Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Castration-Resistant Prostate Cancer Karim Fizazi,1 Michael Carducci,2 Matthew Smith,3 Ronaldo Damião,4 Janet Brown,5 Lawrence Karsh,6 Piotr Milecki,7 Michael Rader,8 Neal Shore,9 Sylvia Tadros,10 Huei Wang,10 Qi Jiang,10 Roger Dansey,10 Carsten Goessl10 1Institut Gustave Roussy, University of Paris, Villejuif, France 2Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA 3Massachusetts General Hospital Cancer Center, Boston, MA, USA 4Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil 5Cancer Research UK Clinical Centre, Leeds, UK 6The Urology Center of Colorado, Denver, CO, USA 7Wielkopolskie Centrum Onkologii, Poznan, Poland 8Union State Bank Cancer Center, Nyack Hospital, Nyack, NY, USA 9Carolina Urological Research Center, Myrtle Beach, SC, USA 10Amgen Inc., Thousand Oaks, CA, USA

Disclosures This study was supported by Amgen Inc. K Fizazi has been a consultant for and received honoraria from Amgen and Novartis. M Carducci has been a consultant for and received research funding from Amgen. M Smith has been a consultant for Amgen and Novartis and received honoraria and research funding from Amgen. R Damião and Piotr Milecki have received research funding from Amgen. J Brown has been a consultant for Amgen and received honoraria from Amgen and Novartis. L Karsh has been a consultant for Amgen and received honoraria and received research funding from Amgen. M Rader has been a consultant for and received honoraria and research funding from Amgen. N Shore has been a consultant for and received honoraria from Amgen. H Wang, S Tadros, R Dansey, Q Jiang, and C Goessl are employed by and have received stocks/stock options from Amgen.

Spinal Cord Compression Background Up to 75% of advanced prostate cancer patients develop bone metastasis1 Bone metastases lead to osteoclast-mediated bone destruction Clinical consequences include skeletal-related events (SREs)2 IV zoledronic acid (ZA) is the only bisphosphonate approved to delay or prevent SREs in castration-resistant prostate cancer3 Radiation to Bone Pathologic Fracture Spinal Cord Compression Surgery to Bone 1Coleman R. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006; 12(20 Suppl):6243s-6249s. 2Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27:165-76. 3Saad F, Gleason DM, Murray R. J Natl Cancer Inst. 2002;94:1458-1468.

PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT RANKL Is a Central Mediator of the “Vicious Cycle” of Bone Destruction in Metastatic Cancer RANKL RANK Tumor Cell PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT PDGF, BMPs TGF-β, IGFs FGFs Activated Osteoclast Osteoblasts Adapted from Roodman D. N Engl J Med. 2004;350:1655.

PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT Denosumab May Interrupt the “Vicious Cycle” of Cancer-Induced Bone Destruction RANKL RANK Denosumab Tumor Cell Formation Inhibited PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT PDGF, BMPs TGF-β, IGFs FGFs Apoptotic Osteoclast Osteoblasts Adapted from Roodman D. N Engl J Med. 2004;350:1655.

RANKL and OPG Expression in Osteoblasts When Co-cultured With Prostate Cancer Cells CTR OSB + 2b OSB + 2a OSB + LNCaP OSB + PC3 CTR OPG RANKL Fizazi et al. Clin Cancer Res 2003;9:2587–2597

Denosumab: Properties and Clinical Program Properties of Denosumab Fully human monoclonal antibody with high affinity and specificity for human RANKL Advanced cancer dose: subcutaneous 120 mg monthly In clinical trials No requirement for renal monitoring or dose adjustment1 No acute phase reactions attributed to denosumab1,2 Pivotal Studies in Patients With Bone Metastases Denosumab superior to ZA for preventing/delaying SREs in breast cancer (N=2046; HR=0.82; P<0.0001, non-inferiority endpoint; adjusted P=0.01, superiority endpoint)3 Denosumab non-inferior (trend to superior) to ZA for preventing/delaying SREs in solid tumors and multiple myeloma (N=1776; HR= 0.84; P=0.0007, non-inferiority endpoint; adjusted P=0.06, superiority endpoint)4 To date, approximately 11,000 patients have been exposed to denosumab in clinical trials of patients with cancer or bone loss 1Fizazi K et al. J Clin Oncol. 2009;27:1564-1571 2Ellis et al. J Clin Oncol. 2008;26:4875-4882 3Stopeck A et al. Eur J Cancer Suppl. 2009;7:2(Abs 2LBA) 4Henry D, et al. Eur J Cancer Suppl. 2009;7:11(Abs 20LBA)

