Managing Bone Lesions in Cancer

Matthew Raymond Smith, MD, PhDProfessor of MedicineHarvard Medical School Program Director, Genitourinary OncologyMassachusetts General Hospital Cancer CenterBoston, Massachusetts

Managing Skeletal-Related Events in Patients With Cancer: A Master Class in Breast Cancer, Prostate Cancer, and Multiple Myeloma

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Faculty

Matthew Raymond Smith, MD, PhDProfessor of MedicineHarvard Medical School Program Director, Genitourinary OncologyMassachusetts General Hospital Cancer CenterBoston, Massachusetts

Allan Lipton, MDProfessor of Medicine and OncologyMilton S. Hershey Medical CenterPenn State Cancer InstituteHershey, Pennsylvania

Noopur Raje, MDDirector, Center for Multiple MyelomaMassachusetts General Hospital Cancer CenterBoston, Massachusetts

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


Bone Involvement in DifferentTumor Types

DiseasePrevalence (US)(in Thousands)

Incidence of Bone Metastases in

Patients With Advanced Disease, %

Median Survival of Patients With Bone

Metastases, Mos

Myeloma 49.6[1] 84[2] 37-58[4]

Lung 327[1] 30-40[3] 8-10[5]

Breast 2051[1] 65-75[3] 19-25[6]

Prostate 1477[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.


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.


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

0 10 20 30 40 50 60


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.


PlaceboPamidronate

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

9 21

Pat

ien

ts (

%)

0

10

20

30

40

50

60

Mos

51

P < .001P = .015


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

Pamidronate90 mg

Zoledronicacid 4 mg

All SREs

Pat

ien

ts W

ith

SR

E (

%)

Rosen LS, et al. Cancer J. 2001;7:377-387.


MRC Myeloma IX: Analysis Schematic for Zoledronic Acid vs Clodronate

Endpoints (zoledronic acid vs clodronate)Primary: PFS, OS, and ORRSecondary: 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


0 6 12 18 24 30 36 42 48 54 60 66 72

MRC Myeloma IX: ZOL ↓ SREs* vs CLO Regardless of Bone Lesions at Baseline

Bone Lesions at Baseline No Lesions at Baseline0.5

0.4

0.3

0.2

0.1

0

Mos From Randomization

SR

Es/

Pat

ien

t

668

682

415

402

325

297

250

212

189

164

136

117

100

75

69

50

50

37

35

24

18

12

6

4

0

0

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

18

11

12

8

7

5

4

0

0

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.

0 6 12 18 24 30 36 42 48 54 60 66 72

0.5

0.4

0.3

0.2

0.1

0


MRC Myeloma IX: Zoledronic Acid Improved OS and PFS vs Clodronate

RiskReduction

HR (Zoledronic Acid vs Clodronate)0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

P Value

.01180.842 16%

In favor of ZOL In favor of CLO

OS

.017912%0.883PFS

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.


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 mgq12wk§e

Raje N, et al. ASH 2010. Abstract 2971.


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.


Summary of Bisphosphonates in MM

Inhibit bone resorption

Pamidronate better than placebo

Pamidronate and zoledronic acid equivalent

Zoledronic acid has a survival advantage


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


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.


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.


Roodman GD. J Clin Invest. 2008;118:462-464.

Bortezomib/Lenalidomide in MBD

Myeloma cells

Bone

OCLOsteoblasts

OCL precursor

Lenalidomide

OAFs

Bortezomib

BMP-2 Runx-2 MSCs


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 FunctionMenu: On Murine OC BX4471 Is a Potent Inhibitor of Osteoclastogenesis

Resorbed area on dentine slicesTRAP + multinucleated cells

MLN3897 10 nM MLN3897 10 nM

P < .05P < .05

Pro-cathepsin KCathepsin K

C-tubulin

Cathepsin K expression

- +- +

++ --

PB2PB1

MLN3807 10 nMMLN3807 10 nM

MLN3807(nM)MLN3807(nM)

0.2 2 10

12

Pc

t A

rea

as

%

of

To

tal

Are

a

TR

AP

+ M

N C

ell

(% o

f c

on

ne

ct)

1086420

0.2 2 100 100 0

140

100806040200

120

CCR1 Inhibition Decreases Osteoclastogenesis


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.


