Established Benefitsof Bisphosphonates;

Focus on Breast and Prostate Cancers

Prof. Mohamed Abdulla, Department of Clinical Oncology,Kasr El-Aini School of Medicine,

Cairo University.“Tanta Cancer Center- April, 13th,2009”

Bone as a Dynamic Structure: Normal Turnover

Osteoblast RANKL

Bone

Osteoclast

Bone as a Dynamic Structure: Normal Turnover

•Annual turnover rate of about 25% in cancellous bone and 2-3% in cortical bone•The process takes about 4-6 months.•1 osteoclast resorbs what 100 osteoblasts build.

The Vicious Cycle of Bone Destruction

• PTHrP released by tumor cells

Tumor Cells

PTHrP

BMP

PDGF

FGFs

IGFs

TGF-β

Osteoclast

Mundy GR, Yoneda T. N Engl J Med.1998;339:398-400.

• Osteoclastic resorption stimulated

• Peptides (eg, TGF-β) released by bone resorption

• Tumor cell production of PTHrP increased

• More bone resorption

• Tumor cell proliferation

Bone

1. Parkin DM, et al. Int J Cancer. 2001;94(2):153-156; 2. Coleman RE. Cancer Treat Rev. 2001;27(3):165-176; 3. Coleman RE. Cancer. 1997;80(8):1588-1594; 4. Zekri J, et al. Int J Oncol. 2001;19(2):379-382.

5-year world prevalence,thousands1

Incidence of bone metastases

in cancers2Median survival,

months2-4

Myeloma 144 70 - 95 6 - 54Renal 480 20 - 25 12Melanoma 533 14 - 45 6Bladder 1,000 40 6 - 9Thyroid 475 60 48Lung 1,394 30 - 40 6 - 7Breast 3,860 65 - 75 19 - 25Prostate 1,555 65 - 75 12 - 53

More

lyti

cM

ore

lyti

c

More

bla

sti

cM

ore

bla

sti

c

Metastatic Bone Disease Is PrevalentMetastatic Bone Disease Is Prevalent

Bone Complications and Quality of Life

1. Groot MT, et al. Eur Urol. 2003;43:226-232. 2. Weinfurt KP, et al. ESMO 2002. Abstract 662P. 3. Weinfurt KP, et al. Med Care. 2004;42:164-175. 4. Saad F, et al. Eur Urol. 2004;46:731-740. 5. Oefelein MG, et al. J Urol. 2002;168:1005-1007. 6. Riggs BL, et al. Bone. 1995;17:505S-511S.

Skeletal complications

Negative impact on survival[5]

Increased medical costs[1]

Impaired mobility[6]

Diminished quality of life[2-4]

Increased medical costs[1]

Diminished quality of life[2-4]

Negative impact on survival[5]

Increased medical costs[1]

Diminished quality of life[2-4]

Impaired mobility[6]

Negative impact on survival[5]

Increased medical costs[1]

Diminished quality of life[2-4]

Impaired mobility[6]

Pathologic Fractures Negatively Affect SurvivalPathologic Fractures Negatively Affect Survival

Data from Saad F, et al. Cancer. 2007;110(8):1860-1867.

Hazard ratio

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

Decreased mortality Increased mortality

.04

P value

29%

Riskincrease

1.29

< .0152%1.52

Prostate cancer

Breast cancer

FDA Accepts Composite Endpoints to Evaluate Therapy Benefit

Composite endpoints based on occurrence of skeletal-related events (SREs) defined as– Radiation to bone for bone pain or to treat or

prevent pathologic fractures or spinal cord compression

– Pathologic fracture– Spinal cord compression– Surgery to bone

Johnson JR, et al. J Clin Oncol. 2003;21:1404-1411.

Patients With Bone Metastases Are at High Patients With Bone Metastases Are at High Risk for Developing Skeletal-Related EventsRisk for Developing Skeletal-Related Events

SRE, skeletal-related event.

1. Lipton A, et al. Cancer. 2000;88(5):1082-1090; 2. Saad F, et al. Eur Urol Suppl. 2007;6(11):683-688.

68%

49%43%

33%

11%

4%3%8%

25%

52%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Breast1

24 MonthsProstate2

24 MonthsCancer Type

Placebo arms of large randomized studies

Pat

ien

ts W

ith

SR

E, %

Pathologic fractureRadiation therapySurgical interventionSpinal cord compression

SREsAny

Management of

Bone Metastases

Ionizing

Irradiation

Chemo-Hormonal

Therapy

& Drug

Therapy

Orthopedic

Procedures

Drug Therapy

External BeamRadiationTheerapy

RadioactiveIsotopes

Ionizing External Beam Rth:

• Used over a Century for Palliation of Bone Mets. Related Effects.

