1. 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, 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

2. 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.

3. 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: Saad F, Gleason DM, Murray R. J Natl Cancer Inst. 2002;94:

4. 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.

5. 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.

6. 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

7. 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: Ellis et al. J Clin Oncol. 2008;26: Stopeck 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)

8. 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

9. 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:

10. 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)

11. 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

12. 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 (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 (5.9%)
Other 108 (11.4%)
*Does not include three subjects with insufficient IRB oversight

13. Time to First On-Study SRE
HR 0.82 (95% CI: 0.71, 0.95) P = (Non-inferiority)
P = (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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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)

20. 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

21. 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

22. 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

23. 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

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