1. Matthew Raymond Smith, MD, PhD Professor of Medicine Harvard Medical School Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts Managing Skeletal-Related Events in Patients With Cancer: A Master Class in Breast Cancer, Prostate Cancer, and Multiple Myeloma This program is supported by an educational donation provided by

2. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer About These Slides  Our thanks to the presenters who gave permission to include their original data  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (e-mail permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Faculty Matthew Raymond Smith, MD, PhD Professor of Medicine Harvard Medical School Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts Allan Lipton, MD Professor of Medicine and Oncology Milton S. Hershey Medical Center Penn State Cancer Institute Hershey, Pennsylvania Noopur Raje, MD Director, Center for Multiple Myeloma Massachusetts General Hospital Cancer Center Boston, Massachusetts

4. Mitigating Bone Complications in Multiple Myeloma—What’s Current and on the Horizon

5. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Bone Involvement in Different Tumor Types Disease Prevalence (US) (in Thousands) Incidence of Bone Metastases in Patients With Advanced Disease, % Median Survival of Patients With Bone Metastases, Mos Myeloma49.6 [1] 84 [2] 37-58 [4] Lung327 [1] 30-40 [3] 8-10 [5] Breast2051 [1] 65-75 [3] 19-25 [6] Prostate1477 [1] 65-75 [3] 30-35 [7] 1. National Cancer Institute. 2. Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33. 3. Coleman RE. Oncologist. 2004;9(suppl 4):14-27. 4. Palumbo A, et al. Blood. 2004;104:3052-3057. 5. Smith W, et al. Semin Oncol. 2004;31(suppl 4):11-15. 6. Lipton A. J Support Oncol. 2004;2:205-213. 7. Tu SM, et al. Cancer Treat Res. 2004;118:23-46.

6. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Factors Increasing Osteoclast Activity in Bone Metastasis RANK ligand OPG MIP-1 alpha 1,25(OH)2D3 PTHrP Prevents Promotes Increased osteoclastic activity and decreased OPG OPG RANKL Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

7. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Prevalence of Skeletal Complications in Myeloma Berenson JR, et al. N Engl J Med. 1996;334:488-493. Berenson JR, et al. J Clin Oncol. 1998;16:593-602. Patients With SREs (%) † * * *9-mo data. † Placebo arm of pamidronate randomized trial. Total Pathologic Fracture Radiation to Bone Hypercalcemia of Malignancy Surgery to Bone Spinal Cord Compression 0102030405060

8. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Current Treatment of MM Bone Disease  Bisphosphonates  Surgical procedures –Vertebroplasty –Balloon kyphoplasty  Radiotherapy  Treatment of myeloma Roodman GD. Hematology Am Soc Hematol Educ Program. 2008:313-319.

9. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Placebo Pamidronate Berenson JR, et al. N Engl J Med. 1996;334:488-493. Berenson JR, et al. J Clin Oncol. 1998;16:593-602. Pamidronate Decreases SREs in Patients With Myeloma 24 41 38 921 Patients (%) 0 10 20 30 40 50 60 Mos 51 P <.001 P =.015

10. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Zoledronic Acid vs Pamidronate in Multiple Myeloma  13-month follow-up: zoledronic acid was shown to be effective compared with pamidronate across all clinical endpoints  The proportion of patients requiring radiation therapy to bone was significantly lower in the zoledronic acid 4 mg group than in the pamidronate group (15% vs 20%, respectively, P =.031)  Zoledronic acid not inferior to pamidronate in reducing the risk of skeletal complications 44% 46% 0 20 40 60 Pamidronate 90 mg Zoledronic acid 4 mg All SREs Patients With SRE (%) Rosen LS, et al. Cancer J. 2001;7:377-387.

11. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer MRC Myeloma IX: Analysis Schematic for Zoledronic Acid vs Clodronate Endpoints (zoledronic acid vs clodronate) Primary: PFS, OS, and ORR Secondary: time to first SRE, SRE incidence, and safety Patients with newly diagnosed MM (stage I, II, III) (N = 1960) Clodronate 1600 mg/day PO + intensive or nonintensive chemotherapy (n = 979) Zoledronic acid 4 mg IV q 3-4 wks* + intensive or nonintensive chemotherapy (n = 981) Treatment continued until disease progression *Dose-adjusted for patients with impaired renal function, per the prescribing information. Morgan G, et al., Lancet. 2010;376:1989-1999

12. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer 061218243036424854606672 MRC Myeloma IX: ZOL ↓ SREs* vs CLO Regardless of Bone Lesions at Baseline Bone Lesions at BaselineNo Lesions at Baseline 0.5 0.4 0.3 0.2 0.1 0 Mos From Randomization SREs/Patient 668 682 415 402 325 297 250 212 189 164 136 117 100 75 69 50 37 35 24 18 12 6464 0000 Zoledronic acid Clodronate Pts at Risk, n Mos From Randomization 302 276 241 212 185 159 135 118 92 91 63 56 38 37 28 24 18 11 12 8787 5454 0000 Zoledronic acid Clodronate Pts at Risk, n CLO ZOL CLO ZOL Highlights the importance of treating all patients regardless of skeletal morbidity at presentation Morgan GJ, et al. ASH 2010. Abstract 311. Reprinted with permission. Morgan G, et al. Lancet. 2010;376:1989-1999. 061218243036424854606672 0.5 0.4 0.3 0.2 0.1 0

13. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer MRC Myeloma IX: Zoledronic Acid Improved OS and PFS vs Clodronate Risk Reduction HR (Zoledronic Acid vs Clodronate) 00.2 0.40.60.811.21.41.61.82 P Value.0118 0.842 16% In favor of ZOL In favor of CLO OS.017912% 0.883 PFS Zoledronic acid significantly reduced the relative risk of death by 16% vs clodronate (HR: 0.842; 95% CI: 0.736-0.963; P =.0118) Reprinted from The Lancet, 376(9757), Morgan GJ, Davies FE, Gregory WM, et al., First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial.989-1999, Copyright 2010, with permission from Elsevier.

14. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Z-MARK Study Design Patients with MM who received IV bisphosphonate therapy 52-104 wks before first zoledronic acid dose on study* (N = 121) uNTx ≥ 50 † uNTx < 50 † ZOL 4 mg q4wk ‡§║ Bone marker-directed ZOL dosing x 96 wk SRE, PD, or ↑ uNTX ≥ 50 † ZOL 4 mg q4wk ‡§║ *Patient had to receive ≥ 4 doses of IV bisphosphonate; last previous IV bisphosphonate dose must have been administered ≥ 3 wks before initial zoledronic acid dose on study. † nmol/mmol creatinine. ‡ Patients will remain on zoledronic acid q 4 wks for remainder of the study. § All patients were reminded to take supplemental oral calcium (≥ 500 mg) and vitamin D (≥ 400 IU) daily. ║ Dose adjusted for patients with mild to moderate renal impairment at study entry. Prospective, single-arm, open-label, multicenter study ZOL 4 mg q12wk §e Raje N, et al. ASH 2010. Abstract 2971.

15. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Results  SREs by end of Year 1 –2 patients receiving zoledronic acid q12wk –Spinal cord compression (1 patient) –Radiation therapy to bone x 4 (1 patient) –0 patients receiving zoledronic acid q4wk  uNTX –Baseline uNTX –Median: 17 nmol/mmol Cr –Range: 7-71 nmol/mmol Cr –Median % change from baseline in uNTX –Wk 12-36: 0  –11.7  (range, -80.5  –344.4  ) – Wk 48: 0% (range, -67.5%–188.9%) Raje N, et al. ASH 2010. Abstract 2971.

16. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Summary of Bisphosphonates in MM  Inhibit bone resorption  Pamidronate better than placebo  Pamidronate and zoledronic acid equivalent  Zoledronic acid has a survival advantage

17. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Denosumab: Inhibiting RANK in Bone Disease  High affinity human monoclonal antibody that binds RANKL  Administered via subcutaneous injection  Specific: does not bind to TNF-α, TNF-β, TRAIL, or CD40L  Inhibits formation and activation of osteoclasts

18. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Phase II Study of Denosumab in Relapsed and Plateau-Phase MM  Effective for myeloma bone disease  Median changes in bone resorption markers were -70% and -52% for relapsed and plateau-phase patients Vij R, et al. Am J Hematol. 2009;84:650-656.

19. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Denosumab vs Zoledronic Acid  Phase III trial in 1776 patients with solid tumors (not breast or prostate) or myeloma –Primary endpoint: median time to first SRE  Denosumab was noninferior to zoledronic acid in delaying time to first on-study SRE (HR: 0.84; 95% CI: 0.71-0.98; P =.0007)  Serious adverse events were similar  ONJ infrequent and similar (10 vs 11 patients) Henry D, et al. J Clin Oncol. 2011;29:1125-1132.

20. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Roodman GD. J Clin Invest. 2008;118:462-464. Bortezomib/Lenalidomide in MBD Myeloma cells Bone OCL Osteoblasts OCL precursor Lenalidomide OAFs Bortezomib BMP-2Runx-2MSCs

21. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer This research was originally published in Blood. Vallet S, et al. MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. 2007 Nov 15;110(10):3744-52. © the American Society of Hematology. CCR1 and Osteoclastogenesis/Osteoclasts Function Menu: On Murine OC BX4471 Is a Potent Inhibitor of Osteoclastogenesis Resorbed area on dentine slices TRAP + multinucleated cells MLN3897 10 nM P <.05 Pro-cathepsin K Cathepsin K C-tubulin Cathepsin K expression -+-+ ++-- PB2PB1 MLN3807 10 nM MLN3807(nM) 0.2210 12 Pct Area as % of Total Area TRAP + MN Cell (% of connect) 10 8 6 4 2 0 0.22100100 0 140 100 80 60 40 20 0 120 CCR1 Inhibition Decreases Osteoclastogenesis

22. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer DKK1 and sFRP-2 in Myeloma Bone Disease  Inhibitors of the WNT signaling pathway  WNT signaling is a critical pathway for OBL differentiation  Secreted by myeloma cells  Marrow plasma from patients with high levels of DKK1 or sFRP-2 inhibit murine OBL differentiation  DKK1 gene expression levels correlated with extent of bone disease in MM patients Tian E, et al. N Engl J Med. 2003;349:2483-2489. Oshima T, et al. Blood. 2005;106:3160-3165.

23. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Anti-DKK1 BHQ880 Reverses Inhibitory Effect of MM Cells on Osteoblastogenesis huIL-6 ng/mL No MM Cells With MM Cells P =.0002 P =.0003 P =.002 2 0 4 6 8 - BHQ880 + BHQ880 BHQ880, 1  g/mL Isotype Control No MM Cells With MM Cells A B This research was originally published in Blood. Fulciniti M, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. 2009;114:371-379. © the American Society of Hematology. Calcium Deposition (% of control) 50 100 150 0 P =.08 P =.0001 No MM Cells With MM Cells - BHQ880 + BHQ880

24. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Activin decreases bone mineral density and strength Activin and Bone Growth Reduced bone formation Activin Activin inhibits osteoblasts Osteoblast Activin receptor type IIA Activin receptor type IIA Activin stimulates osteoclasts Increased bone resorption Osteoclast

25. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Activin A Levels Are Elevated in Patients With MM and Osteolytic Disease Activin A Levels Are Increased in Bone Marrow Plasma of Patients With MM Activin A Is Produced by the Microenvironment, Notably BMSCs and Osteoclasts Average Levels of Activin A MM 0-1 OL: 28.62 ± 6.2 pg/mL MM > 1 OL: 112.07 ± 30.4 pg/mL Non-MM: 30.6 ± 7.9 pg/mL Vallet S, et al. Proc Natl Acad Sci U S A. 2010;107:5124-5129. Copyright 2010 National Academy of Sciences, U.S.A. *P <.05; † P <.01 NS 150 100 50 0 pg/mL MM 0-1 OL MM > 1 OL Non MM ** 3500 2500 500 0 pg/mL OC 3000 2000 1500 1000 BMSCOBMM Mean 1300 Mean 1884 NS Mean 299 Mean 8.2 † †

26. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Phase II Study of hActRIIA-IgG1 in Patients With Osteolytic Lesions of MM ClinicalTrials.gov. NCT00747123.  Randomized, double blind, placebo controlled  Dose ranging, multiple dose, parallel assignment  N = 30  All patients receiving backbone MPT regimen 0.5 mg/kg ACE-011, SQ monthly x 4 (n = 8) 0.1 mg/kg ACE-011, SQ monthly x 4 (n = 8) 0.3 mg/kg ACE-011, SQ monthly x 4 (n = 8) Placebo, SQ monthly x 4 (n = 6)

27. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Results  28 patients had at least 1 previous treatment  13 patients receiving bisphosphonates  75% of patients had Hb increase of 1.5 gm/dL vs 17% of patients receiving placebo  Increased BSAP and slightly decreased S-CTX levels among BP-naive patients Abdulkadyrov KM, et al. ASH 2009. Abstract 749

28. Optimal Management of Bone Metastases in Patients With Breast Cancer

29. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Scope of the Problem  400,000 new patients/yr in the United States develop bone metastases

30. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Incidence of Skeletal-Related Events Lung Cancer/Others † Prostate Cancer* Multiple Myeloma † Breast Cancer* Coleman RE. Oncologist. 2004;9(suppl 4):14-27. *24 mos. † 21 mos. ‡ Placebo arm of pamidronate or zoledronic acid randomized trials. 48 49 51 68 020406080 Patients With SREs (%) ‡

31. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Patients With Bone Lesions Are at High Risk for Skeletal Complications Pathologic fracture Radiation therapy Surgical intervention Spinal cord compression Breast [1] 24 mos Prostate [2] 24 mos NSCLC + other solid tumors [5] 21 mos Multiple myeloma* [3,4] 21 mos Cancer Type Placebo Arms of Large Randomized Studies Patients With SRE (%) *21-mo data except for surgical intervention and spinal cord compression, for which only 9-mo data are available. 1. Lipton A, et al. Cancer. 2000;88:1082-1090. 2. Saad F, et al. AUA 2003. Abstract 1472. 3. Berenson JR, et al. J Clin Oncol. 1998;16:593-602. 4. Berenson JR, et al. N Engl J Med. 1996;334:488-493. 5. Rosen LS, et al. Cancer. 2004;100:2613-2621. 52 25 37 22 34 11 4 4 5 3 8 2 4 34 33 43 0 10 20 30 40 50 60

32. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Skeletal-Related Events and OS Mos As advances are made in cancer treatment, survival is increased—and with it, the risk of skeletal-related events Median Time to a Skeletal-Related Event and Median Survival 1. Rosen LS, et al. Cancer. 2004;100:2613-2621. 2. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 3. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. 4. Berenson JR, et al. N Engl J Med. 1996;334:488- 493. 5. Kumar SK, et al. Blood. 2008;111:2516-2520. 6. Saad F, et al. J Natl Cancer Inst. 2004;96:879-892. 7. Coleman RE. Cancer. 1997;80(8 suppl):1588-1594. 53.0 44.8 26.7 12.3 11 9 12 5.1 0204060 Prostate [6,7] Myeloma [4,5] Breast [3] Lung [1,2] Skeletal-related event Survival