Anti-DKK1 BHQ880 Reverses Inhibitory Effect of MM Cells on Osteoblastogenesis

hu

IL-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/mLIsotype 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.

Cal

ciu

m D

ep

osi

tio

n(%

of

co

ntr

ol)

50

100

150

0

P = .08

P = .0001

P = .0001

No MM Cells

With MM Cells

- BHQ880+ BHQ880


Activin decreases bone mineral density and strength

Activin and Bone Growth

Reducedbone

formation

Activin

Activin inhibits osteoblasts

Osteoblast

Activinreceptortype IIA

Activin

Activinreceptortype IIA

Activin stimulates osteoclasts

Increasedbone

resorption

Osteoclast


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/mLMM > 1 OL: 112.07 ± 30.4 pg/mLNon-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

NS150

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

BMSC OB MM

Mean1300

Mean1884

NS

Mean299 Mean

8.2

††


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)



Placebo, SQ monthly x 4 (n = 6)


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

Optimal Management of Bone Metastases in Patients With

Breast Cancer


Scope of the Problem

400,000 new patients/yr in the United States develop bone metastases


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

0 20 40 60 80

Patients With SREs (%)‡


Patients With Bone Lesions Are at High Risk for Skeletal Complications

Pathologic fractureRadiation therapySurgical interventionSpinal cord compression

Breast[1]

24 mosProstate[2]

24 mosNSCLC + other solid tumors[5]

21 mos

Multiple myeloma*[3,4]

21 mosCancer Type

Placebo Arms of Large Randomized Studies

Pat

ien

ts W

ith

SR

E (

%)

*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 53

8

2 4

3433

43

0

10

20

30

40

50

60


Skeletal-Related Events and OS

MosAs 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

0 20 40 60

Prostate[6,7]

Myeloma[4,5]

Breast[3]

Lung[1,2] Skeletal-related eventSurvival

Pamidronate, Zoledronic Acid, and Denosumab


0 50 100 150 200 250 300 350 400Days 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 Pro

po

rtio

n o

f P

atie

nts

Wit

h B

on

e M

etas

tase

s W

ith

ou

t an

SR

E

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 mgPlacebo


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 Ratio P Value

Total 0.841 .030

Breast carcinoma hormonal therapy stratum 0.693 .009

Breast carcinoma chemotherapy stratum 0.955 .749

Multiple myeloma stratum 0.932 0.593

Rosen LS, et al. Cancer. 2003;98:1735-1744.


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 withadvanced 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.


Time to First On-Study SRE

Zoledronic acid 1020 829 676 584 498 427 296 191 94 29

Denosumab 1026 839 697 602 514 437 306 189 99 26

Patients at Risk, n

*Adjusted for multiplicity.

KM Estimate ofMedian Mos

DenosumabZoledronic acid

Not reached26.4

HR: 0.82 (95% CI: 0.71-0.95; P < .001 noninferiority; P = .01 superiority*)

Mos

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 30

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.


Time to First and Subsequent SRE*: Multiple Event Analysis

*Events that occurred at least 21 days apart.†Adjusted for multiplicity.


Rate ratio: 0.77 (95% CI: 0.66-0.89;P = .001†)

Mos

0

1.5

Cu

mu

lati

ve M

ean

N

um

ber

of

SR

Es

0 3 6 9 12 15 18 21 24 27 30

0.5

1.0



Time to Experiencing Mod or Severe Pain (Worst Pain Score > 4 Pts/Brief Pain Inv)

KM Estimate ofMedian Days


8864

HR: 0.87 (95% CI: 0.79-0.97;P = .009)

Pro

po

rtio

n o

f S

ub

ject

s

0 3 6 9 12 15 18 21 24 27

Stopeck A, et al. SABCS 2009. Abstract 22. Reprint permission granted.

