A Call to Action: Emerging Strategies to Optimize Bone Health in Breast Cancer This program is supported by an educational donation from December 11, 2009

A Call to Action: Emerging Strategies to Optimize Bone Health in Breast Cancer

This program is supported by an educational donation from

December 11, 2009San Antonio Marriott RivercenterSan Antonio, Texas

clinicaloptions.com/oncologyA Call to Action: Emerging Strategies to Optimize Bone Health in Breast Cancer

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Gregory R. Mundy, MDJohn A. Oates Chair in Translational Medicine Director, Vanderbilt Center for Bone Biology Professor of Medicine Pharmacology, Orthopaedics, Cancer BiologyVanderbilt University Nashville, Tennessee

Biology of Bone Metastasis


Cancer-Bone Disease

Bone metastasis

Osteoporosis

Hypercalcemia


Cascade of Paracrine and Autocrine Transcriptional Events in Bone Formation


Breast

Cerebrum

Liver

Bone

Cancer Cell Metastasis


5-Yr World 5-Yr World Prevalence,Prevalence,ThousandsThousands[1][1]

Incidence of Incidence of Bone MetastasesBone Metastasesin Cancers, %in Cancers, %[2][2]

Median Median Survival, Survival,

MosMos[2-4][2-4]

Myeloma 144 70-95 6-54

Renal 480 20-25 12

Melanoma 533 14-45 6

Bladder 1000 40 6-9

Thyroid 475 60 48

Lung 1394 30-40 6-7

Breast 3860 65-75 19-25

Prostate 1555 65-75 12-53

Mo

re ly

tic

Mo

re b

las

tic

1. Ferlay J, et al. IARC Globocan 2000. Cancer Incidence, Mortality, and Prevalence. 2. Coleman RE. Cancer Treat Rev. 2001;27:165-176. 3. Coleman RE. Cancer. 1997;80:1588-1594. 4. Zekri J, et al. Int J Oncol. 2001;19:379-382.

Cancer Bone Disease Is Prevalent


Breast Cancer: Bone Metastasis

Toshiyuki Yoneda. Reprint permission granted.

CancerBoneBone

OcOc


Vehicle Zoledronic Acid

T

T

T

Susan S. Padalecki. Reprint permission granted.

Bisphosphonates and Effects on Breast Cancer Bone Metastases


Vehicle RANK.Fc

T

T

T

Babatunde Oyajobi. Reprint permission granted.

RANK.Fc Decreased Tumor Burden in Bones of Myeloma-Bearing Mice


Vicious Cycle

Bone-derived factors

Tumor-derived boneresorbing factors

The Vicious Cycle in the Bone Microenvironment


Bone 92%

Primary BreastTumor ~ 60%

Nonbone 17%

Southby J, et al. Cancer Res. 1990;50:7710-7716.Powell GJ, et al. Cancer Res. 1991;51:3059-3061.

PTHrP Expression in Breast Cancer Metastases


Neutralization of PTHrP or PTHrP production

Ocl bone resorption

Bone destruction

Tumor burden in bone

PTHrP AbIgG

MDA-MB-231Guise TA, et al. J Clin Invest. 1996;98:1544-1549. Copyright permission granted.Gallwitz WE, et al. J Clin Invest. 2002;110:1559-1572. Copyright permission granted.

PTHrP Mediates Local Osteolysis


Hh

Gli family

PTHrP

Physiological Pathological

Growth plate[1] Breast cancer[2]

1. Miao D, et al. Exp Cell Res. 2004;294:210-222.2. Sterling JA, et al. Cancer Res. 2006;66:7548-7553.

Hedgehog Signaling and PTHrP


Gli2

PTHrP

RANKL

Resorption

TGF

What Drives PTHrP in Metastatic Cancer Cells?


PTHrP

MDA-231/dominant-negative TßRI cotransfected with:

TβRI (T204D)Empty Vector

TGFβ Blockade Is Reversed by a Constitutively Active TβRI or PTHrP

Yin JJ, et al. J Clin Invest. 1999;103:1979-206. Copyright permission granted.


1 GPa 20 GPa

Hard

1MPa 100 MPa

Basement Membrane

Medium

1 kPa 100 kPa

Breast Tumor

Soft

Healthy Breast

Tissue Culture Plastic

Bone

The Bone Microenvironment Is Stiffer Than the Primary Site


Gli2

PTHrP

RANKL

Resorption

TGFBone modulus

What Drives PTHrP in Metastatic Cancer Cells?