• Bone Relief in The Majority of Patients.• Reducing The Rate of Bone Destruction.• 6-12 Months of Pain Control.• Disadvantages:

1. Myelosuppression.

2. Dose to Surrounding Critical Structures.

Radioactive Isotopes:

Radio-Radio-nuclidenuclide

Carrier Carrier LigandLigand

Half Half Life Life

(Days)(Days)

ß ß Energy Energy (MeV)(MeV)

GammGamma a

Energy Energy (MeV)(MeV)

Max. Max. Range Range

mmmm

89StSt Chloride

50.5 1.46 - 7.0

153SmSm EDTMP 1.9 0.81 0.103 2.5

186ReRe HEDP 3.8 1.07 0.137 4.5

188188ReRe HEDP 0.7 2.12 0.155 11.0

• 40-90% Effective Pain Relief.• Onset of Action: 1 week.• Duration of Response: 18 months.• Repeated Doses.• Potentiation of Analgesic Effect When

Combined with Cth (Platinum).• Tumoricidal Effect (-- spots in B/S)• Thrombocytopenia & Neutropenia.

Radioactive Isotopes:

Inhibit osteoclast formation and migration, and osteolytic activity; promote apoptosis

Local release during bone resorption

Concentrated in newly mineralizing bone and under osteoclasts

Modulate signaling from osteoblasts to osteoclasts

Mechanism of action of bisphosphonatesMechanism of action of bisphosphonatesMechanism of action of bisphosphonatesMechanism of action of bisphosphonates

Osteoclastic activationOsteoclastic activationOsteoclastic activationOsteoclastic activation

Receptor expressed on mature Receptor expressed on mature Osteoclasts and precursorsOsteoclasts and precursors

Cytokine expressed by osteoblasts, stromal Cytokine expressed by osteoblasts, stromal cells, some tumour cells and myeloma cells cells, some tumour cells and myeloma cells leading to leading to

osteoclastic activationosteoclastic activation

Natural antagonist of RANK ligand secreted by Natural antagonist of RANK ligand secreted by bone lining cells (Decoy/scavenger bone lining cells (Decoy/scavenger receptor)receptor)

Receptor expressed on mature Receptor expressed on mature Osteoclasts and precursorsOsteoclasts and precursors

Cytokine expressed by osteoblasts, stromal Cytokine expressed by osteoblasts, stromal cells, some tumour cells and myeloma cells cells, some tumour cells and myeloma cells leading to leading to

osteoclastic activationosteoclastic activation

Natural antagonist of RANK ligand secreted by Natural antagonist of RANK ligand secreted by bone lining cells (Decoy/scavenger bone lining cells (Decoy/scavenger receptor)receptor)

RANKRANK

RANK Ligand (= Trance)RANK Ligand (= Trance)

OsteoprotegerinOsteoprotegerin

New molecular insightsNew molecular insightsRANK/RANKL/OsteoprotogerinRANK/RANKL/Osteoprotogerin

(members of TNF family)(members of TNF family)

New molecular insightsNew molecular insightsRANK/RANKL/OsteoprotogerinRANK/RANKL/Osteoprotogerin

(members of TNF family)(members of TNF family)

Bisphosphonates:

• All bind with high affinity to hydroxyapetit crystals in bones “Half life in bones = 300 days”.

• Inhibit physiologic and pathologic bone resorption.• All have common final effect:

1. Inhibition of Osteoclastic Function

Reduced Bone Turnover & Resorption.

2. Increased Production of Osteoprotegerin by Osteoblasts.

•Theriault ,Expert Rev.Anticancer Ther.,2003 •Theriault ,Expert Rev.Anticancer Ther.,2003

The Goal of Bisphosphonate Therapy

• Preserve patient’s functional independence and quality of life by . . .– Preventing skeletal-related events (SREs)

• Prevent first and subsequent SREs• Delay the onset of the first SRE

– Palliating and controlling bone pain

• Reduce the need for analgesics and palliative radiotherapy

P

P

OH

OH

OHO

OH

OHO

N

etidronateetidronate

Classes of BisphosphonatesClasses of Bisphosphonates1,21,2Classes of BisphosphonatesClasses of Bisphosphonates1,21,2

