1. Skeletal Integrity in Oncology: What Physicians Need to Know This program is supported by an educational donation from Matthew R. Smith, MD, PhD Associate Professor of Medicine Harvard Medical School Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts

2. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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 Skeletal Integrity in Oncology Program Faculty Program Director Matthew R. Smith, MD, PhD Associate Professor of Medicine Harvard Medical School Program Director, Genitourinary Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts Co-Chairs Allan Lipton, MD Professor of Medicine and Oncology Milton S. Hershey Medical Center Penn State Cancer Institute Hershey, Pennsylvania G. David Roodman, MD, PhD Professor of Medicine, Vice Chair for Research Department of Medicine/Hematology-Oncology University of Pittsburgh School of Medicine Director, Myeloma Program Department of Medicine/Hematology-Oncology University of Pittsburgh Cancer Institute VA Pittsburgh Healthcare System Pittsburgh, Pennsylvania

4. clinicaloptions.com/oncology Skeletal Integrity in Oncology Program Faculty James Berenson, MD President and Chief Executive Officer Medical and Scientific Director Institute for Myeloma and Bone Cancer Research West Hollywood, California Adam M. Brufsky, MD, PhD Associate Professor of Medicine Hematology/Oncology University of Pittsburgh School of Medicine Associate Director for Clinical Investigations University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania Michael A. Carducci, MD Professor of Oncology and Urology Department of Oncology Kimmel Cancer Center at Johns Hopkins Baltimore, Maryland Celestia S. Higano, MD, FACP Professor Departments of Medicine and Urology University of Washington Seattle, Washington Paul H. Lange, MD, FACS Professor and Chairman of the Department of Urology University of Washington Seattle, Washington

5. clinicaloptions.com/oncology Skeletal Integrity in Oncology Program Faculty Benjamin Leder, MD Associate Professor of Medicine Harvard Medical School Massachusetts General Hospital Boston, Massachusetts Noopur Raje, MD Director, Center for Multiple Myeloma Massachusetts General Hospital Cancer Center Boston, Massachusetts Alison T. Stopeck, MD Associate Professor of Medicine Arizona Cancer Center University of Arizona Tucson, Arizona Katherine N. Weilbaecher, MD Associate Professor in Medicine and Cell Biology Division of Oncology Washington University School of Medicine St Louis, Missouri Maurizio Zangari, MD Professor of Medicine Department of Hematology University of Utah Salt Lake City, Utah

6. clinicaloptions.com/oncology Skeletal Integrity in Oncology Table of Contents  Disruption of Bone Homeostasis in Patients With Cancer  Bone-Targeted Therapy for Cancer-Related or Cancer Treatment–Induced Bone Complications –Bone Health Checklist for Oncologists  Mitigating Bone Complications in Multiple Myeloma  Strategies to Prevent and Manage Bone Compromise in Breast Cancer  Strategies for Bone-Directed Therapy in Prostate Cancer

7. Disruption of Bone Homeostasis in Patients With Cancer

8. clinicaloptions.com/oncology Skeletal Integrity in Oncology Normal Bone Remodeling Is a Coupled and Balanced Process Osteoclastic bone resorption Osteoblasts mediate new bone formation Hattner R, et al. Nature. 1965:206:489-490.

9. clinicaloptions.com/oncology Skeletal Integrity in Oncology Osteoporosis Imbalance in Bone Homeostasis Breast cancer, myeloma Prostate cancer

10. clinicaloptions.com/oncology Skeletal Integrity in Oncology Regulatory Influences: Systemic Hormones  PTH, PTHrP  1,25-(OH)2 vitamin D3  Calcitonin  Gonadal steroids (estrogen, androgen)  GH  IGF-1

11. clinicaloptions.com/oncology Skeletal Integrity in Oncology Hormonal Mediation of Bone Homeostasis  Hormonal influence in bone remodeling integral to bone health, especially trabecular bone  Process dynamic and continuous throughout life span  Balance and integration with other influences critical  Surge of gonadal hormones at puberty necessary for maximal skeletal maturity and strength  Natural hormonal waning with age decreases bone strength  Process predictable regardless of other influences

12. clinicaloptions.com/oncology Skeletal Integrity in Oncology Effects of Gonadal Steroid Deprivation  Loss of gonadal hormones increases bone resorption –Life span and activity of osteoblasts decreased, resulting in less new bone deposition –Osteoclastic activity is less suppressed, increasing rate of resorption  Resulting imbalance promotes osteoporosis/osteopenia

13. clinicaloptions.com/oncology Skeletal Integrity in Oncology Osteoporosis From Hormonal Deprivation  Normally seen in both aging men and women  Fractures in spine most prevalent  Trabecular bone at highest risk  Deprivation accelerated by systematic cancer therapy  Especially problematic with use of antihormonal cancer agents (prostate and breast cancer)

14. clinicaloptions.com/oncology Skeletal Integrity in Oncology Pathogenesis of Osteolytic Bone Metastases  Tumor-derived osteoclast activating factors –Parathyroid hormone– related protein –Interleukin-6, -8, -11 –Tumor necrosis factor –Macrophage colony- stimulating factor  Bone-derived tumor growth factors –Transforming growth factor  –Insulin-like growth factors –Fibroblast growth factors –Platelet-derived growth factor –Bone morphogenic proteins Bone Tumor Cells in Bone Osteoclast (+) Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664.