1D11 Decreases Metastasis

Treatment Lytic Bone Lesions Adrenal Gland Kidney

PBS 4/7 3/7 5/7

Control antibody(13C4)

5/8 6/8 6/8

TGFβcontrol(1D11)

0/8 3/8 2/8

Scott Lonning. Reprint permission granted.


1D11 (10 mg/ Kg)2 wks of treatment, 3 times each wk

(treatment started 2 wks after tumor inoculation)

1D1113C4Control Antibody

Control 1D11

1D11 Reduces Osteolytic Lesion in Cardiac Injection Model (MDA-MB-231)

Swati Biswas. Reprint permission granted.

Ave

rag

e L

esio

n A

rea

*†

2 Wks 4 Wks0

5000

10,000

15,000

20,000

25,000

Ave

rag

e L

esio

nN

um

ber

2 Wks 4 Wks-10123456789

10

*†


13C4 1D11

1D11 Decreases Tumor Burden

Swati Biswas. Reprint permission granted.


Tb Th, mm 22.6 ± 3.4 34.2 ± 3.9* Oc S/BS, % 2.6 ± 0.3* 6.4 ± 1.2 Ob S/BS, % 6.7 ± 0.9 12.7 ± 1.5*

Control 1D11

*P < .05

BV/TV, % 6.9 ± 0.6 14.9 ± 2.0*

James Edwards. Reprint permission granted.

1D11 Treatment Alters Osteoclast and Osteoblast Numbers


Control 1D11

1D11 Increases Bone Volume

James Edwards. Reprint permission granted.

BV

/TV

(%

)

*

Control 1D110

5

10

15

20

25

*

BM

D (

mg

HA

/ccm

)

Control 1D11950

970

975

980

985

990

965

960

955 *P < .05


T1

Tumorcells

T2


T1

T2

Gli2

PTHrPPTHrPOsteoclasts

TGFβ TGFβ

Tumorcells


Tumorcells

Stromalcells

Hematopoieticprecursors

T cells andB cells

Osteoblasts Osteoclasts

Michael Gnant, MDPresidentAustrian Breast & Colorectal Cancer Study GroupVienna, Austria

Traditional Approaches for Managing Bone Health in Breast Cancer: Bisphosphonates


Cancer Treatment–Induced Bone Loss

Rapid and severe bone loss resulting from cancer therapies that lead to estrogen or androgen deprivation

Various cancer therapies decrease BMD and increase fracture risk

– Androgen-deprivation therapy

– Estrogen-deprivation therapy

– Chemotherapy

– Surgical (castration)

CTIBL has significant clinical, social, and economic consequences; treatment-related fractures are associated with decreased quality of life and shorter survival


Bone Loss With Cancer Therapies

1. Kanis JA. Osteoporosis. 1997:22-55. 2. Eastell R, et al. J Bone Mineral Res. 2002. 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.

Bo

ne

Lo

ss a

t 1

Yr

Naturally Occurring Bone Loss

CTIBL

0

2

4

6

8

10

Normal Men[1]

Postmenopausal Women[1]

Menopausal Women[1]

Al Therapy inPostmenopausal

Women[2]

ADT[3]

Al Therapy+ GnRH

Agonist inPremenopausal

Women[4]

Premature Menopause

Secondary toChemotherapy[5]

0.51.0

2.02.6

4.6

7.07.7


N Median F/U,Mos

AromataseInhibitor, %

Tamoxifen, % P Value

ATAC[1] 6186 68 11.0 7.7 < .0001

BIG 1-98[2] 8010 26 5.8 4.1 .0006

IES[3] 4724 56 7.0 4.9 .003

ARNO[4] 3224 28 2.4 1.2 NR

Placebo %

MA.17[5] 5187 30 5.3 4.6 .25

In the ATAC trial, after 2 yrs of anastrozole treatment, BMD decreased at lumbar spine (median loss: 4.1%) and total hip (median loss: 3.9%)[6]

BMD increases of 2.2% and 1.2% were observed with tamoxifen in lumbar spine and total hip, respectively[6]

1. Howell A, et al. Lancet. 2005;365:60-62. 2. Thürlimann B, et al. N Engl J Med. 2005;353:2747-2757. 3. Coombes RC, et al. ASCO 2006. Abstract LBA527. 4. Jakesz R, et al. Breast Cancer Res Treat. 2004;88:S7. Abstract 2. 5. Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271. 6. Eastell R, et al. J Bone Miner Res. 2006;21:1215-1223.