Study Design: International, Randomized, Double-Blind, Active-Controlled Study Key Inclusion Hormone-refractory (castration resistant) prostate cancer and bone metastases Key Exclusion Current or prior IV bisphosphonate treatment Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 950) Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 951) Calcium and Vitamin D supplemented in both treatment groups Accrual period from May 2006 to December 2008 Analysis cut-off date October 2009 *Per protocol and Zometa® label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine. 8

Sequential Testing of Primary and Secondary Endpoints Primary Efficacy Endpoint (Non-inferiority) Time to first on-study SRE Only if P<0.05 Secondary Efficacy Endpoints (Superiority) Time to first on-study SRE Time to first-and-subsequent on-study SRE (multiple events) Hochberg adjustment for multiplicity between the two secondary endpoints Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1998;75:800-802.

Baseline Characteristics Characteristic, n (%) or median Zoledronic Acid (N = 951) Denosumab (N = 950) Age (years) 71.0 ECOG performance status of 0 or 1 886 (93) 882 (93) Stratification factors: Proportion of subjects with PSA ≥ 10 ng/mL 806 (85) 805 (85) Chemotherapy (≤ 6 weeks before randomization) 132 (14) Previous SRE 231 (24) 232 (24) Time from first bone metastasis to randomization (months): median (Q1, Q3) 5.2 (1.3, 16.1) 3.9 (1.2, 15.7)

IV Zoledronic Acid (N = 946) Drug Exposure and Adjustments for Renal Function Overall Exposure IV Zoledronic Acid (N = 946) SC Denosumab (N = 942) Median number of doses (Q1, Q3) 10.5 (5.0, 17.0) 13.0 (6.0, 19.0) Cumulative exposure (patient-years) 913.6 991.3 Adjustments for Renal Function Subjects with dose adjustments for creatinine clearance at baseline, n (%) 213 (22.5) NA Subjects with doses withheld for serum creatinine increases on study, n (%) 143 (15.1) Total number of doses withheld due to serum creatinine increases on study 592 NA = Not applicable per protocol

Patient Disposition Randomized Subjects: 1901* Zoledronic Acid Subjects: 951 Denosumab Subjects: 950 Discontinued: 743 (78.1%) Discontinued: 722 (76.0%) Reasons for Discontinuation Death 269 (28.3%) Consent Withdrawn 164 (17.2%) Disease Progression 113 (11.9%) Adverse Event 43 (4.5%) Other 154 (16.2%) Reasons for Discontinuation Death 294 (30.9%) Consent Withdrawn 147 (15.5%) Disease Progression 117 (12.3%) Adverse Event 56 (5.9%) Other 108 (11.4%) *Does not include three subjects with insufficient IRB oversight

Time to First On-Study SRE HR 0.82 (95% CI: 0.71, 0.95) P = 0.0002 (Non-inferiority) P = 0.008 (Superiority) Risk Reduction 18% 1.00 0.75 Proportion of Subjects Without SRE 0.50 KM Estimate of Median Months 0.25 Denosumab 20.7 Zoledronic acid 17.1 3 6 9 12 15 18 21 24 27 Study Month Subjects at risk: Zoledronic Acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39

Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) 2.0 Rate Ratio = 0.82 (95% CI: 0.71, 0.94) Risk Reduction 18% 1.8 P = 0.008 1.6 1.4 1.2 Cumulative Mean Number of SREs per Patient 1.0 0.8 0.6 Events 0.4 Denosumab 494 0.2 Zoledronic acid 584 0.0 3 6 9 12 15 18 21 24 27 30 33 36 Study Month *Events occurring at least 21 days apart

Percent of Subjects With First SRE Spinal Cord Compression First On-study SRE by Type 30 All subjects 25 20.0 20 14.7 15 Percent of Subjects With First SRE 10 3.3 5 0.3 Radiation to Bone Spinal Cord Compression Surgery to Bone Fracture

Prostate-Specific Antigen (PSA) 600 Zoledronic acid (N = 951) Denosumab (N = 950) 500 400 Median (Q1, Q3) PSA (ng/mL) 300 200 100 3 6 9 12 15 18 21 24 27 30 33 Study Month

Without Disease Progression Proportion of Subjects Overall Disease Progression HR = 1.06 (95% CI: 0.95, 1.18) 1.00 P = 0.30 0.75 Without Disease Progression Proportion of Subjects 0.50 0.25 Denosumab Zoledronic acid 3 6 9 12 15 18 21 24 27 Study Month Subjects at risk: Zoledronic Acid 951 708 507 356 246 168 108 74 50 33 Denosumab 950 715 518 370 273 180 111 71 51 32