15. clinicaloptions.com/oncology Skeletal Integrity in Oncology SREs Reflect Morbidity From Bone Metastases  Pathological fractures –Nonvertebral –Vertebral compression  Spinal cord compression/collapse  Radiation therapy  Surgery to bone  Hypercalcemia SREs

16. Bone-Directed Therapy for Cancer-Related or Cancer Treatment–Induced Bone Complications

17. clinicaloptions.com/oncology Skeletal Integrity in Oncology A Bone Health Checklist for Oncologists Cancer-Related Osteoporosis Risk Factors  Androgen deprivation therapy  Aromatase inhibitor therapy  Premature menopause Osteoporosis Risk Factors  Older than 65 yrs of age  Low BMI  Previous nontraumatic fracture  Currently smoking  Parental hip fracture Tests  DEXA every 2 yrs  25(OH)D level (target > 40 ng/mL)  Serum calcium level Treat any of the following  Hip or vertebral fracture  T-score ≤ -2.5  T-score -1 to -2.5 with 10-yr probability of hip fracture ≥ 3% or major osteoporotic fracture ≥ 20%

18. clinicaloptions.com/oncology Skeletal Integrity in Oncology Available at: http://www.sheffield.ac.uk/FRAX/. Image used with permission of the WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield. FRAX is registered to Professor JA Kanis, University of Sheffield.http://www.sheffield.ac.uk/FRAX/ The FRAX Index: Assessing Fracture Risk

19. clinicaloptions.com/oncology Skeletal Integrity in Oncology Bisphosphonates  Inhibitors of bone loss  Potency varies greatly depending on R 1 and R 2 side chains Relative R 1 R 2 Potency EtidronateOH– CH 3 1 ClodronateCl– Cl 10 TiludronateH– S – – Cl 10 PamidronateOH–(CH 2 ) 2 – NH 2 100 AlendronateOH–(CH 2 ) 3 – NH 2 1000 RisedronateH–CH 2 – N 5000 Ibandronate OH (CH 2 ) 2 -N-(CH 2 ) 4 -CH 3 10,000 CH 3 Zoledronic acidOH –N N 100,000 OHR1R1 R2R2 PCPO O No N N

20. clinicaloptions.com/oncology Skeletal Integrity in Oncology Effect of Bisphosphonates on Vicious Cycle of Bone Destruction  Decrease activity of osteoclasts –Reduction in release of peptides –Slowed tumor-cell growth –Reduced production of PTHrP and other factors –Decrease in bone resorption PTHrP Tumor Cells IL-6 IL-8 PGE 2 TNF-  CSF-1 BMP PDGF FGFs IGFs TGF-β Osteoclast Bone Adapted from Mundy GR, et al. N Engl J Med. 1998;339:398-400.

21. clinicaloptions.com/oncology Skeletal Integrity in Oncology Use of IV Bisphosphonates  Treatment of osteoporosis  Treatment of hypercalcemia  Prevent or decrease onset of fractures  Provide pain relief in bone metastasis  Improve quality of life  Antitumor effects Doggrell SA. Expert Rev Anticancer Ther. 2009;9:1211-1218. Winter MC, et al. Curr Opin Oncol. 2009;21:499-506.

22. clinicaloptions.com/oncology Skeletal Integrity in Oncology IV Bisphosphonates: Adverse Effects  Bone pain: responsive to NSAIDs  Nausea (minor)  Flulike symptoms  Anemia  Hypocalcemia Papapetrou PD. Hormones (Athens). 2009;8:96-110.

23. clinicaloptions.com/oncology Skeletal Integrity in Oncology Acute Phase Reaction  Fever, myalgias, arthralgias  Occurs within 12-48 hrs of treatment  More common during first dose  Less severe with subsequent treatment  Managed conservatively

24. clinicaloptions.com/oncology Skeletal Integrity in Oncology Renal Function: Use of Bisphosphonates  Changes in kidney function are related to C max –Rate of infusion is the key factor in prevention of kidney problems –Rates faster than 0.3-0.7 mg/min are associated with problems  Importantly, rate of infusion has no impact on prevention of skeletal complications –Efficacy related to AUC (how much remains in patient)  Zoledronic acid and pamidronate affect different parts of the kidney –Zoledronic acid: tubular –Pamidronate: glomerular  Reduce the risk of renal dysfunction –Monitor serum creatinine before each infusion –Make sure patient is hydrated at time of treatment

25. clinicaloptions.com/oncology Skeletal Integrity in Oncology Incidental finding of osteonecrosis in a patient complaining of a dislodged dental restoration. The patient underwent dental extraction in the region of the exposed bone 1 yr before presentation. She has no symptoms. ONJ

26. clinicaloptions.com/oncology Skeletal Integrity in Oncology ONJ: Clinical Features and Working Diagnosis  Clinical features of suspected ONJ –Exposed bone in maxillofacial area that occurs in association with dental surgery or occurs spontaneously, with no evidence of healing  Working diagnosis of ONJ –No evidence of healing after 6 wks of appropriate evaluation and dental care –No evidence of metastatic disease in the jaw or osteoradionecrosis Weitzman R, et al. Crit Rev Oncol Hematol. 2007;62:148-152.

27. clinicaloptions.com/oncology Skeletal Integrity in Oncology Frequency of ONJ in Malignant Bone Disease StudyStudy Type Pts Treated With BP, n Pts With Suspect or Proven ONJ, n Frequency, % Hoff et al, MDACC ASCO 2006 [1] Chart review4019340.8 Durie et al [2] Web-based survey120315212.6 Pozzi et al, Italian Multicenter study [3] Chart review888161.8 Badros et al [4] Chart review/ observational 340113.2 Tosi et al, analysis of Bologna 2002 trial [5] Retrospective review of trial database 25962.7 Zervas et al [6] Observational2542811.0 Dimopoulos et al [7] Chart review202157.4 Cafro et al [8] Chart review1181411.9 Berenson et al [9] Chart review 300 144.7 1. Hoff AO, et al. ASCO 2006. Abstract 8528. 2. Durie GM, et al. N Engl J Med. 2005;353:99-102. 3. Pozzi S, et al. ASH 2005. Abstract 5057. 4. Badros A, et al. J Clin Oncol. 2006;24:945-952. 5. Tosi P, et al. ASH 2005. Abstract 3461. 6. Zervas K, et al. Br J Haematol. 2006;134:620-623. 7. Dimopoulos M, et al. Haematologica. 2006;91:968-971. 8. Cafro A, et al. ASH 2005. Abstract 5152. 9. Berenson J, et al. Clin Lymphoma Myeloma. 2009;9:311-315.