Adjuvant Studies With AIs in Breast Cancer: Increased Fracture Rate


Tamoxifen

LetrozoleAnastrozole

Placebo

Fra

ctu

res

(%)

11.0

7.7

5.7

4.0

5.34.6

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)

1. Howell A, et al. Lancet. 2005;365:60-62. 2. Coleman RE, et al. Lancet Oncol. 2007;8:119-127. 3. Thurlimann B, et al. N Engl J Med. 2005;353:2747-2757. 4. Goss PE, et al. J Natl Cancer Inst. 2005;97:1262-1271.

Steroidal and Nonsteroidal AIs Increase Fracture Risk Compared With Tamoxifen


*P < .001; †P < .01; ‡P < .05 between treatments.

-4

-3

-2

-1

0

1

0 1 2 3 4 5Yrs

LS

-BM

D (

% C

han

ge

Fro

m B

asel

ine)

P < .0001 P = .215

**

†‡

‡

Placebo

Clodronate

Powles TJ, et al. ASCO 2004. Abstract 528.

Effect of Adjuvant Oral Clodronate on Lumbar Spine Bone Mineral Density


Ongoing Trials of Zoledronic Acid for Prevention of AI-Associated Bone Loss Premenopausal

– ABCSG-12 bone substudy (n = 404)

Postmenopausal

– Z-FAST (N = 602)

– ZO-FAST (N = 1066)

– E-ZO-FAST (N = 527)

Total patients enrolled: N = 2599


Z/Z0-FAST Trial Design

Letrozole 2.5 mg/day*

Zoledronic acid 4 mg IV q6m

Letrozole 2.5 mg/d*

Add zoledronic acid if: BMD T-score < -2 or clinical

or asymptomatic fracture at 36 mos

RANDOMIZE

IMMEDIATE

DELAYED†

5 yrs

Eligibility:ER+/PgR+ early breast cancerPostmenopausalT-score ≥ -2

Stratification:Adjuvant CT (yes vs no)T-score (> -1 vs between -1 and -2)

Accrual complete—ZO-FAST: N = 1066; Z-FAST: N = 602

*Plus daily calcium 1000-1200 mg and vitamin D 400-800 IU.†Initiation determined by a postbaseline T-score < -2, any clinical fracture, or an asymptomatic fracture at 36 mos.


Z0-FAST Primary Endpoint Mean % Change in BMD From Baseline to 36 Mos

Eidtmann H, et al. SABCS 2008. Abstract 44. Reprint permission granted.

4.391.89

-4.90-3.52

ImmediateDelayed

Lumbar SpineP < .0001

HipP < .0001

BM

D C

han

ge

(%)

6

4

2

0

-2

-4

-6


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

Mea

n (

SE

M)

% C

han

ge

in B

MD

Upfront ZOL (4 mg/6 mos) Delayed ZOL (4 mg/6 mos)

Brufsky A, et al. SABCS 2009. Abstract 4083. Reprint permission granted.

Z-FAST: Upfront ZOL Increases BMD in Lumbar Spine and Hip (N = 602)

P < .0001, all time points*†

8

6

4

2

0

-2

-4

-6

Months12 24 36 48 61

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

0-1

-4

-6

Months12 24 36 48 61

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


T-score ≥ -2.0, no risk factors

Monitor risk status and BMD every 1-2 yrs*

Calcium and vitamin D supplements

*≥ 5% drop in BMD should trigger zoledronic acid treatment (4 mg / 6 mos). Use lowest T-score from 3 sites.

T-score < -2.0

Zoledronic acid 4 mg/6 mos +

calcium and vitamin D supplements

Monitor BMD every 2 yrs

Data for oral bisphosphonates are emergingEvidence from 4 clinical trials indicates that zoledronic acid prevents

AI-associated bone loss

Any 2 of the following risk factors: T-score < -1.5

Older than 65 yrs of age

Low BMI (< 20)

Family history of hip fracture

Personal history of fragility fracture after 50 yrs of age

Oral corticosteroid use of > 6 mos

Smoking (current or history of)

Hadji P, et al. Ann Oncol. 2008;19:1407-1416 by permission of Oxford University Press.