Proportion of Subjects Survived Overall Survival HR = 1.03 (95% CI: 0.91, 1.17) 1.00 P = 0.65 0.75 Proportion of Subjects Survived 0.50 0.25 Denosumab Zoledronic acid 3 6 9 12 15 18 21 24 27 30 Study Month Subjects at risk: Zoledronic Acid 951 864 745 635 519 401 297 207 143 98 55 Denosumab 950 872 746 645 552 427 310 233 156 99 54

Summary of Adverse Events Subject incidence, n (%) Zoledronic Acid (N = 945) n (%) Denosumab (N = 943) n (%) Adverse events (AEs) 918 (97) 916 (97) Most common AEs in either arm Anemia 341 (36) 337 (36) Back Pain 287 (30) 304 (32) Decreased appetite 274 (29) 267 (28) Nausea 245 (26) 272 (29) Fatigue 222 (24) 257 (27) CTC Grade 3, 4, or 5 AEs 672 (71) 718 (76) Serious AEs 568 (60) 594 (63) AEs leading to treatment discontinuation 138 (15) 164 (17)

Forest Plot of Adverse Events With Unadjusted P < 0.05 Zoledronic Acid Denosumab (N = 945) (N = 943) n (%) n (%) Pyrexia 133 (14.1) 100 (10.6) Influenza like illness 33 (3.5) 11 (1.2) Myalgia 57 (6.0) 37 (3.9) Chills 28 (3.0) 11 (1.2) Cholelithiasis 10 (1.1) (0.0) Cognitive disorder 11 (1.2) 1 (0.1) Blood glucose increased 15 (1.6) 5 (0.5) Drug hypersensitivity 1 (0.1) 7 (0.7) Ilium fracture 1 (0.1) 7 (0.7) Hypercalcemia 2 (0.2) 9 (1.0) Blood alkaline phosphatase 1 (0.1) 9 (1.0) Oral herpes 1 (0.1) 10 (1.1) Tooth abscess 2 (0.2) 11 (1.2) Cerebrovascular accident 5 (0.5) 15 (1.6) Sinusitis 5 (0.5) 16 (1.7) Osteonecrosis 10 (1.1) 21 (2.2) Toothache 12 (1.3) 26 (2.8) Hypophosphatemia 13 (1.4) 28 (3.0) Influenza 24 (2.5) 40 (4.2) Prostatic specific antigen increased 19 (2.0) 36 (3.8) Thoracic vertebral fracture 30 (3.2) 47 (5.0) Hyperhidrosis 11 (1.2) 31 (3.3) Muscle spasms 27 (2.9) 51 (5.4) Hypocalcemia 51 (5.4) 116 (12.3) -15 -10 -5 5 10 15 Risk Difference (% in Denosumab - % in Zoledronic Acid) Risk greater with Zoledronic Acid Risk greater with Denosumab

Adverse Events of Interest Subject incidence, n (%) Zoledronic Acid (N = 945) Denosumab (N = 943) Infectious AEs 375 (39.7) 402 (42.6) Infectious serious AEs 108 (11.4) 130 (13.8) Acute phase reactions (first 3 days) 168 (17.8) 79 (8.4) Renal AEs* 153 (16.2) 139 (14.7) Cumulative rate of osteonecrosis of the jaw (ONJ)† 12 (1.3) 22 (2.3) Year 1 5 (0.5) 10 (1.1) Year 2 8 (0.8) Hypocalcemia 55 (5.8) 121 (12.8) New primary malignancy 18 (1.9) *Includes renal failure, increased blood creatinine, acute renal failure, renal impairment, increased blood urea, chronic renal failure, oliguria, hypercreatininemia, anuria, azotemia, decreased creatinine renal clearance, decreased urine output, abnormal blood creatinine, proteinuria, decreased glomerular filtration rate, and nephritis. †P = 0.09

ONJ Subjects with positively adjudicated ONJ, n (%) Zoledronic Acid N = 12 (1.3%) Denosumab N = 22 (2.3%) Risk factors Tooth extraction, dental appliance, or poor oral hygiene 10 (83) 17 (77) Chemotherapy 9 (75) 14 (64) Treatment* Limited surgery (eg, debridement) 3 (25) 10 (45) Bone resection 1 (8) 2 (9) Outcome* Resolution (mucosal coverage) 4 (18) *As of April 2010

Summary Denosumab was superior to zoledronic acid in preventing/delaying: First SREs Multiple SREs Notable adverse events occurring in both treatment groups included hypocalcemia and ONJ Denosumab continues to be studied as a potential treatment option for bone metastases Administered as a monthly SC injection No need for renal monitoring or dose adjustment No need to manage acute phase reactions

Acknowledgements We thank all patients, their families, investigators, and study site staff who participated in the 20050103 study for their contributions.