28. clinicaloptions.com/oncology Skeletal Integrity in Oncology Relative Risk Factors for ONJ  Cancer  Radiation therapy  Corticosteroids  Poor dental hygiene  Poor diet  Dental work  Trauma  Ethanol or tobacco use  Coagulopathy  Chemotherapy  Infection  Bisphosphonates

29. clinicaloptions.com/oncology Skeletal Integrity in Oncology Managing ONJ  Make a diagnosis –Get someone to evaluate who knows the entity  Assess its severity –It takes on a wide spectrum  Maintain excellent dental hygiene and regular exams  Keep surgical intervention to a minimum  There is no standard treatment –Antibacterial and antifungal rinses (chlorhexidine gluconate and nystatin) –Systemic oral antibacterial, antiviral, and antifungal treatment

30. clinicaloptions.com/oncology Skeletal Integrity in Oncology Preventive Dental Measures Reduce Incidence of ONJ > 50% PRE, preimplementation of preventive measures; POST, postimplementation of preventive measures. 0.014 0.029 0 0.01 0.02 0.03 0.04 PRE GroupPOST Group Incidence Rate (Cases/Yr) Ripamonti CI, et al. Ann Oncol. 2009;20:137-145.  A retrospective study in cancer patients receiving BPs

31. clinicaloptions.com/oncology Skeletal Integrity in Oncology The Central Role of the Osteoclast in Osteolytic Bone Destruction Growth factors Osteoclast differentiation Osteolysis Direct effects on osteoclast differentiation Tumor cells Bone loss Active osteoclast Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

32. clinicaloptions.com/oncology Skeletal Integrity in Oncology Factors Increasing Osteoclast Activity in Bone Metastasis RANKL OPG MIP-1 alpha 1,25(OH)2D3 PTHrP

33. clinicaloptions.com/oncology Skeletal Integrity in Oncology Normal RANKL/OPG Prevents Promotes Osteoclastic Activity RANKL OPG Hofbauer LC, et al. JAMA. 2004;292:490-495.

34. clinicaloptions.com/oncology Skeletal Integrity in Oncology The RANK/RANKL/OPG Pathway in Osteolytic Bone Disease Prevents Promotes Increased osteoclastic activity and decreased OPG OPGRANKL Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

35. clinicaloptions.com/oncology Skeletal Integrity in Oncology Denosumab: Inhibiting RANK in Bone Disease  High affinity human monoclonal antibody that binds RANKL  Administered via SC injection  Specific: does not bind to TNF-α, TNF-β, TRAIL, or CD40L  Inhibits formation and activation of osteoclasts

36. Mitigating Bone Complications in Multiple Myeloma

37. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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. Available at: http://seer.cancer.gov/csr/1973-1999/prevalence.pdf. 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.

38. clinicaloptions.com/oncology Skeletal Integrity in Oncology Prevalence of Osteolytic Bone Destruction in Multiple Myeloma  Frequency of skeletal abnormalities and bone pain detected by x-ray (N = 824) 71 68 63 60 Lytic Lesions Bone Pain at Diagnosis OsteopeniaPathologic Fractures Patients (%) 0 10 20 30 40 50 60 70 80 90 100

39. clinicaloptions.com/oncology Skeletal Integrity in Oncology Melton LJ 3rd, et al. J Bone Miner Res. 2005;20:487-493 Fracture Incidence Myeloma Patients  Retrospective cohort study of 168 patients with myeloma  ~ 20% present with pathologic fracture at diagnosis –1-yr rate of pathologic fracture is 40% –Even with disease control, rate of fracture continues to rise –~ 60% of patients will sustain a pathologic fracture during the course of their disease  Patients with fracture have 20% increased risk of death

40. clinicaloptions.com/oncology Skeletal Integrity in Oncology Bone Is Removed by Osteoclast Activity and Replaced by Osteoblast Activity Courtesy of Dr. G R Mundy, Vanderbilt University.

41. clinicaloptions.com/oncology Skeletal Integrity in Oncology Bone Remodeling Is Uncoupled in MM Hattner R, et al. Nature. 1965;206:489-490. NormalMyeloma

42. clinicaloptions.com/oncology Skeletal Integrity in Oncology Malignant Disease and the Skeleton Tumor Bone formation: blastic metastases Bone resorption: lytic metastases, hypercalcemia

43. clinicaloptions.com/oncology Skeletal Integrity in Oncology Bone Cell Stimulation in Malignancy Multiple Myeloma Osteolytic Solid Tumors Including Breast Cancer OsteoclastsOsteoblasts

44. clinicaloptions.com/oncology Skeletal Integrity in Oncology Bone Scans in Myeloma Can Underestimate Bone Involvement

45. clinicaloptions.com/oncology Skeletal Integrity in Oncology Current Treatment of MM Bone Disease  Surgical procedures –Vertebroplasty –Balloon kyphoplasty  Radiotherapy  Bisphosphonates  Novel agents  Treatment of myeloma

46. clinicaloptions.com/oncology Skeletal Integrity in Oncology Surgical Treatment of Vertebral Compression Fractures in Cancer Patients  Operative management –Vertebral column reconstruction –A or P decompression with internal fixation –Oncology patients are generally poor candidates for open surgery due to soft bone/tumor mass and comorbidities  Minimally invasive procedures –Vertebroplasty –Balloon kyphoplasty

47. clinicaloptions.com/oncology Skeletal Integrity in Oncology Tumor-Related VCFs: Vertebroplasty Fourney DR, et al. J Neurosurg. 2003;98(1 suppl):21-30. Reproduced with permission from the American Association of Neurological Surgeons. http://www.aans.org/http://www.aans.org/

48. clinicaloptions.com/oncology Skeletal Integrity in Oncology Tumor-Related VCFs: Balloon Kyphoplasty Introduction  Allows precise, minimally invasive access to the vertebral body  Provides working channel Balloon inflation  Reduces the fracture  Compacts the bone  May elevate endplates Removal  Leaves a defined cavity and trabecular dam that can be filled with an approved bone void filler of the physician’s choice

49. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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 Skeletal-Related Events in Myeloma Patients 24 41 38 921 Patients (%) 0 10 20 30 40 50 60 Mos 51 P <.001 P =.015

50. clinicaloptions.com/oncology Skeletal Integrity in Oncology Zoledronic Acid and Pamidronate in Multiple Myeloma  Patients with no SRE similar between pamidronate and zoledronic acid over the study period (13 wks)  Median time to first SRE ~ 1 yr for both pamidronate and zoledronic acid Rosen LS, et al. Cancer J. 2001;7:377-387. 44 46 0 20 40 60 Pamidronate 90 mg Zoledronic acid 4 mg All SREs Patients With SRE (%) 80 100