Practical Guidance for Prevention of CTIBL


What if BMD Is Unavailable?

Total risk factors should be evaluated

– Cancer treatments

– Chemotherapy, aromatase inhibitors

– Age

– Corticosteroid use

– Adult history of fracture

– Family history of hip fracture

– Other comorbidities

– Tobacco use

– Alcohol abuse

– Chronic disease (diabetes, RA, COPD, asthma, GI, or liver disease)

Hadji P, et al. Ann Oncol. 2008;19:1407-1416.


Available at: http://www.shef.ac.uk/FRAX.

The FRAX Index: Assessing Fracture Risk


Clinical Presentation and Working Diagnosis of ONJ 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.

*Refer for appropriate dental evaluation and care as soon as possible.


Osteoclast Formation, Function, and Survival Inhibited by Denosumab

Matureosteoclast

CFU-M

Prefusion osteoclast

Multinucleatedosteoclast

Osteoblast

Growth factors HormonesCytokines

RANK

RANKL

OPG

Bone

YY

YYYY

YY

Denosumab

Mechanism of Action of Denosumab

Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.


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

Randomize1:1:1:1

Surgery(+ RT)

Tamoxifen 20 mg/day

Goserelin3.6 mg q28d

Anastrozole 1 mg/day + Zoledronic acid 4 mg q6mos

Anastrozole 1 mg/day

Tamoxifen 20 mg/day + Zoledronic acid 4 mg q6mos

Gnant M, et al. N Engl J Med. 2009;360:679-691.


Gnant M, et al. Lancet Oncol. 2008;9:840-849.

Results 4 Treatment Groups (% Change LS)

10

5

0

-5

-10

-15

% C

han

ge

BM

D (

g/c

m2)

Baseline Baseline

Baseline Baseline

No Zoledronic Acid

Tamoxifen Anastrozole

36 60

-9.0P < .0001

-4.5NS

-13.6P < .0001

-7.8P = .003

36 60

36 60 36 60

Zoledronic Acid

Tamoxifen Anastrozole

+1.0NS

+5.2P = .04

-0.1NS

+3.1NS


100

90

80

70

60

50

40

30

20

10

00 12 24 36 48 60 72 84

Mos Since Randomization

DF

S (

%)

HR (95% CI)Events, n vs No ZOL P Value

ZOL 54 0.64 (0.46-0.91).01

No ZOL83(n = 904) (n = 899)

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

Fir

st E

ven

t p

er

Pat

ien

t (n

) 10

10

9

6

29

41

2010

Secondary malignancyContralateral BCDistantLocoregional


Delayed ZOL(n = 532)

Upfront ZOL(n = 532)

50

45

40

35

30

25

20

15

10

5

Pat

ien

ts (

n)

3

5

20

30

10

2

*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.

Disease Recurrence (36 Mos)[2]*

1. Coleman R, et al. SABCS 2009. Abstract 4082. 2. Eidtmann H, et al. SABCS 2008. Abstract 44.

ZO-FAST 48 Mos: Upfront ZOL Significantly ↓ the Risk of DFS Events by 41%

LocalDistantLymph node

0

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 6 36 42 48 54 60 66

Study Month

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

ZOL 4 mg upfront

ZOL 4 mg delayed

Patients at Risk, nZOL upfront 520 503 487 271 5ZOL delayed 511 480 473 284 5

12 18 24 30

Upfront DelayedPatients , n 532 533

Events/censored 32/500 53/480Median follow-up 48.0 48.1HR (95% CI) 0.59 (0.38-0.92)Upfront vs delayedLog rank P value .0175

DFS at Median Follow-up 48 mos[1]


AZURE: Adjuvant Zoledronic Acid RedUce REcurrence in Breast Cancer Primary endpoint: DFS

Secondary endpoints: bone metastases–free survival, SREs, OS, predictive biomarkers

Standard therapy

Standard therapyZoledronic acid 4 mg

6 doses q3-4w 8 doses q3m 5 doses q6m

3360 patientswith stage II/IIIbreast cancer

Stratification: N+/N-

T-score ER status

Adjuvant systemic therapy Pre/postmenopausal

Statins

R

Follow-up without

treatment:5 yrs for

recurrence and

survival

Treatment duration 5 yrs


42.4 28.2Median % Path CR

5.8 10.9

33% (P = .002)

88% P = .03*

Winter MC, et al. SABCS 2008. Abstract 5101.