pamidronatepamidronatezoledronic zoledronic acidacid

1. Thurlimann B. Bisphosphonates in Clinical Oncology: Focus on Pamidronate. 1999.

2. Fleisch H. Endocr Rev. 1998.

HO

HO OHOH

OH

O

O

P

P

CH3

HO

HO OHOH

OH

O

O

P

P

CH3

OH

OH

OH

OHO

OP

P

Cl

Cl OH

OH

OH

OHO

OP

P

Cl

Cl

HOOH

OH

OHO

OP

PSCl

HOOH

OH

OHO

OP

PSCl

HO

O

OP

POH

OHOH

OHH2N

HO

O

OP

POH

OHOH

OHH2N

OHOH

OHO

ON P

P

OH

HO

CH3

CH3

OHOH

OHO

ON P

P

OH

HO

CH3

CH3

H2NHO

HO

OH

OH

OH

O

O

P

PH2N

HO

HO

OH

OH

OH

O

O

P

P

NN

O

O

P

P

HO OH

OH

OH

OHNN

O

O

P

P

HO OH

OH

OH

OH

clodronateclodronate

tiludronatetiludronate

alendronatealendronate

ibandronateibandronate

risedronaterisedronate

Bisphosphonate Indications—Focus on BCBisphosphonate Indications—Focus on BC

IndicationIndication

Prevention of SREsPrevention of SREs

HCMHCMMultiple Multiple myelomamyeloma

Breast Breast cancercancer

Prostate Prostate cancercanceraa

Other solidOther solidtumorstumors

Clodronate Clodronate (oral)(oral) Pamidronate Pamidronate (IV)(IV) Zoledronic acid Zoledronic acid (IV)(IV) Ibandronate Ibandronate (oral and IV)(oral and IV)

= European Registration = Worldwide Registration

BC, breast cancer; SRE, skeletal-related event; HCM, hypercalcemia of malignancy; IV, intravenous.a In the United States, prostate cancer must have progressed despite hormone therapy.Prescribing information for pamidronate and zoledronic acid is available at: www.pamidronate.com and www.zometa.com. Further information for clodronate and ibandronate is available at www.bayer.nl/ebbsc/cms/nl/healthcare/bayer_schering_pharma and www.roche.com.

Oral clodronate 1,600 mgOral clodronate 1,600 mg(Kristensen 1999)(Kristensen 1999) 31%31%

(Paterson 1993)(Paterson 1993) 17%17%

(Tubiana-Hulin 2001)(Tubiana-Hulin 2001) 8%8%

PP value valueRiskRisk

reductionreduction

00 0.20.2 0.40.4 0.60.6 0.80.8 11 1.21.2 1.41.4 1.61.6 1.81.8 22

ZOL 4 mgZOL 4 mg 41%41% .001 .001(Kohno 2005)(Kohno 2005)

0.590.59

PAM 90 mgPAM 90 mg 23%23% < .001< .001(Aredia study 18 and 19)(Aredia study 18 and 19)

0.770.77

Ibandronate 6 mgIbandronate 6 mg 18%18% .04 .04(Body 2003)(Body 2003)

0.820.82

Ibandronate 50 mgIbandronate 50 mg 14%14% .08 .08(Body 2004)(Body 2004)

0.860.86

0.690.69

0.830.83

0.920.92

.03 (pooled).03 (pooled)

Cochrane database comparing placebo-controlled trials in breast cancer setting.Cochrane database comparing placebo-controlled trials in breast cancer setting.ZOL, zoledronic acid; PAM, pamidronate.Adapted from Pavlakis N, et al. Cochrane Database Syst Rev. 2005:CDC003474.

SRE Risk Reduction in BC—Results From an SRE Risk Reduction in BC—Results From an Independent Meta-analysisIndependent Meta-analysis

30.7

25.4

8.8

03.5 2.6

52.2

38.9

17.7

0.8

11.58.8

0

10

20

30

40

50

60

All SREs PathologicFractures

Radiation toBone

Surgery toBone

SCC HCM

Pat

ien

ts (

%)

Zoledronic Acid Reduced All Types of SREsZoledronic Acid Reduced All Types of SREsat 1 Year in Patients With Bone Metastases From BCat 1 Year in Patients With Bone Metastases From BC

SRE, skeletal-related event; BC, breast cancer; SCC, spinal cord compression; HCM, hypercalcemia of malignancy.

Adapted from Kohno N, et al. J Clin Oncol. 2005;23(15):3314-3321.

Zoledronic acid 4 mg (n = 114) Placebo (n = 113)P = .001

Breast Cancer—Benefits of ZOL Are Beyond Those Breast Cancer—Benefits of ZOL Are Beyond Those of PAM and Continue After the Onset of SREsof PAM and Continue After the Onset of SREsBreast Cancer—Benefits of ZOL Are Beyond Those Breast Cancer—Benefits of ZOL Are Beyond Those of PAM and Continue After the Onset of SREsof PAM and Continue After the Onset of SREs

Riskreduction

Relative risk

In favor of zoledronic acidIn favor of zoledronic acid In favor of pamidronateIn favor of pamidronate

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

P value

All SREs(n = 766)

.0150.711

29%

.0450.690

31%Excluding first SRE

• ZOL reduced the risk of experiencing any SRE on study or after the first SRE by ~30% vs PAMa in a large, double-blind, phase III trial

a As determined by Andersen-Gill multiple event analysis.ZOL, zoledronic acid (4 mg q 3-4 wks); PAM, pamidronate (90 mg q 3-4 wks); SRE, skeletal-related event.Adapted from Zheng M, et al. Poster presented at: 9th International Conference on Primary Therapy of Early Breast Cancer; January 26-29, 2005; St. Gallen, Switzerland. Poster 104.