Zoledronic acid 1020 463 318 250 209 172 126 93 56 17

Denosumab 1026 511 378 312 256 214 159 109 59 27

Patients at Risk, nMos

0

1.00

0.25

0.50

0.75


Pro

po

rtio

n o

f S

ub

ject

s W

ith

ou

tD

isea

se P

rog

ress

ion

0 3 6 9 12 15 18 21 24 27 30

Disease Progression

HR: 1.00 (95% CI: 0.89-1.11;P = .93)

Mos

Zoledronic acid 1020 842 686 563 462 370 240 148 65 17

Denosumab 1026 858 693 567 453 351 241 128 65 20

Patients at Risk, n


0

1.00

0.25

0.50

0.75



Overall Survival

Zoledronic acid 1020 962 897 834 757 699 515 352 184 54

Denosumab 1026 984 916 849 771 690 511 336 177 57

HR: 0.95 (95% CI: 0.81-1.11;P = .49)

Mos

0

1.00

Pro

po

rtio

n o

f S

ub

ject

s S

urv

ived

0 3 6 9 12 15 18 21 24 27 30

0.25

0.50

0.75

Patients at Risk, n




Adverse Events

Adverse Event, % Zoledronic Acid (n = 1013)

Denosumab (n = 1020)

Overall 97.2 95.8

Serious 46.5 44.4

Acute phase reactions (first 3 days) 27.3 10.4

Renal toxicity

Overall 8.5 4.9

Serious 1.5 0.2

ONJ* 1.4 2.0

*P = .39

Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.


Skeletal Complication Risk: Incremental Benefits in Breast CancerNo bisphosphonate

64% risk at 2 yrs Pamidronate ~ 20% risk reduction

64% 51% 34%

Zoledronic acid Additional ~ 20%

risk reduction

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.

Novel Strategies for Bone-Directed Therapy in Prostate

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


Clinical Complications of Osteoblastic Metastases Pain

Fractures

Spinal cord compression

Myelophthisis


0200

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)

BA

P (

U/L

)

Correlation coefficient = 0.67

Normal

400600800

1000120014001600180020002200240026002800300032003400360038004000

0 200 400 600 800 1000 1200 1400

25%50%75%

25%

75%


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.


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.

90 180 270 360 450 5400

20

40

60

80

Pat

ien

ts W

ith

ou

t E

ven

t (%

)

0

10

30

50

70

90

100

163 113 92 70 5 0214155 102 68 46 4 0221

149 103 69 43 1 0208

Zol acid 4 mgZol 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


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


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, nDenosumab

Zoledronic acid950951

758733

582544

472407

361299

259207

168140

11593

7064

3947

1.00

0.75

0.50

0.25

00 3 6 9 12 15 18 21 24 27

Study Mo

Pro

po

rtio

n o

f P

atie

nts

W

ith

ou

t an

SR

E



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

00 3 6 9 12 15 18 21 24 27

Study Mo

Cu

mu

lati

ve M

ean

Nu

mb

er o

f S

RE

s p

er P

atie

nt

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

30 33 36

Events494584

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


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.


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


Spectrum of Bone Disease in Prostate Cancer




MetastasisPrevention


PSA and PSADT Are Associated With Shorter Bone Metastasis-Free Survival

Inci

den

ce o

f B

on

e M

ets

or

Dea

th

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/mLPSA 7.7-24.0 ng/mLPSA > 24.0 ng/mL

0

0.2

0.4

0.6

0.8

1.0

0Yrs Since Randomization0.5 1.0 1.5 2.0 2.5 3.0

PSADT < 6.3 mosPSADT 6.3-18.8 mosPSADT > 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.