Neoadjuvant AZURE—Reduces Tumor Size and Improve Pathologic Response

Chemotherapy aloneChemotherapy + zoledronic acid

Res

idu

al I

nva

sive

Tu

mo

r S

ize

(mm

)

60

50

40

30

20

10

0

*Multivariate analysis (N = 171).


Bisphosphonates in Breast Cancer

Hypercalcemia 1a A ++

Bone metastasis 1a A ++

Tumor therapy–induced osteopenia 1b B ++

Prevention of bone metastases

– Primary breast cancer 1b B +*

– Advanced breast cancer 2b C +/-

Prevention of bone loss in patients withincreased risk of osteoporosis 2b C +

Treatment beyond progression 5 D ++

Oxford/AGOLOE/GR

*Study participation recommended.


ADJUVANT METASTATIC

Early stage (BC I-III) ABCSG-12 trial[1]

E/Z/ZO-FAST trials[2]

Later stage (BC II/III) AZURE trial[3]

Metastatic BC Trial 010, 1501[4,5]

Description

Low Moderate Very highTumor burden

Potential site for harboring tumor cells and seeding metastatic disease

Ongoing, active destruction of skeletal integrity through

tumor cell–mediated, osteoclast bone resorption

Key clinical issue with skeleton

Prevent metastases, improve DFS/RFS

Stop vicious cycle of bone destruction; significantly reduce the risk of SREs

Treatment goal with

zoledronic acid

4 mg IV q6m 4 mg IV up 8 x/yr 4 mg IV q3-4wDose ZOL needed

Early Late

1. Gnant M, et al. N Engl J Med. 2009;360:679-691. 2. Brufsky A, et al. Oncologist. 2008;13:503-514. 3. Coleman R, et al. Eur J Cancer Suppl. 2007;5(4). Abstract 0-48. 4. Rosen LS, et al. Cancer J. 2001;7:377-387. 5. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321.

Dosing Rationale in Breast Cancer


Lower Incidence of Invasive and ER+ BC With Oral Bisphosphonate Use in WHI Women’s Health Initiative

– 154,768 postmenopausal women aged 50-79 yrs

Oral bisphosphonate use (vs nonuse) associated with

– ↓ incidence of invasive BC: 3.29 vs 4.38 cases/1000 person-yrs (P < .01)

– ↓ incidence of ER+ BC: 2.56 vs 3.28 cases/1000 person-yrs (P = .02)

– ↑ incidence of in situ BC: 1.53 vs 0.92 cases/1000 person-yrs (P = .002)

Potential confounding factor: correlation between estrogen level and breast cancer vs osteoporosis/osteopenia risk may have resulted in women already at lower risk for breast cancer to be more likely to receive bisphosphonate therapy

Chlebowski RT, et al. SABCS 2009. Abstract 21.


Conclusions

Modern adjuvant therapies for breast cancer have improved efficacy but can compromise bone integrity

– Adjuvant chemotherapy can cause ovarian failure

– Estrogen/androgen suppression BMD and fracture risk

Bisphosphonates are important therapeutic agents for the treatment and prevention of CTIBL

There is a strong suggestion of additional antitumor benefits by adjuvant zoledronic acid

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

Targeting Osteoclast Inhibition: Mechanisms, Rationale, and Data


Scope of the Problem

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


Osteotropic Tumors

1. Ferlay J, et al. IARC Globocan 2002. Cancer Incidence, Mortality, and Prevalence Worldwide.2. Coleman RE. Cancer Treat Rev. 2001;27:165-176. 3. Coleman RE. Cancer. 1997;80:1588-1594. 4. Zekri J, et al. Int J Oncol. 2001;19:379-382. 5. Chiappori A, et al. Oncology. 2005;68:382-390.

