Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastasesin 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, France2Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

3Massachusetts General Hospital Cancer Center, Boston, MA, USA4Hospital Universitario Pedro Ernesto, Rio de Janeiro, Brazil

5Cancer Research UK Clinical Centre, Leeds, UK6The Urology Center of Colorado, Denver, CO, USA7Wielkopolskie Centrum Onkologii, Poznan, Poland

8Union State Bank Cancer Center, Nyack Hospital, Nyack, NY, USA9Carolina 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.

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

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.

Pathologic Fracture

Radiation to Bone

Surgery to Bone

Spinal Cord Compression

RANKL Is a Central Mediator of the “Vicious Cycle” of Bone Destruction in Metastatic Cancer

PTHrP, BMP,TGF-β, IGF, FGF,VEGF, ET1, WNT

Osteoblasts

Activated Osteoclast

PDGF, BMPsTGF-β, IGFs

FGFs

Adapted from Roodman D. N Engl J Med. 2004;350:1655.

RANKL

RANKTumor

Cell

Denosumab May Interrupt the “Vicious Cycle” of Cancer-Induced Bone Destruction

PDGF, BMPsTGF-β, IGFs

FGFs

Osteoblasts

RANKL

RANK

DenosumabTumor Cell

FormationInhibited

Apoptotic Osteoclast

PTHrP, BMP,TGF-β, IGF, FGF,VEGF, ET1, WNT

Adapted from Roodman D. N Engl J Med. 2004;350:1655.

RANKL and OPG Expression in Osteoblasts When Co-cultured With Prostate Cancer Cells

OPG

RANKL

CTR CTROSB+ 2b

OSB+ 2a

OSB + LNCaP

OSB+ PC3

Fizazi et al. Clin Cancer Res 2003;9:2587–2597

Denosumab: Properties and Clinical Program

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;26:4875-48823Stopeck 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)

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

Study Design: International, Randomized, Double-Blind, Active-Controlled Study

Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 951)

Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 950)

Key Inclusion• Hormone-refractory (castration resistant) prostate cancer and bone metastases

Key Exclusion• Current or prior IV bisphosphonate treatment

*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.

• Calcium and Vitamin D supplemented in both treatment groups• Accrual period from May 2006 to December 2008• Analysis cut-off date October 2009

Sequential Testing of Primary and Secondary Endpoints

Primary Efficacy Endpoint (Non-inferiority)

Time to first on-study SRE

Only if P<0.05

Hochberg adjustment for multiplicity between the two secondary endpointsHochberg adjustment for multiplicity between the two secondary endpoints

Secondary Efficacy Endpoints (Superiority)

Time to first on-study SRE Time to first-and-subsequent on-study SRE (multiple events)

Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1998;75:800-802.

Baseline Characteristics

Characteristic, n (%) or medianZoledronic Acid

(N = 951)Denosumab

(N = 950)

Age (years) 71.0 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) 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)

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 FunctionSubjects 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) NA

Total number of doses withheld due to serum creatinine increases on study

592 NA

NA = Not applicable per protocol

Patient Disposition

Denosumab Subjects: 950Zoledronic Acid Subjects: 951

Randomized Subjects: 1901*

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

Discontinued: 743 (78.1%) Discontinued: 722 (76.0%)

Time to First On-Study SRE

Zoledronic Acid 951 733 544 407 299 207 140 93 64 47

Denosumab 950 758 582 472 361 259 168 115 70 39

Subjects at risk:

0

1.00

Pro

po

rtio

n o

f S

ub

ject

s W

ith

ou

t S

RE

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

KM Estimate ofMedian Months

DenosumabZoledronic acid

20.717.1

HR 0.82 (95% CI: 0.71, 0.95)P = 0.0002 (Non-inferiority)P = 0.008 (Superiority)

Study Month

18%18%Risk

Reduction

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)

Study Month

0.0

2.0

0 3 6 9 12 15 18 21 24 27

Cu

mu

lati

ve

Mea

n N

um

ber

of

SR

Es

per

Pat

ien

t

30 33 36

0.2

0.6

1.0

1.4

1.8

0.4

0.8

1.2

1.6

18%18%Risk

Reduction

Denosumab Zoledronic acid 584584

494494

Events

P = 0.008

Per

cen

t o

f S

ub

ject

s W

ith

Fir

st S

RE

Radiationto Bone

FractureSurgeryto Bone

Spinal CordCompression

20.0

14.7

3.3

0.3

First On-study SRE by Type

All subjects

0

5

10

15

20

25

30

Prostate-Specific Antigen (PSA)M

edia

n (

Q1,

Q3)

PS

A (

ng

/mL

)

Study Month

0

100

200

300

400

500

600

0 3 6 9 12 15 18 21 24 27 30 33

Zoledronic acid (N = 951)

Denosumab (N = 950)

Overall Disease Progression

Zoledronic Acid 951 708 507 356 246 168 108 74 50 33

Denosumab 950 715 518 370 273 180 111 71 51 32

0

Pro

po

rtio

n o

f S

ub

ject

sW

ith

ou

t D

isea

se P

rog

ress

ion

0 3 6 9 12 15 18 21 24 27

Study MonthSubjects at risk:

1.00

0.25

0.50

0.75

DenosumabZoledronic acid

HR = 1.06 (95% CI: 0.95, 1.18)P = 0.30

Overall Survival

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

0

Pro

po

rtio

n o

f S

ub

ject

s S

urv

ived

0 3 6 9 12 15 18 21 24 27 30

Subjects at risk:

1.00

0.25

0.50

0.75

HR = 1.03 (95% CI: 0.91, 1.17)

DenosumabZoledronic acid

Study Month

P = 0.65

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

Risk greater with Zoledronic Acid Risk greater with Denosumab

Risk Difference (% in Denosumab - % in Zoledronic Acid)

Zoledronic Acid Denosumab(N = 945) (N = 943)n (%) n (%)

133 (14.1) 100 (10.6)33 (3.5) 11 (1.2)57 (6.0) 37 (3.9)28 (3.0) 11 (1.2)10 (1.1) 0 (0.0)11 (1.2) 1 (0.1)15 (1.6) 5 (0.5) 1 (0.1) 7 (0.7) 1 (0.1) 7 (0.7) 2 (0.2) 9 (1.0) 1 (0.1) 9 (1.0) 1 (0.1) 10 (1.1) 2 (0.2) 11 (1.2) 5 (0.5) 15 (1.6) 5 (0.5) 16 (1.7)10 (1.1) 21 (2.2)12 (1.3) 26 (2.8)13 (1.4) 28 (3.0)24 (2.5) 40 (4.2)19 (2.0) 36 (3.8)30 (3.2) 47 (5.0)11 (1.2) 31 (3.3)27 (2.9) 51 (5.4)51 (5.4) 116 (12.3)Hypocalcemia

Muscle spasmsHyperhidrosis

Thoracic vertebral fractureProstatic specific antigen increased

InfluenzaHypophosphatemia

ToothacheOsteonecrosis

SinusitisCerebrovascular accident

Tooth abscessOral herpes

Blood alkaline phosphataseHypercalcemia

Ilium fractureDrug hypersensitivity

Blood glucose increasedCognitive disorder

CholelithiasisChills

MyalgiaInfluenza like illness

Pyrexia

-15 -10 -5 0 5 10 15

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) 22 (2.3)

Hypocalcemia 55 (5.8) 121 (12.8)

New primary malignancy 10 (1.1) 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

Subjects with positively adjudicated ONJ, n (%)

Zoledronic AcidN = 12 (1.3%)

DenosumabN = 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) 1 (8) 4 (18)

ONJ

*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.