51. clinicaloptions.com/oncology Skeletal Integrity in Oncology Myeloma Bone Disease Myeloma cells Tumor-derived osteoclast activating factors  Macrophage inflammatory protein  IL-3 Tumor-derived osteoblast inhibitory factors  DKK1, IL-3, sFRP2, IL-7 Bone Osteoclast Osteoblasts (-) Stromal cells –RANKL –IL-6 Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664. (+)

52. clinicaloptions.com/oncology Skeletal Integrity in Oncology RANKL OPG Pearse RN, et al. Proc Natl Acad Sci U S A. 2001;98:11581-11586. Copyright 2001. National Academy of Sciences, U.S.A. RANK Ligand Is Increased and OPG Is Decreased in Myeloma

53. clinicaloptions.com/oncology Skeletal Integrity in Oncology Effect of Denosumab vs Pamidronate on Urinary NTX in Patients With Myeloma 9080706050403020100 0 20 40 60 Urine NTX (mmol BCE/mmol Creatinine) 50 30 Days Values are expressed as absolute medians Pamidronate 90 mg Denosumab 3.0 mg/kg Denosumab 0.3 mg/kg Denosumab 0.1 mg/kg Denosumab 1.0 mg/kg Reproduced and adapted with permission from the American Association for Cancer Research: Body JJ, et al. Clin Cancer Res. 2006;12:1221-1228.

54. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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 PP patients Vij R, et al. Am J Hematol. 2009;84:650-656.

55. clinicaloptions.com/oncology Skeletal Integrity in Oncology Denosumab vs Zoledronate  Phase III trial in 1776 patients with solid tumors (not breast or prostate) or myeloma –Primary endpoint: median time to first SRE  Delay in time to first SRE or subsequent SRE was not statistically different  Serious adverse events were similar  ONJ infrequent and similar (10 vs 11 patients) Henry D, et al. EJC Supplements. 2009;7(3):12. Abstract 20LBA.

56. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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.

57. clinicaloptions.com/oncology Skeletal Integrity in Oncology Anti-DKK1 Increases Bone Formation in the SCID-Rab MM Model This research was originally published in Blood. Yaccoby S, et al. Blood. 2007;109:2106-2111. © The American Society of Hematology. Control Anti-DKK1 P <.001 BMD (% Change) 10 5 0 -5 -10 -15 -20 Control Anti-DKK1 Pre-RxFinal Bone resorption Bone formation

58. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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

59. clinicaloptions.com/oncology Skeletal Integrity in Oncology Activin A Levels Are Elevated in Patients With MM and Osteolytic Disease Activin A levels are increased in bone marrow plasma of MM patients 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 † †

60. clinicaloptions.com/oncology Skeletal Integrity in Oncology Normal MiceMice + Tumor + RAP-011 Chantry A, et al. Cancer Treat Rev. 2008;34: Supplement 1 pg 3. Reprinted with permission. RAP-011 Prevents Development of Myeloma Bone Lesions

61. clinicaloptions.com/oncology Skeletal Integrity in Oncology Novel Therapeutic Targets for MM Bone Disease TargetPotential Therapy RANKLAnti-RANKL MIP-1aCCR1 antagonist DKK1/sFRP-2WNT agonist, anti-DKK1, bortezomib Activin AACE-011

62. clinicaloptions.com/oncology Skeletal Integrity in Oncology Agents Used to Treat Multiple Myeloma Also Affect Bone Thalidomide Lenalidomide Bortezomib

63. clinicaloptions.com/oncology Skeletal Integrity in Oncology Giuliani N, et al. Blood. 2007;110:334-338. Effect of Bortezomib on Bone Formation in MM Patients  Analysis of in vivo effect of bortezomib in a cohort of MM patients –Significant increase in the number of osteoblastic cells x mm 2 of bone tissue observed in MM patients responding to bortezomib treatment –No significant increase in nonresponders –Osteoblastic cells x mm 2 of bone tissue in responder MM patients after therapy decreased compared with healthy bone from the control group –Significant increase in the number of Runx-2/Cbfa1–positive osteoblastic cells in responder MM patients compared with nonresponders

64. Strategies to Prevent and Manage Bone Compromise in Breast Cancer

65. clinicaloptions.com/oncology Skeletal Integrity in Oncology Causes of Cancer Treatment–Induced Bone Loss Bone loss GnRH agonists Bilateral oophorectomyBilateral orchiectomy Chemotherapy-induced ovarian failure Elevated bone turnover Pfeilschifter J, et al. J Clin Oncol. 2000;18:1570-1593. Theriault RL. Oncology (Williston Park). 2004;18(5 suppl 3):11-15. Dempster DW. Osteoporos Int. 2003;14 suppl 5:S54-S56. Diminished bone quality Aromatase inhibitors Glucocorticoids Hypogonadism

66. clinicaloptions.com/oncology Skeletal Integrity in Oncology Bone Loss With Cancer Therapies 1. Kanis JA. The European Foundation for Osteoporosis and Bone Disease. Osteoporos Int. 1997;7:390- 406. 2. Eastell R, et al. J Bone Miner Res. 1990;5:1237-1241. 3. Maillefert JF, et al. J Urol. 1999;161:1219- 1222. 4. Gnant M, et al. Lancet Oncol. 2008;9:840-849. 5. Shapiro CL, et al. J Clin Oncol. 2001;19:3306- 3311. Bone Loss at 1 Yr (%) Naturally Occurring Bone Loss CTIBL 0 2 4 6 8 10 Normal Men [1] Postmenopausal Women [1] Menopausal Women [1] Al Therapy in Postmenopausal Women [2] ADT [3] Al Therapy + GnRH Agonist in Premenopausal Women [4] Premature Menopause Secondary to Chemotherapy [5] 0.5 1.0 2.0 2.6 4.6 7.0 7.7

67. clinicaloptions.com/oncology Skeletal Integrity in Oncology Tamoxifen Letrozole Anastrozole Placebo Fractures (%) 11.0 7.7 5.7 4.0 5.3 4.6 7.0 5.0 P <.0001 P <.001 0 2 4 6 8 10 12 14 P =.003 P =.25 Exemestane ATAC [1] (68 Mos) IES [2] (58 Mos) BIG 1-98 [3] (26 Mos) MA.17 [4] (30 Mos) Steroidal and Nonsteroidal AIs Increase Fracture Risk Compared With Tamoxifen 1. Howell A, et al. Lancet. 2005;365:60-62. 2. Coleman RE, et al. Lancet Oncol. 2007;8:119-127. 3. Thürlimann B, et al. N Engl J Med. 2005;353:2747-2757. 4. Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271.