5-Yr WorldPrevalence, Thousands[1]

Incidence of Bone Metastases in

Advanced Cancers[2]

Median Survival, Mos[2-5]

Breast 4406 65-75 19-25

Prostate 2369 65-75 12-53

Lung 1369 30-40 6-7

Bladder 1110 40 6-9

Melanoma 643 14-45 < 6

Renal 586 20-25 12

Thyroid 531 60 48


Bone

Tumor Cells in Bone

Osteoclast

Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664.

(+) (+)

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


Incidence of Skeletal-Related Events

Lung Cancer/Others†

Prostate Cancer*

Multiple Myeloma†

Breast Cancer*

Coleman RE. The 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 (%)‡


Data are from placebo-control arms of bisphosphonate trials.1. Lipton A, et al. Cancer. 2000;88:1082-1090. 2. Rosen LS, et al. Cancer. 2004;100:2613-2621.3. Berenson JR, et al. J Clin Oncol. 1998;16:593-602. 4. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.

2.71

2.20

3.70

1.47

0

1.0

2.0

3.0

4.0

Mea

n S

RE

s/Y

r

Breast cancer[1]

Lung cancer and other solid tumors[2]

Multiple myeloma[3]

Prostate cancer[4]

Patients With Cancer

Patients Experience Multiple SREs/Yr


Patients With Bone Lesions Are at High Risk for Developing Skeletal Complications

Pathologic fractureRadiation therapySurgical interventionSpinal cord compression

Breast[1]

24 mosProstate[2]

24 mosNSCLC + other solid tumors[4]

21 mos

Multiple myeloma*[3]

21 mos

Cancer 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. Rosen LS, et al. Cancer. 2004;100:2613-2621.

52

25

37

22

34

11

4 5 53

83 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 SREs

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

44.8

26.7

12.3

11

9

12

5.3

0 20 40 60

Prostate

Myeloma

Breast

Lung

SRESurvival


Zoledronic Acid Reduces the Risk of SREs Across All Tumor Types

In favor of ZOL In favor of placebo

Prostate

Solid Tumors

Lung Cancer

RCC

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0Relative Risk of SRE

Breast

Kohno N, et al. J Clin Oncol. 2005;23:3314-332. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.Rosen LS, et al. Cancer. 2004;100:2613-2621. Lipton A, et al. Cancer. 2003;98:962-969.

RiskReduction, %

P Value

41 .019

36 .002

31 .003

32 .016

58 .010


RANK Ligand Is a Key Mediator in the “Vicious Cycle” of Bone Destruction

Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.

Bone

RANK

RANKL

Bone Resorption

Osteoclast

Cancer Cells in Bone

Growth Factors (TGF-β, IGFs, FGFs,

PDGFs, BMPs)

Cytokines and Growth Factors (IL-6, IL-8, IL-1, PGE-2, TNF-,

CSF-1, PTHrP)R

AN

KL

Direct Effectson Tumor?

OsteoblastLineage


Denosumab Characteristics

Fully human monoclonal antibody to RANKL

High affinity IgG2 antibody

No binding to TNF-α, TNF-ß, TRAIL, or CD40L

Administration via SC injection


Phase I: Serum Levels of Denosumab in Breast Cancer Patients

Body JJ, et al. Clin Cancer Res. 2006;12:1221-1228. Copyright permission granted.

8.26

20.7

29.7

46.3

Days

0 14 28 42 56 70 840.1

1

10

100

1000

10,000

100,000

0.1 mg/kg SC (n = 5-7)0.3 mg/kg SC (n = 5-7)1.0 mg/kg SC (n = 6-7)3.0 mg/kg SC (n = 3)

Half-life, Days

Tmax

Den

osu

mab

S

eru

m C

on

cen

trat

ion

(n

g/m

L)

(Mea

n ±

SD

)


Study 20040113 Schema Breast Cancer Patients With Bone MetastasesPrimary endpoint

% change in uNTx at Wk 13

Secondary endpoints % change in uNTx at Wk 25

Proportion with > 65% reduction in uNTx at weeks 13 and 25

Proportion experiencing an SRE

Time to first SRE

Screening/ Randomization

Denosumab30 mg SC q4w





Bisphosphonate* IV q4w

Follow-up at Wks 33, 45, 57

*IV BPs used in this study:Zoledronic acid (n = 39)Pamidronate (n = 3)Ibandronate (n = 1)

Lipton A, et al. Clin Cancer Res. 2008;14:6690-6696. Copyright permission granted.