Inci

den

ce o

f B

on

e M

ets

or

Dea

th


Denosumab to Prevent Metastases

Primary endpoint: bone metastasis-free survival

Denosumab 120 mg monthlyPatients with CRPCand no bone metastases;

PSA > 8 or PSADT < 10 mos

(N = 1435)Placebo monthly

Smith MR, et al. 2011 AUA. Plenary. ClinicalTrials.gov. NCT00286091.


Primary Endpoint: Bone Metastasis-Free Survival

716716

691695

569605

500521

421456

375400

345368

300324

259279

215228

1.0

0.8

0.6

0.4

00 3 6 9 12 15 18 21 24 27

Study Mo

Pro

po

rtio

n o

f P

atie

nts

Wit

hB

on

e M

etas

tasi

s–F

ree

Su

rviv

al

PlaceboDenosumab

0.2

30 33 36 39 42

Median Mos25.229.5

HR: 0.85 (95% CI: 0.73-0.98; P = .028)

PlaceboDenosumab

168185

137153

99111

6059

3635

Patients at Risk, n

Smith MR, et al. 2011 AUA. Plenary.


Time to Symptomatic Bone Metastasis

Note: Symptomatic bone metastases before or coinciding with imaging diagnosing.

716716

667683

565603

474503

411441

368385

347360

293308

242260

189200

1.0

0.8

0.6

0.4

00 3 6 9 12 15 18 21 24 27

Study Mo

Pro

po

rtio

n o

f P

atie

nts

Wit

ho

ut

Sym

pto

mat

ic B

on

e M

etas

tasi

s

PlaceboDenosumab

0.2

30 33 36 39

HR: 0.67 (95% CI: 0.49-0.92; P = .01)

142160

130143

9496

5147

PlaceboDenosumab

Patients at Risk, n

Smith MR, et al. 2011 AUA. Plenary.


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


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


Spectrum of Bone Disease in Prostate CancerTreatment-Related

Fractures





Proportion of Patients With Fractures1-5 Yrs After Cancer Diagnosis

Shahinian VB, et al. N Engl J Med. 2005;352:154-164.

0

3

6

9

12

15

18

Any Fracture Fracture Resulting in Hospitalization

Fre

qu

ency

(%

)

+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


LumbarSpine

TotalHip

P < .001 for each comparison

12-mo data

Per

cen

t C

han

ge

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

-1

0

1

2

GnRH agonistControl


Annual Zoledronic Acid Increases BMD During GnRH Agonist Therapy

LumbarSpine

TotalHip

Final 12-mo dataBM

D P

erce

nt

Ch

ang

e

-6

-4

-2

0

2

4

6Placebo

Zoledronic acid

Michaelson MD, et al. J Clin Oncol. 2007;25:1038-1042.


LumbarSpine

TotalHip

12-mo data

Greenspan SL, et al. Ann Intern Med. 2007;146:416-424.

Alendronate Increases BMD During GnRH Agonist Therapy

BM

D P

erce

nt

Ch

ang

e

-3

-2

-1

0

1

2

3

4

5Placebo

Alendronate

P < .005 for each comparison


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 q6mfor 3 yrs

Placebo q6mfor 3 yrs


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

Per

cen

t C

han

ge

in B

MD

F

rom

Bas

elin

e

10

8

6

4

2

0

-2

-4

-601 3 6 12 24 36

Placebo

Difference at 24 mos: 4.8 percentage points

Total Hip

Mos

Per

cen

t C

han

ge

in B

MD

F

rom

Bas

elin

e

10

8

6

4

2

0

-2

-4

-601 3 6 12 24 36


Denosumab to Prevent Fractures

12Mos

24 36

P = .004 P = .004 P = .006

1.9

0.3

3.3

1.0

3.9

1.5

0

2

4

6

8

10

New

Ver

teb

ral

Fra

ctu

re (

%) Placebo

Denosumab

13 2 22 7 26 10Patients, nSmith MR. N Engl J Med. 2009;361:745-755. Copyright © 2009 Massachusetts Medical Society.All rights reserved.


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

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