68. clinicaloptions.com/oncology Skeletal Integrity in Oncology SABRE: Prevention of AI-Induced Bone Loss With Risedronate *P values from paired t-test for open-label, noncomparative groups. † P values from ANCOVA in favor of anastrozole plus risedronate. Anastrozole Alone Lower Risk (n = 26) Moderate Risk (n = 114) Anastrozole + Placebo Anastrozole + Risedronate Anastrozole + Risedronate Higher Risk (n = 33) Percent Change in BMD From Baseline to 24 Mos P =.0109*P =.5988* P =.0006* P =.0104* P <.0001 † -2.0 0 1.0 2.0 3.0 4.0 5.0 -3.0 Lumbar spine Total hip Van Poznak C, et al. J Clin Oncol. 2010;28:967-975.

69. clinicaloptions.com/oncology Skeletal Integrity in Oncology Ellis GK, et al. J Clin Oncol. 2008;26:4875-4882. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Prevention of AI-Induced Bone Loss With Denosumab Percent Change in BMD From Baseline at Lumbar Spine 8 7 6 5 4 3 2 1 0 -2 -3 1 3 61224 Mos 5.5% Difference at 12 Mos 7.4% Difference at 24 Mos *P <.0001 vs placebo Placebo (n = 122) Denosumab (n = 123) * * * * *

70. clinicaloptions.com/oncology Skeletal Integrity in Oncology ABCSG-12 Trial Design  Accrual 1999-2006  1803 premenopausal patients with breast cancer  Endocrine responsive (ER+ and/or PgR+)  Stage I and II, < 10 positive nodes  No chemotherapy except neoadjuvant  Treatment duration: 3 yrs Randomize Surgery (+ RT) Tamoxifen 20 mg/day Goserelin 3.6 mg q28d Anastrozole 1 mg/day + Zoledronic Acid 4 mg q6m Anastrozole 1 mg/day Tamoxifen 20 mg/day + Zoledronic Acid 4 mg q6m Gnant M, et al. N Engl J Med. 2009;360:679-691.

71. clinicaloptions.com/oncology Skeletal Integrity in Oncology Gnant M, et al. Lancet Oncol. 2008;9:840-849. Adjuvant Endocrine Therapy ± Zoledronic Acid: Changes in BMD 10 5 0 -5 -10 -15 Percent Change in Lumbar Spine BMD (g/cm 2 ) From Baseline Mo No Zoledronic Acid TamoxifenAnastrozole 3660 -9.0 P <.0001 -4.5 NS -13.6 P <.0001 -7.8 P =.003 3660 36603660 Zoledronic Acid TamoxifenAnastrozole +1.0 NS +5.2 P =.04 -0.1 NS +3.1 NS

72. clinicaloptions.com/oncology Skeletal Integrity in Oncology Letrozole Key endpoints Primary: BMD Secondary: Bone markers, fractures, time to recurrence/relapse Letrozole + Zoledronic Acid 4 mg q6mo 2193 patients with stage I-IIIa breast cancer  Postmenopausal or amenorrheic due to cancer treatment  ER + and/or PgR +  T-score ≥ -2 SD Delayed Zoledronic Acid If 1 of the following occurs:  BMD T-score < -2 SD  Clinical fracture  Asymptomatic fracture at 36 mos Treatment duration 5 yrs R Z-FAST/ZO-FAST/E-ZO-FAST

73. clinicaloptions.com/oncology Skeletal Integrity in Oncology 1.96% *P values correspond to intergroup comparisons. † Intragroup comparisons from baseline to all time points for all treatment groups were significant (P ≤.0003 for all). Lumbar Spine Mean (SEM) Percent Change in BMD Up-front ZOL 4 mg/6 mos Delayed ZOL 4 mg/6 mos Brufsky A, et al. SABCS 2009. Abstract 4083. Reprint permission granted. Z-FAST: Up-front ZOL Increases BMD in Lumbar Spine and Hip (N = 602) P <.0001, all time points* † 8 6 4 2 0 -2 -4 -6 Mos 1224364861 3.14% 3.85% 4.64% 6.19% -2.33% -2.89% -2.99% -3.05% -2.42% ∆ 4.29% ∆ 6.03% ∆ 6.84% ∆ 7.69% ∆ 8.61% 1.26% Total Hip P <.001, all time points* † 4 3 2 1 0 -4 -6 Mos 1224364861 1.41% 1.68% 1.70% 2.57% -1.88% -3.15% -3.46% -4.02% -4.12% ∆ 3.14% ∆ 4.56% ∆ 5.14% ∆ 5.72% ∆ 6.69% -2 -3 -5

74. clinicaloptions.com/oncology Skeletal Integrity in Oncology Fractures in E/Z/ZO-FAST (3 Trials)  Over 36 mos of therapy, patients receiving up-front ZOL experienced fewer fractures than patients whose treatment was delayed Fractures, % StudyMosUp-front ZOLDelayed ZOL Z-FAST [1] 365.76.3 ZO-FAST [2] 365.06.0 E-ZO-FAST [3] 120.81.9 1. Brufsky AM, et al. Clin Breast Cancer. 2009;9:77-85. 2. Eidtmann H, et al. Ann Oncol. 2010;[Epub ahead of print]. 3. Llombart A, et al. ECCO 2007. Abstract 2044.