25 wks of treatment


Median (Q1, Q3) Percent Change in uNTx From Baseline Over Time

Lipton A, et al. Clin Cancer Res. 2008;14:6690-6696. Copyright permission granted.

Med

ian

(Q

1, Q

3) P

erce

nt

Ch

ang

e in

uN

Tx

/Cr

0 25211713952Study Wk

-100

-80

-60

-40

-20

0

20

Denosumab 180 mg q4wDenosumab 60 mg q12wDenosumab 180 mg q12wAll denosumab

IV BPDenosumab 30 mg q4wDenosumab 120 mg q4w


SREs Through Wk 25

Through study Wk 25, 16% of IV BP-treated patients and 12% of denosumab-treated patients experienced ≥ 1 on-study SRE


Phase III Dose Selection Rationale

Suppress bone resorption (uNTx) maximally

– 120 mg q4w showed trend toward greater suppression of bone turnover than 30 mg q4w

Minimize “escape” from suppression of bone resorption

– q12w dosing had more “escape” from suppression, favoring q4w dosing

Choose safe and convenient dosing

– More grade 2 and 3 decreases in serum calcium levels (asymptomatic) with the 180-mg dose

Selected phase III dose: 120 mg q4w


Study 20040114 Schema Patients With Bone Metastases and High NTx Study features Bone metastases from solid tumors (except lung) or MM bone disease Patients receiving IV BP and

uNTx > 50 nM/mM 45 patients per group (N=135) Open label, randomized ECOG PS 0, 1, 2

Screening/ Randomization



Bisphosphonate IV q4w

Extension/ Follow-up

25 wks of treatment

Fizazi J, et al. J Clin Oncol. 2009;27:1564-1571.


Study 20040114: Results

Primary endpoint: urinary N-telopeptide suppression to < 50 nM/mM creatinine at Wk 13

– Rates were higher among patients who switched to either dose of denosumab vs those who continued receiving bisphosphonates

The time to the first SRE in patients who continued bisphosphonates was shorter than the time to the first SRE in each of the denosumab arms or in the pooled denosumab arms


Study Design: International, Randomized, Double-Blind, Active-Controlled StudyKey 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 SC placebo 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.


Baseline Characteristics

Characteristics, n (%) or median Zoledronic Acid(N = 1020)

Denosumab(N = 1026)

Women 1011 (99) 1018 (99)

Age, yrs 56 57

ECOG performance score of 0 or 1 932 (91) 955 (93)

Hormone receptor positive 726 (71) 740 (72)

Time from first bone metastasis to randomization, mos

2 2

Previous SRE 373 (37) 378 (37)

Presence of visceral metastases 525 (51) 552 (54)



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 reached26.5

HR: 0.82 (95% CI: 0.71-0.95)P < .0001 (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



Time to First and Subsequent SRE*: Multiple Event Analysis

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

Total No. of Events


474608

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)

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

Denosumab 1026 511 378 312 256 214 159 109 59 27

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

Mos

0

1.00

0 3 6 9 12 15 18 21 24 27

0.25

0.50

0.75

Patients at Risk, n



Mos

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

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

Denosumab 1026 858 693 567 453 351 241 128 65 20

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


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 96

Serious 46 44

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



Incremental Benefits in Breast Cancer

64% risk of skeletal complication with no bisphosphonate at 2 yrsApprox 33% risk reduction with pamidronate

64% 43% 34%

Further 20% risk reduction with zoledronic acidFurther 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. 2003;100:36-43. Stopeck A, et al. ECCO/ESMO 2009. Abstract 2LBA.


Solid Tumors and Multiple Myeloma Phase III TrialKey inclusion

Adults with solid tumors and bone metastases (excluding breast and prostate) or multiple myeloma

Key exclusion

Current or previous intravenous 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 = 890)

Denosumab 120 mg SC and Placebo IV* q4w (n = 886)

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).


