1.154 (95% CI: 0.862-1.545) P =.177 P values are exploratory HR: 0.800 (95% CI: 0.639-1.000) P =.021 M00-244: Time to Disease Progression by Region - ITT 0 0.2 0.4 0.6 0.8 1.0 0.1 0.3 0.5 0.7 0.9 0 180 360 540 720 900 1080 1260 1440 1620 1800 0 0.2 0.4 0.6 0.8 1.0 0.1 0.3 0.5 0.7 0.9 0 180 360 540 720 900 1080 1260 1440 1620 1800

52. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Progression was a composite endpoint comprising  Clinical progression (intervention with chemotherapy, radiotherapy, surgery, or a new dose of hormone-based therapy)  Cancer pain requiring opiates  Soft tissue metastasis or  Death in the absence of progression Double-blind randomization ZD4054 10 mg ZD4054 15 mg Placebo HRPC patients with bone metastases who were asymptomatic or mildly symptomatic for pain No prior chemotherapy Progression* Survival † Increase in PSA or new metastases on bone scan did not count as progression events *Primary endpoint. † Secondary endpoint. Once-daily oral treatment James ND, et al. Eur Urol. 2009;55:1112-1123. Study 6 (EPOC): Phase II Study in HRPC

53. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer ITT Population ZD405 15 mg (n = 98) 10 mg (n = 107) Placebo (n = 107) Events, n8399 Clinical302836 Opiate212823 Objective274032 Death538 James ND, et al. Eur Urol. 2009;55:1112-1123. ITT Population ZD4054 15 mg (n = 98) 10 mg (n = 107) Placebo (n = 107) Deaths, n343351 Median OS, mos23.524.517.3 Chemotherapy use, n (%)27 (28)28 (26)25 (23) Study 6 (EPOC): Results

54. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Study 15 ZD4054 vs placebo Metastatic (M1) Asymptomatic or mildly symptomatic for pain No metastases (M0) Asymptomatic or mildly symptomatic for pain Metastatic (M1) Symptomatic Study 14 ZD4054 vs placebo Study 33 ZD4054 + docetaxel vs docetaxel alone ENTHUSE (ENDOTHELIN A USE) ZD4054 Phase III Trial Program

55. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Phase III Denosumab Trial: Delaying Bone Metastases  Randomized, double blind, placebo controlled  Denosumab 60 mg, subcutaneous every 4 wks  Primary outcome measure: time to first bone met or death from any cause  Enrollment: 1435 men, rising PSA on ADT  PSA > 8 ng/mL or PSADT ≤ 10 mos  No bone mets, soft tissue mets permitted  Estimated study completion: June 2010 Available at: http://clinicaltrials.gov/ct2/show/NCT00286091.

56. Evolving Evidence for the Treatment of Bone Metastases in Prostate Cancer

57. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Prostate Cancer Bone Metastases  Heterogeneous –Osteoblastic –Osteolytic Roudier. J Urol. 2008  High bone turnover with highest levels uNTx Coleman RE, et al. J Clin Oncol. 2005;23:4925-4935. uNTx High Moderate Low Patients (%) 0 25 50 75 100 Prostate cancer Breast cancer Multiple Myeloma NSCLCOther solid tumors Primary Cancer

58. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Skeletal-Related Events (Consequences of Bone Metastases)  Data from patients treated on the placebo arm of phase III zoledronic acid trials in men and women with metastatic cancer to bone  Pain is associated with each SRE ProstateBreast Patients Affected (%) Radiation therapy Pathologic fracture 0 20 60 10 40 30 50 Surgery Spinal cord compression

59. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Skeletal Complications Reduce Quality of Life TotalPhysicalFunctionalEmotional FACT-G Change (Standard Deviation) Weinfurt. Ann Oncol. 2005. Kinnane. Eur J Oncol Nurs. 2007. Pathological fracture Radiation to bone -0.7 -0.6 -0.4 0 -0.5 -0.2 -0.3 -0.1 Other SREs

60. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Bone Directed Agents Studied in Metastatic Prostate Cancer *Not all metastatic. † Also includes breast and other cancers. 1. Saad. J Natl Cancer Inst. 2004. 2. Small. J Clin Oncol. 2003. 3. Smith. J Urol. 2008. 4. Fizazi. J Clin Oncol. 2009. 5. Nilsson. Lancet Oncol. 2007. 6. Yu. ASCO 2008. 7. James. European Urol. 2009. AgentPhaseSRE uNTx or CTX Other Zoledronic acid [1] IIIDecr Pain decr Pamidronate [2] III No diffDecrNo diff pain Toremifene* [3] III NR Decr fractures Denosumab †[4] R II Decr Decr fractures in non-met Radium 223 [5] R II Decr Improved OS Dasatinib [6] IINRDecr Studied as an anticancer agent ZD4054 [7] R II NRNo diffImproved OS

61. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer What Have We Learned About Bone Markers From the Zoledronic Acid Trials?  BPs inhibit bone breakdown, reflected by a lowering of uNTx values  Approximately 20% of patients with bone mets treated with zoledronic acid have elevated uNTx > 50 [1]  Elevated uNTx levels on zoledronic acid predict [1] –Increased risk of SREs –Progressive bone lesions –Death  Normalization of uNTx [2] –Improves survival –Decreases SREs 1. Coleman. J Clin Oncol. 2005. 2. Lipton. Cancer. 2008.

62. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Proportion Achieving uNTx Levels < 50 Denosumab normalized uNTx levels more frequently than continuing IV BP therapy Fizazi K, et al. J Clin Oncol. 2009;27:1564-1571. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. IV BP Q4W Denosumab 180 mg Q12W Denosumab 180 mg Q4W All Randomized Patients Patients With uNTx Levels 50-100 nM/mM Creatinine Patients With uNTx Levels > 100 nM/mM Creatinine Patients Achieving uNTx Levels <50 nM BCE/mM Creatinine at Week 13 (%) 0 10 50 80 100 90 70 60 20 30 40 29 64 78 41 65 88 68 63 17

63. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Proportion With First SRE on Study Denosumab had a lower incidence of first SRE on study than BP IV BP Q4W Denosumab 180 mg Q12W Denosumab 180 mg Q4W Study Day Proportion of Patients With a First On-Study SRE Pooled denosumab group 020406080100120140160180200 0 20 30 25 5 10 15 IV BP Q4W (n = 35) Denosumab 180 mg Q12W (n = 35) 180 mg Q4W (n= 35) Pooled Denosumab (n = 73) N (%)6 (17)4 (11)2 (5)6 (8) Odds ratioN/A0.360.260.31 95% CI of odds ratioN/A0.08-1.760.05-1.440.08-1.18 Fizazi K, et al. J Clin Oncol. 2009;27:1564-1571. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

64. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer IsotopeEmissionLETUseRangeDNA Damage Hits to Kill Cell 89 Strontium 153 Samarium BetaLowPalliationmmSingle10 2- 10 3 223 RadiumAlphaHigh Not approved < 100 µm Double strand 1-5 Alpha particle Beta particle Characteristics of Radioisotopes

65. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Phase II Radium 223 Study: Design Nilsson. Lancet Oncol. 2007. Patients with hormone-refractory prostate cancer Local external-beam radiotherapy (N = 64) SREs Pain Bone markers PSA Safety Survival Follow-up of long-term toxic effects and survival Bone markers PSA M24M18M12 Study unmasked M9M6W16W124 injections q4 wks RANDOMIZERANDOMIZE Treatment Saline (placebo) every 4 wks 50 kBq/kg 223 Ra every 4 wks

66. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Role of Src in Prostate Tumor Cell and Osteoclast Activities Tumor cells Systemic factorsLocal factors Osteoclast activity Growth factors Osteolysis Bone complications Direct bone destruction Activated osteoclast Bone Src

67. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Tumor cells Systemic factorsLocal factors Osteoclast activity Growth factors Osteolysis Direct bone destruction Bone Src Dasatinib Dasatinib in PC: Inhibition of Tumor Cells and Osteoclast Activity Through Src

68. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Phase II Study: Dasatinib in Chemo-Naive Men With Progressive Metastatic CRPC  Target recruitment: 50 patients  Amendment added 50 patients at 100 mg QD Tumor evaluation 12 wks Patients with CRPC Tumor evaluation 24 wks  Initial starting dose: 100 mg BID  After 25 patients: starting dose amended to 70 mg BID

69. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Maximum uNTx Change From Baseline BisphosphonateNo bisphosphonate Max % Change From Baseline Decrease 100 80 60 40 0 20 -20 -40 -60 -80 -100 Yu EY, et al. ASCO 2008. Abstract 5156.

70. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Patients With Bone Metastases  At risk for SREs  Without treatment, SREs occur ~ every 8 mos  Median time to first SRE 11 mos after diagnosis  Over 24 months, almost 50% experience SRE  The longer a patient lives, the more likely he is to experience SRE  SREs cause impaired QoL and decreased survival

71. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Concluding Remarks  Zoledronic acid is current standard of care regarding prevention or delay of SREs  Based on zoledronic acid studies, markers of bone turnover such as uNTx appear to be important biomarkers of prognosis, survival  Numerous promising agents in phase III trials  Studies that combine or sequence agents with different mechanisms of action will be warranted

72. clinicaloptions.com/oncology Preventing Bone Loss and Skeletal-Related Events in Patients With Prostate Cancer Now Take the Test...  To earn CME credit for this activity, please close this window and click the “Test” tab in the CME module underneath

73. More Hematology/Oncology Available Online Medical Meeting Coverage: key data plus Expert Analysis panel discussions exploring clinical implications Treatment Updates: comprehensive programs covering the most important new concepts Interactive Cases: test your ability to manage patients clinicaloptions.com/oncology