75. clinicaloptions.com/oncology Skeletal Integrity in Oncology 100 90 80 70 60 50 40 30 20 10 0 012243648607284 Mos Since Randomization DFS (%) HR (95% CI) Events, nvs No ZOL P Value ZOL540.64 (0.46-0.91).01 No ZOL83 No ZOLZOL Gnant M, et al. N Engl J Med. 2009;360:679-691. Copyright © 2009 Massachusetts Medical Society. All rights reserved. ABCSG-12: ZOL Significantly Improves DFS by 36% Median Follow-up: 48 Mos Events (n) 10 9 6 29* 41* 20 10 Secondary malignancy Contralateral BC Distant Locoregional 83 54 *Includes 23 bone metastases in No ZOL group and 16 in ZOL group. 100 90 80 70 60 50 40 30 20 10 0

76. clinicaloptions.com/oncology Skeletal Integrity in Oncology Delayed ZOL (n = 532) Up-front ZOL (n = 532) 50 45 40 35 30 25 20 15 10 5 Patients (n) 3 5 20 30 10 2 Disease Recurrence (36 Mos) [2] * 1. Coleman R, et al. SABCS 2009. Abstract 4082. 2. Eidtmann H, et al. Ann Oncol. 2010;[Epub ahead of print]. ZO-FAST 48 Mos: Up-front ZOL Significantly Reduces the Risk of DFS Events by 41% Local Distant Lymph node 0 1.0 0.8 0.6 0.4 0.2 0 0 63642 48 546066 Study Mo Survival Distribution Function ZOL 4 mg up-front ZOL 4 mg delayed 12 182430 Up-front Delayed Patients, n 532 533 Events/censored 32/500 53/480 Median follow-up 48.0 48.1 HR (95% CI) 0.59 (0.38-0.92) Up-front vs delayed log rank P value.0175 DFS at Median Follow-up 48 Mos [1] *Multiple sites of metastases may be reported for the same patient. Sites of distant metastases include bone, brain, liver, lung, skin, lymph node, and other.

77. clinicaloptions.com/oncology Skeletal Integrity in Oncology 27.4 15.5 Adjusted MeanPath CR % 6.9 11.7 P =.0006* P =.146* Coleman RE, et al. Br J Cancer. 2010;102:1099-1105. AZURE: Neoadjuvant CT + Zoledronic Acid Reduces Residual Invasive Tumor Size Chemotherapy alone Chemotherapy + zoledronic acid Residual Invasive Tumor Size (mm) 60 50 40 30 20 10 0 *Multivariate analysis (N = 205).

78. clinicaloptions.com/oncology Skeletal Integrity in Oncology Scope of the Problem  400,000 new patients/yr in the United States develop bone metastases

79. clinicaloptions.com/oncology Skeletal Integrity in Oncology Hypercalcemia Bone metastasis Fracture Spinal cord compression Bone pain Disease Consequences Primary treatment Symptomatic treatment Optimal Management of Bone Metastases: Treat the Disease

80. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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 (%) ‡

81. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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 Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. Rosen LS, et al. Cancer. 2004;100:2613-2621. Saad F, et al. J Natl Cancer Inst. 2004;96:879-892. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 53.0 44.8 26.7 12.3 11 9 12 5.3 0204060 Prostate Myeloma Breast Lung Skeletal-related event Survival

82. clinicaloptions.com/oncology Skeletal Integrity in Oncology Study Design: International, Randomized, Double-Blind, Active-Controlled Study Key inclusion  Adults with advanced breast cancer and confirmed bone metastases Key exclusion  Current or previous IV bisphosphonate administration 1° Endpoint 2° Endpoints  Time to first on-study SRE (noninferiority)  Time to first on-study SRE (superiority)  Time to first and subsequent on-study SRE (superiority) Zoledronic acid 4 mg IV* and Placebo SC q4w (n = 1020) Denosumab 120 mg SC and Placebo IV* q4w (n = 1026) Supplemental Calcium and Vitamin D *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per zoledronic acid label). Stopeck A, et al. SABCS 2009. Abstract 22.

83. clinicaloptions.com/oncology Skeletal Integrity in Oncology Baseline Characteristics Characteristics Zoledronic Acid (N = 1020) Denosumab (N = 1026) Women, n (%)1011 (99)1018 (99) Median age, yrs5657 ECOG PS 0 or 1, n (%)932 (91)955 (93) Hormone receptor positive, n (%)726 (71)740 (72) Median time from first bone metastasis to randomization, mos 22 Previous SRE, n (%)373 (37)378 (37) Presence of visceral metastases, n (%)525 (51)552 (54) Stopeck A, et al. SABCS 2009. Abstract 22. Reprint permission granted.

84. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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 26.5 HR: 0.82 (95% CI: 0.71-0.95; P <.0001 noninferiority; P =.01 superiority)* Mos 1.00 Proportion of Subjects Without SRE 036912151821242730 0.25 0.50 0.75 Stopeck A, et al. SABCS 2009. Abstract 22. Reprint permission granted. 0

85. clinicaloptions.com/oncology Skeletal Integrity in Oncology Time to First and Subsequent SRE*: Multiple Event Analysis *Events that occurred at least 21 days apart. † Adjusted for multiplicity. Total Number of Events Denosumab Zoledronic acid 474 608 Rate ratio: 0.77 (95% CI: 0.66-0.89) P =.001 † Mos 1.5 Cumulative Mean Number of SREs 036912151821242730 0.5 1.0 Stopeck A, et al. SABCS 2009. Abstract 22. Reprint permission granted. 0

86. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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 0 1.00 0369121518212427 0.25 0.50 0.75 Stopeck A, et al. SABCS 2009. Abstract 22. Reprint permission granted. Zoledronic acid1020463318250209172126935617 Denosumab10265113783122562141591095927 Patients at Risk, n Mos

87. clinicaloptions.com/oncology Skeletal Integrity in Oncology Proportion of Subjects Without Disease Progression 036912151821242730 Disease Progression HR: 1.00 (95% CI: 0.89-1.11; P =.93) Stopeck A, et al. SABCS 2009. Abstract 22. Reprint permission granted. 0 1.00 0.25 0.50 0.75 Mos Zoledronic acid10208426865634623702401486517 Denosumab10268586935674533512411286520 Patients at Risk, n Denosumab Zoledronic acid

88. clinicaloptions.com/oncology Skeletal Integrity in Oncology Overall Survival Zoledronic acid102096289783475769951535218454 Denosumab102698491684977169051133617757 HR: 0.95 (95% CI: 0.81-1.11; P =.49) Mos 1.00 Proportion of Subjects Survived 036912151821242730 0.25 0.50 0.75 Patients at Risk, n Denosumab Zoledronic acid Stopeck A, et al. SABCS 2009. Abstract 22. Reprint permission granted. 0

89. clinicaloptions.com/oncology Skeletal Integrity in Oncology Adverse Events Adverse Event, % Zoledronic Acid (n = 1013) Denosumab (n = 1020) Overall97.096.0 Serious46.044.0 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 A, et al. SABCS 2009. Abstract 22. Reprint permission granted.