Solid Tumors and Multiple Myeloma Baseline CharacteristicsCharacteristic, n (%) or median Zoledronic Acid

(n = 890)Denosumab

(n = 886)

Male 552 (62) 588 (66)

Age, yrs 61 60

Primary tumor type

Non-small-cell lung cancer 345 (39) 343 (39)

Multiple myeloma 93 (10) 86 (10)

Other 452 (51) 457 (52)

ECOG performance score of 0 or 1 728 (82) 748 (84)

Time from first bone metastasis to randomization, mos

2 2

Previous SRE 446 (50) 440 (50)

Presence of visceral metastases 448 (50) 474 (53)


Time to First On-Study SRE

*Due to multiplicity adjustment

1° HR: 0.84 (95% CI: 0.71-0.98)P = .0007 noninferiority

2° unadjusted P = .03 superiority*Adjusted P = .06

Zoledronic acidPatients at Risk, n

890 578 376 261 194 126 86 47Denosumab 886 582 387 266 202 134 96 55

Study Mo

Zoledronic acidDenosumab

0

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18 21 24

KM Estimate ofMedian Mos

16.320.6

Pro

po

rtio

n o

f S

ub

ject

s W

ith

ou

t S

RE

Henry D, et al. ECCO/ESMO 2009. Abstract 20LBA.


Time to First-and-Subsequent On-Study SRE (Multiple Event Analysis)



Total No. of SREs

436392

0.0

0.5

1.0

1.5

Study Mo0 3 6 9 12 15 18 21 24 27 30

2° rate ratio: 0.90 (95% CI: 0.77-1.04)P = .14

Cu

mu

lati

ve M

ean

Nu

mb

er o

f S

RE

s


Solid Tumors and Multiple Myeloma: OS

HR: 0.95 (95% CI: 0.83-1.08)P = .43

Zoledronic acidPatients at Risk, n

890 727 540 410 343 232 176 118Denosumab 886 726 557 420 340 247 181 127

Study Mo


0

0.25

0.50

0.75

1.00

0 3 6 9 12 15 18 21 24

Pro

po

rtio

n o

f S

ub

ject

s S

urv

ived

27

6466



Solid Tumors and Multiple Myeloma: Adverse Events Event, n (%) Zoledronic Acid

(n = 878)Denosumab

(n = 878)

Infectious AEs 349 (39.7) 358 (40.8)

Infectious serious AEs 118 (13.4) 128 (14.6)

Acute phase reaction (first 3 days) 127 (14.5) 61 (6.9)

Potential renal toxicity AEs* 96 (10.9) 73 (8.3) Renal failure 25 (2.8) 20 (2.3) Acute renal failure 16 (1.8) 11 (1.3)

Cumulative rates of ONJ† 11 (1.3) 10 (1.1)

New primary malignancy 3 (0.3) 5 (0.6)

*Includes blood creatinine increased, renal failure, renal failure acute, proteinuria, blood urea increased, renal impairment, urine output decreased, anuria, oliguria, azotemia, hypercreatininemia, creatinine renal clearance decreased, renal failure chronic, blood creatinine abnormal.† P = 1.0No neutralizing antidenosumab antibodies were detected.



Metastatic Prostate Cancer Study Schema

Primary endpoint

– Time to the first on-study SRE *End of study; event driven.

Key Eligibility Criteria Men with histologically or

cytologically confirmed prostate cancer

Radiographic evidence of at least 1 bone metastasis

Documented failure of at least one hormonal therapy as evidenced by a rising PSA

Serum testosterone level of < 50 ng/dL due to either surgical or chemical castration

No prior IV bisphosphonate use

Denosumab120 mg SC q4w +

Placebo IV over 15-min infusion

(n = 850)

Zoledronic acid 4 mg IV over 15-min infusion q4w +

Placebo SC q4w(n = 850)

END

OF

STUDY

ENROLLMENT

1 EOS*Study Wk

Treatment PeriodScreening/Enrollment


Adjuvant Prostate Cancer Study Schema

Primary endpoint

– Time to first occurrence of bone metastasis or death from any cause

*End of study.†Event driven.

1 EOS*† Study Week

Treatment PeriodScreening/Enrollment

Key Eligibility Criteria Men with histologically confirmed

prostate cancer No prior or current radiographic

evidence of bone metastasis Serum testosterone level of

< 50 ng/dL due to either surgical or chemical castration

No prior IV bisphosphonate use


Placebo

END

OF

STUDY

ENROLLMENT

For more information on this important clinical topic, go online:

clinicaloptions.com/ActionBoneHealth

clinicaloptions.com/Oncology

Documents

A Call to Action: Emerging Strategies to Optimize Bone Health in Breast Cancer This program is supported by an educational donation from December 11, 2009