33. Pamidronate, Zoledronic Acid, and Denosumab

34. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer 050100150200250300350400 Days After Start of Study Drug 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Proportion of Patients With Bone Metastases Without an SRE P =.004 Kohno N, et al. SABCS 2004. Abstract 3060. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. Reprinted with permission. Zoledronic Acid Significantly Delays Time to First SRE Compared With Placebo Zoledronic acid 4 mg Placebo

35. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Zoledronic Acid Reduces SRE Risk vs Pamidronate in Breast Cancer  Zoledronic acid reduced SRE risk by 16% overall vs pamidronate (N = 417*) and by over 30% in patients in the breast carcinoma hormonal therapy stratum *Patients who entered the extension study in the 4 mg zoledronic acid or pamidronate groups. Multiple Event Analysis Risk RatioP Value Total0.841.030 Breast carcinoma hormonal therapy stratum0.693.009 Breast carcinoma chemotherapy stratum0.955.749 Multiple myeloma stratum0.9320.593 Rosen LS, et al. Cancer. 2003;98:1735-1744.

36. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer International, Randomized, Double-Blind, Active-Controlled Study  Primary endpoint: time to first on-study SRE (noninferiority) Denosumab 120 mg SC + Placebo IV* q4w (n = 1026) Patients with advanced breast cancer and confirmed bone metastases (N = 2046) Zoledronic acid 4 mg IV* + Placebo SC q4w (n = 1020)  Secondary endpoints: time to first on-study SRE (superiority); time to first and subsequent on-study SRE (multiple event analysis)  Current or previous IV bisphosphonate administration not permitted Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. *IV agent dose adjusted for creatinine clearance at baseline and subsequent dosing intervals determined based on serum creatinine levels according to zoledronic acid label.

37. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Time to First On-Study SRE Zoledronic acid10208296765844984272961919429 Denosumab10268396976025144373061899926 Patients at Risk, n *Adjusted for multiplicity. KM Estimate of Median Mos Denosumab Zoledronic acid Not reached 26.4 HR: 0.82 (95% CI: 0.71-0.95; P <.001 noninferiority; P =.01 superiority*) Mos 0 1.00 Proportion of Subjects Without SRE 036912151821242730 0.25 0.50 0.75 Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.

38. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Time to First and Subsequent SRE*: Multiple Event Analysis *Events that occurred at least 21 days apart. † Adjusted for multiplicity. Denosumab Zoledronic acid Rate ratio: 0.77 (95% CI: 0.66-0.89; P =.001 † ) Mos 0 1.5 Cumulative Mean Number of SREs 036912151821242730 0.5 1.0 Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.

39. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Time to Experiencing Mod or Severe Pain (Worst Pain Score > 4 Pts/Brief Pain Inv) KM Estimate of Median Days Denosumab Zoledronic acid 88 64 HR: 0.87 (95% CI: 0.79-0.97; P =.009) Proportion of Subjects 0369121518212427 Stopeck A, et al. SABCS 2009. Abstract 22. Reprint permission granted. Zoledronic acid1020463318250209172126935617 Denosumab10265113783122562141591095927 Patients at Risk, n Mos 0 1.00 0.25 0.50 0.75

40. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Proportion of Subjects Without Disease Progression 036912151821242730 Disease Progression HR: 1.00 (95% CI: 0.89-1.11; P =.93) Mos Zoledronic acid10208426865634623702401486517 Denosumab10268586935674533512411286520 Patients at Risk, n Denosumab Zoledronic acid 0 1.00 0.25 0.50 0.75 Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.

41. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Overall Survival Zoledronic acid102096289783475769951535218454 Denosumab102698491684977169051133617757 HR: 0.95 (95% CI: 0.81-1.11; P =.49) Mos 0 1.00 Proportion of Subjects Survived 036912151821242730 0.25 0.50 0.75 Patients at Risk, n Denosumab Zoledronic acid Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved.

42. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Adverse Events Adverse Event, % Zoledronic Acid (n = 1013) Denosumab (n = 1020) Overall97.295.8 Serious46.544.4 Acute phase reactions (first 3 days)27.310.4 Renal toxicity  Overall 8.54.9  Serious 1.50.2 ONJ*1.42.0 *P =.39 Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

43. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Skeletal Complication Risk: Incremental Benefits in Breast Cancer No bisphosphonate 64% risk at 2 yrs Pamidronate ~ 20% risk reduction 64% 51% 34% Zoledronic acid Additional ~ 20% risk reduction 27% Denosumab Additional 18% risk reduction Lipton A, et al. Cancer. 2000;88:3033-3037. Rosen LS, et al. Cancer. 2003;100:36-43. Stopeck A, et al. ECCO/ESMO 2009. Abstract 2LBA. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

44. Novel Strategies for Bone- Directed Therapy in Prostate Cancer

45. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Spectrum of Bone Disease in Prostate Cancer Treatment-Related Fractures Disease-Related Skeletal Complications Castrate sensitive, nonmetastatic Castrate resistant, nonmetastatic Castrate resistant, metastatic New Bone Metastases

46. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Clinical Complications of Osteoblastic Metastases  Pain  Fractures  Spinal cord compression  Myelophthisis

47. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer 0 200 Reproduced and adapted with permission from the American Association for Cancer Research: Cook RJ, et al. Clin Cancer Res. 2006;12:3361-3367. Figure 1B. Markers of Osteoblast (BAP) and Osteoclast (NTx) Activity in Men With PC NTx (nmol/mmol creatinine) BAP (U/L) Correlation coefficient = 0.67 Normal 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 3400 3600 3800 4000 0 200 400 600800 1000 1200 1400 25% 50% 75% 25% 75%

48. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Zoledronic Acid in Hormone-Refractory Prostate Cancer  Patients on the 8-mg arm reduced to 4 mg because of renal toxicity  Primary outcome: proportion of patients having ≥ 1 SRE  Secondary outcomes: time to first on-study SRE; proportion of patients with SREs, and TTP  Patients with prostate cancer  Hormone refractory  Bone metastases (N = 643) Zoledronic acid 4 mg q3w (n = 214) Placebo q3w (n = 208) Eligibility Criteria Zoledronic acid 4 mg q3w (initially 8 mg) (n = 221) Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.

49. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Days After the Start of Study Drug Saad F, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468, by permission of Oxford University Press. 90180270360450540 0 20 40 60 80 Patients Without Event (%) 0 10 30 50 70 90 100 163113927050214 155102684640221 149103694310208 Zol acid 4 mg Zol acid 8/4 mg Placebo Patients at Risk, n Zoledronic acid 4 mg Zoledronic acid 8/4 mg Placebo Zoledronic Acid vs Placebo: Time to First On-Study SRE

50. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Denosumab 120 mg SC + Placebo IV q4w (n = 950) Zoledronic Acid 4 mg IV + Placebo SC q4w (n = 951) Patients with CRPC and bone metastases, no current or previous IV treatment with bisphosphonate (N = 1901) Denosumab vs Zoledronic Acid to Prevent SREs  Prospective, double-blind, placebo-controlled phase III trial Fizazi K, et al. Lancet. 2011;377:813-822.  Primary endpoint SREs: fracture, radiation or surgery to bone, spinal cord compression

51. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Denosumab vs Zoledronic Acid: Time to First On-Study SRE Reprinted from The Lancet, 377(9768), Fizazi K, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration- resistant prostate cancer: a randomised, double-blind study. 813-822. Copyright 2011, with permission from Elsevier HR: 0.82 (95% CI: 0.71-0.95; P =.0002 for noninferiority analysis; P =.008 for superiority analysis) Median Mos (95% CI) 20.7 (18.8-24.9) 17.1 (15.0-19.4) Patients at Risk, n Denosumab Zoledronic acid 950 951 758 733 582 544 472 407 361 299 259 207 168 140 115 93 70 64 39 47 1.00 0.75 0.50 0.25 0 0369121518212427 Study Mo Proportion of Patients Without an SRE Denosumab Zoledronic acid

52. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) *Events occurring at least 21 days apart. 2.0 1.4 1.0 0.6 0 0369121518212427 Study Mo Cumulative Mean Number of SREs per Patient Denosumab (n = 950) Zoledronic acid (n = 951) Rate ratio: 0.82 (95% CI: 0.71-0.94; P =.004; adjusted P =.008) 1.8 1.6 1.2 0.8 0.4 0.2 303336 Events 494 584 Reprinted from The Lancet, 377(9768), Fizazi K, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. 813-822. Copyright 2011, with permission from Elsevier

53. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Results  Denosumab was superior to zoledronic acid –Delay time to first SRE on study –Reduce the rate of multiple SREs  Rates of adverse events similar (infection)  ONJ infrequent and no statistical difference between arms  Hypocalcemia more frequent in denosumab arm Fizazi K, et al. Lancet. 2011;377:813-822.

54. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Conclusions  Disease-related skeletal complications are common in men with metastatic prostate cancer  Zoledronic acid decreases risk of SREs in men with castrate-resistant disease and bone metastases  Denosumab is superior to zoledronic acid for delay in first SREs and rate of SREs in this setting

55. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Spectrum of Bone Disease in Prostate Cancer Castrate sensitive, nonmetastatic Castrate resistant, nonmetastatic Castrate resistant, metastatic Metastasis Prevention

56. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer PSA and PSADT Are Associated With Shorter Bone Metastasis-Free Survival Incidence of Bone Mets or Death 0 0.2 0.4 0.6 0.8 1.0 0 Yrs Since Randomization 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 0 0.2 0.4 0.6 0.8 1.0 0 Yrs Since Randomization 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 Smith MR, et al. J Clin Oncol. 2005;23:2918-2925. Reprinted with permission. © 2005 American Society of Clinical Oncology. All rights reserved. Incidence of Bone Mets or Death

57. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Denosumab to Prevent Metastases  Primary endpoint: bone metastasis-free survival Denosumab 120 mg monthly Patients with CRPC and no bone metastases; PSA > 8 or PSADT < 10 mos (N = 1435) Placebo monthly Smith MR, et al. 2011 AUA. Plenary. ClinicalTrials.gov. NCT00286091.

58. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Primary Endpoint: Bone Metastasis-Free Survival 716 691 695 569 605 500 521 421 456 375 400 345 368 300 324 259 279 215 228 1.0 0.8 0.6 0.4 0 0369121518212427 Study Mo Proportion of Patients With Bone Metastasis–Free Survival Placebo Denosumab 0.2 3033363942 Median Mos 25.2 29.5 HR: 0.85 (95% CI: 0.73-0.98; P =.028) Placebo Denosumab 168 185 137 153 99 111 60 59 36 35 Patients at Risk, n Smith MR, et al. 2011 AUA. Plenary.

59. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Time to Symptomatic Bone Metastasis Note: Symptomatic bone metastases before or coinciding with imaging diagnosing. 716 667 683 565 603 474 503 411 441 368 385 347 360 293 308 242 260 189 200 1.0 0.8 0.6 0.4 0 0369121518212427 Study Mo Proportion of Patients Without Symptomatic Bone Metastasis Placebo Denosumab 0.2 30333639 HR: 0.67 (95% CI: 0.49-0.92; P =.01) 142 160 130 143 94 96 51 47 Placebo Denosumab Patients at Risk, n Smith MR, et al. 2011 AUA. Plenary.

60. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer ZEUS: Zoledronic Acid to Prevent Metastases  Primary endpoint: first bone metastasis Wirth M, et al. ASCO GU 2008. Abstract 184. Zoledronic acid q3m for 48 mos Patients with high-risk prostate cancer: Gleason sum 8-10, pN+, or PSA > 20 ng/mL at diagnosis; no bone metastases (N = 1433) Placebo q3m for 48 mos Study does not control for ADT 1. Some men will develop bone metastases prior to ADT 2. Dramatic variation in duration of response to ADT

61. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Conclusions: Metastasis Prevention  Prevention of bone metastases is an important unmet clinical need  Failure of previous studies is related, at least in part, to previously poorly defined natural history of castration- resistant nonmetastatic disease  In men with high-risk CRPC, denosumab significantly increased bone metastasis-free survival, time to bone metastasis, and time to symptomatic bone metastasis

62. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Spectrum of Bone Disease in Prostate Cancer Treatment-Related Fractures Castrate sensitive, nonmetastatic Castrate resistant, nonmetastatic Castrate resistant, metastatic

63. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Proportion of Patients With Fractures 1-5 Yrs After Cancer Diagnosis Shahinian VB, et al. N Engl J Med. 2005;352:154-164. 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

64. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Lumbar Spine Total Hip P <.001 for each comparison 12-mo data Percent Change Mittan D, et al. J Clin Endocrinol Metab. 2002;87:3656-3661. GnRH Agonists Decrease BMD in Men With Prostate Cancer -5 -4 -3 -2 0 1 2 GnRH agonist Control

65. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy Lumbar Spine Total Hip Final 12-mo data BMD Percent Change -6 -4 -2 0 2 4 6 Placebo Zoledronic acid Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.

66. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Lumbar Spine Total Hip 12-mo data Greenspan SL, et al. Ann Intern Med. 2007;146:416-424. Alendronate Increases BMD During GnRH Agonist Therapy BMD Percent Change -3 -2 0 1 2 3 4 5 Placebo Alendronate P <.005 for each comparison

67. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Denosumab Fracture Prevention Study  Primary endpoints: BMD, new vertebral fractures ClinicalTrials.gov. NCT00089674. Current androgen deprivation therapy for patients with prostate cancer who are older than 70 yrs of age or with T score < -1.0 (N = 1468) Denosumab q6m for 3 yrs Placebo q6m for 3 yrs

68. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Denosumab to Increase BMD in Patients With Prostate Cancer Receiving ADT Smith MR. N Engl J Med. 2009;361:745-755. Copyright © 2009 Massachusetts Medical Society. All rights reserved. Denosumab Difference at 24 mos: 6.7 percentage points Lumbar Spine Mos Percent Change in BMD From Baseline 10 8 6 4 2 0 -2 -4 -6 0136122436 Placebo Difference at 24 mos: 4.8 percentage points Total Hip Mos Percent Change in BMD From Baseline 10 8 6 4 2 0 -2 -4 -6 0136122436

69. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Denosumab to Prevent Fractures 12 Mos 2436 P =.004 P =.006 1.9 0.3 3.3 1.0 3.9 1.5 0 2 4 6 8 10 New Vertebral Fracture (%) Placebo Denosumab 1322272610Patients, n Smith MR. N Engl J Med. 2009;361:745-755. Copyright © 2009 Massachusetts Medical Society. All rights reserved.

70. clinicaloptions.com/oncology Managing Skeletal-Related Events in Patients With Cancer Summary: Prevention of Treatment- Related Fractures  Androgen deprivation therapy increases fracture risk  Bisphosphonates increase BMD during androgen deprivation therapy  Denosumab increases BMD and decreases fractures during androgen deprivation therapy

71. Go Online at CCO for More Education on Bone Health in Patients With Cancer! clinicaloptions.com/oncology