90. clinicaloptions.com/oncology Skeletal Integrity in Oncology Incremental Benefits in Breast Cancer 64% risk of skeletal complication with no bisphosphonate at 2 yrs Approx 33% risk reduction with pamidronate 64% 43% 34% Further 20% risk reduction with zoledronic acid 27% Additional 18% risk reduction with denosumab Lipton A, et al. Cancer. 2000;88:3033-3037. Rosen LS, et al. Cancer. 2004;100:36-43. Stopeck A, et al. ECCO/ESMO 2009. Abstract 2LBA.

91. Strategies for Bone-Directed Therapy in Prostate Cancer

92. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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

93. clinicaloptions.com/oncology Skeletal Integrity in Oncology Clinical Complications of Osteoblastic Metastases  Pain  Fractures  Spinal cord compression  Myelophthisis

94. clinicaloptions.com/oncology Skeletal Integrity in Oncology Reprinted with permission from the American Association of 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

95. clinicaloptions.com/oncology Skeletal Integrity in Oncology Brown JE, et al. J Natl Cancer Inst. 2005;97:59-69. http://jnci.oxfordjournals.org Copyright © 2005 Oxford University Press. Mos High NTx Low NTx Elevated NTx Is Associated With Greater Risk for SRE and Death Proportion With at Least 1 SRE (%) 0 20 40 60 80 100 03691215182124 Mos Proportion Died (%) 0 20 40 60 80 100 03691215182124

96. clinicaloptions.com/oncology Skeletal Integrity in Oncology Zoledronic Acid Study 039  Primary endpoint: incidence of skeletal-related events Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. Placebo q3w Zoledronic Acid q3w Randomize Castrate-resistant prostate cancer patients with bone metastases (N = 643)

97. clinicaloptions.com/oncology Skeletal Integrity in Oncology Mos 0 1 3 6 9 12 15 -80 -60 -40 -20 0 20 Change From Baseline (%) Zoledronic Acid Inhibits Urinary NTx Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. http://jnci.oxfordjournals.org Copyright © 2002 Oxford University Press. Zoledronic acid Placebo

98. clinicaloptions.com/oncology Skeletal Integrity in Oncology ZOL Reduced the Cumulative Incidence of Skeletal-Related Events  Skeletal-related events –Radiation to bone –Pathologic fracture –Spinal cord compression –Surgery to bone –Change in antineoplastic therapy Saad F, et al. J Natl Cancer Inst 2004;96:879–882. Saylor PJ, et al. Prostate Cancer Prostatic Dis. 2010;13:20-27.  Patients in ZOL (4 mg) arm had significantly fewer SREs vs placebo (33.2 vs 44.2%; P =.02)  Median time to first SRE extended from 321 to 488 days (P =.009).

99. clinicaloptions.com/oncology Skeletal Integrity in Oncology Denosumab to Prevent Skeletal-Related Events  Primary endpoint skeletal-related events: fracture, radiation or surgery to bone, spinal cord compression ClinicalTrials.gov. NCT00321620. 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)

100. clinicaloptions.com/oncology Skeletal Integrity in Oncology Baseline Characteristics Characteristic Zoledronic Acid (N = 951) Denosumab (N = 950) Age, median yrs71.0 ECOG performance score of 0 or 1, n (%)886 (93)882 (93) Stratification factors  Proportion of subjects with PSA ≥ 10 ng/mL, n (%) 806 (85)805 (85)  Chemotherapy (≤ 6 wks before randomization), n (%) 132 (14)  Previous SRE, n (%)231 (24)232 (24) Time from first bone metastasis to randomization, median mos (Q1, Q3) 5.2 (1.3, 16.1)3.9 (1.2, 15.7) Fizazi K, et al. ASCO 2010. Abstract LBA4507. Reprinted with permission.

101. clinicaloptions.com/oncology Skeletal Integrity in Oncology Drug Exposure and Adjustments for Renal Function Fizazi K, et al. ASCO 2010. Abstract LBA4507. Reprinted with permission. Overall ExposureZoledronic Acid (n = 946) Denosumab (n = 942) Median number of doses (Q1, Q3)10.5 (5.0, 17.0)13.0 (6.0, 19.0) Cumulative exposure, patient-yrs913.6991.3 Adjustments for Renal Function Subjects with dose adjustments for creatinine clearance at baseline, n (%) 213 (22.5)Not applicable* Subjects with doses withheld for serum creatinine increases on study, n (%) 143 (15.1)Not applicable* Total number of does withheld due to serum creatinine increases on study 592Not applicable* *Per protocol.

102. clinicaloptions.com/oncology Skeletal Integrity in Oncology Denosumab vs Zoledronic Acid: Time to First On-Study SRE Fizazi K, et al. ASCO 2010. Abstract LBA4507. Reprinted with permission. 1.00 0.75 0.50 0.25 0 0369121518212427 Proportion of Subjects Without SRE Study Mo Denosumab Zoledronic acid HR: 0.82 (95% CI: 0.71-0.95; P =.0002 noninferiority; P =.008 superiority) KM Estimate of Median, Mos 20.7 17.1 Patients at Risk, n Zoledronic acid Denosumab 951 950 733 758 544 582 407 472 299 361 207 259 140 168 93 115 64 70 47 39

103. clinicaloptions.com/oncology Skeletal Integrity in Oncology Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) *Events occurring at least 21 days apart. Rate ratio: 0.82 (95% CI: 0.71-0.94; P =.008) Study Mo 0.0 2.0 0369121518212427 Cumulative Mean Number of SREs per Patient 303336 0.2 0.6 1.0 1.4 1.8 0.4 0.8 1.2 1.6 Denosumab Zoledronic acid584 494 Events Fizazi K, et al. ASCO 2010. Abstract LBA4507. Reprinted with permission.

104. clinicaloptions.com/oncology Skeletal Integrity in Oncology Overall Disease Progression 0 Proportion of Subjects Without Disease Progression 0369121518212427 Study Mo 1.00 0.25 0.50 0.75 Denosumab Zoledronic acid HR: 1.06 (95% CI: 0.95-1.18) Zoledronic acid951708507356246168108745033 Denosumab950715518370273180111715132 Patients at Risk, n Fizazi K, et al. ASCO 2010. Abstract LBA4507. Reprinted with permission.

105. clinicaloptions.com/oncology Skeletal Integrity in Oncology Overall Survival Zoledronic acid9518647456355194012972071439855 Denosumab9508727466455524273102331569954 Proportion of Subjects Survived 036912151821242730 Patients at Risk, n HR: 1.03 (95% CI: 0.91-1.17) 0 1.00 0.25 0.50 0.75 Study Month Denosumab Zoledronic acid Fizazi K, et al. ASCO 2010. Abstract LBA4507. Reprinted with permission.

106. clinicaloptions.com/oncology Skeletal Integrity in Oncology Denosumab vs Zoledronic Acid: Safety Fizazi K, et al. ASCO 2010. Abstract LBA4507. Reprinted with permission. Adverse Event, %Zoledronic Acid (n = 945) Denosumab (n = 943) Serious adverse events6063 Adverse events causing treatment discontinuation1517 Anemia36 Back pain3032 Decreased appetite2928 Nausea2629 Fatigue2427 Acute-phase reactions (first 3 days)17.88.4 Renal adverse events16.214.7 ONJ1.32.3 Hypocalcemia5.812.8 New primary malignancy1.11.9

107. clinicaloptions.com/oncology Skeletal Integrity in Oncology Conclusions  Disease-related skeletal complications are common in men with metastatic prostate cancer  Zoledronic acid decreases risk of skeletal-related events in men with castrate-resistant disease and bone metastases  Denosumab is superior to zoledronic acid for delay in first skeletal-related events and rate of skeletal-related events in this setting

108. clinicaloptions.com/oncology Skeletal Integrity in Oncology Spectrum of Bone Disease in Prostate Cancer Metastasis Prevention Castrate sensitive, nonmetastatic Castrate resistant, nonmetastatic Castrate resistant, metastatic

109. clinicaloptions.com/oncology Skeletal Integrity in Oncology Natural History of Castrate-Resistant Nonmetastatic Prostate Cancer Smith MR, et al. J Clin Oncol. 2005;23:2918-2925.  Patients (n = 201) in the analysis from the placebo control group of aborted clinical trial that investigated the effects of zoledronic acid on time to first bone metastasis in castrate-resistant nonmetastatic prostate cancer  Patients with bone metastases at 2 yrs: 33%  Median bone metastasis-free survival: 30 mos  Baseline PSA (> 10 ng/mL) and PSA doubling time independently predicted shorter time to first bone metastasis, metastasis-free survival, and OS

110. clinicaloptions.com/oncology Skeletal Integrity in Oncology Denosumab to Prevent Metastases  Primary endpoint: bone metastasis–free survival ClinicalTrials.gov. NCT00286091. RANDOMIZERANDOMIZE Denosumab 60 mg monthly Patients with castrate- resistant prostate cancer and no bone metastases; PSA > 8 or PSADT < 10 mos (Planned N = 1435) Placebo monthly Accrual complete: Q2 2008 Final analyses: 2010

111. clinicaloptions.com/oncology Skeletal Integrity in Oncology ZEUS: Zoledronic Acid to Prevent Metastases  Primary endpoint: first bone metastasis Wirth M, et al. ASCO GU 2008. Abstract 184. RANDOMIZERANDOMIZE 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

112. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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 castrate- resistant nonmetastatic disease  An ongoing randomized clinical trial in high-risk subjects will evaluate whether denosumab prevents metastases

113. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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

114. clinicaloptions.com/oncology Skeletal Integrity in Oncology Incidence/1,000,000 Person-Yrs Age (Yrs) 4000 3000 2000 1000 35-39≥ 85 Hip Spine MenWomen Melton LJ 3rd, et al. J Bone Miner Res. 1992;7:1005-1010. Fracture Risk by Sex and Age 35-39

115. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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

116. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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

117. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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.

118. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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

119. clinicaloptions.com/oncology Skeletal Integrity in Oncology EndpointSubjectsSample Size BMDAll50-100 Vertebral fracturesHigh risk>1000 Hip fracturesHigh risk> 5000 Clinical Trial Design for Osteoporosis

120. clinicaloptions.com/oncology Skeletal Integrity in Oncology Denosumab Fracture Prevention Study  Primary endpoints: bone mineral density, new vertebral fractures ClinicalTrials.gov. NCT00089674. Current androgen deprivation therapy for prostate cancer patients older than 70 yrs of age or with T score < -1.0 (N = 1468) Denosumab q6m for 3 yrs Placebo q6m for 3 yrs

121. clinicaloptions.com/oncology Skeletal Integrity in Oncology Denosumab to Increase BMD in Prostate Cancer Patients 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

122. clinicaloptions.com/oncology Skeletal Integrity in Oncology 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.

123. clinicaloptions.com/oncology Skeletal Integrity in Oncology Summary: Prevention of Treatment- Related Fractures  Androgen deprivation therapy increases fracture risk  Bisphosphonates increase bone mineral density during androgen deprivation therapy –Not shown to prevent treatment-related fractures in men with prostate cancer  Denosumab increases bone mineral density and decreases fractures during androgen deprivation therapy

124. Go Online for More Educational Activities on Managing Skeletal Integrity in Cancer Patients! Text-based modules reviewing the latest clinical trial data as well as important clinical considerations for managing bone complications in patients with breast cancer, multiple myeloma, and prostate cancer clinicaloptions.com/oncology