Zoledronic Acid Significantly Reduces Mean Zoledronic Acid Significantly Reduces Mean Composite Brief Pain Inventory (BPI) ScoreComposite Brief Pain Inventory (BPI) Score

Patients continued to receive chemotherapy or standard treatment for breast cancer.IV, intravenous.

1. Lipton A, et al. Cancer. 2000;88(5):1082-1090; 2. Body J-J, et al. Ann Oncol. 2003;14(9):1399-1405.Reprinted from Kohno N, et al. J Clin Oncol. 2005;23(15):3314-3321.

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

BP

I M

ean

Ch

ang

e F

rom

Bas

elin

e

2 4 8 12 16 20 24 28 32 36 40 44 48 52

Time on Study, Weeks

* * ** * *

*

**

**

0

* *

De

crea

sed

pa

in

De

crea

sed

pa

in

Incre

ase

d p

ain

In

crea

sed

pa

in

*P < .05

• Similar results observed in trials of IV pamidronate (90 mg q 3-4 wk)1 and IV ibandronate (6 mg q 3-4 wk)2

ZOL 4 mg q 4 wk

Placebo

0

1

2

3

4

5

6

7

8

9

10

Me

an

Ch

an

ge

fro

m B

as

elin

e in

EO

RT

C

QL

Q C

30

sc

ore

Global Health PhysicalFunctioning

RoleFunctioning

SocialFunctioning

EmotionalFunctioning

* *

**

ZOL Significantly Improves Most Quality-of-Life ZOL Significantly Improves Most Quality-of-Life Measures in Patients With Bone Metastases From BCMeasures in Patients With Bone Metastases From BC

Graph depicts overall mean change from baseline quality-of-life scores reported at final visit after 9 infusions.ZOL, zoledronic acid; BC, breast cancer; EORTC QLQ, European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire.*P < 0.05 compared with baseline values.

Reprinted from Wardley A, et al. Br J Cancer. 2005;92(10):1869-1876.

• Reduces the viability of human breast cancer cells Reduces the viability of human breast cancer cells in vitroin vitro11

1. Senaratne SG, et al. Br J Cancer. 2000.

* These points have reached statistical significance.

Zoledronic Acid—Anti-tumour PotentialZoledronic Acid—Anti-tumour PotentialZoledronic Acid—Anti-tumour PotentialZoledronic Acid—Anti-tumour Potential

Cell

via

bili

ty (

% c

on

trol)

aft

er

Cell

via

bili

ty (

% c

on

trol)

aft

er

4 d

ays

of

treatm

en

t4

days

of

treatm

en

t

Bisphosphonate concentration (µM)Bisphosphonate concentration (µM)

11 1010 100100 10001000

00

5050

100100

zoledronic acidzoledronic acid

pamidronatepamidronate

clodronateclodronate

*

* ** *

*

*

*

*

*

*

*

Ovarian Suppression Plus TAM or ANA +/- ZA: Ovarian Suppression Plus TAM or ANA +/- ZA: ABCSG-12 Trial DesignABCSG-12 Trial Design

Gnant M, et al. ASCO 2008. Abstract LBA4.

Accrual 1999-2006

1,803 premenopausal breast cancer patients

Endocrine-responsive (ER and/or PR positive)

Stage I & II, <10 positive nodes

No chemotherapy except neoadjuvant

Treatment duration: 3 years

Tamoxifen20 mg/d

Anastrozole 1 mg/d

Tamoxifen 20 mg/d +Zoledronic acid 4 mg Q6Mos

Anastrozole 1 mg/d +Zoledronic acid 4 mg Q6Mos

Surgery (+RT)

Randomize 1:1:1:1

Goserelin 3.6 mg Q28D

Disease-Free Survival: ZA Vs No ZADisease-Free Survival: ZA Vs No ZA

Gnant M, et al. ASCO 2008. Abstract LBA4.

Time since randomization, mosNumber at riskNo ZA

ZA 899904 838

851 744735 565

573441434 270

265 161131

6059

Dis

eas

e-fr

ee s

urv

ival

, %

0

20

40

60

80

100

90

70

50

30

10

0 12 24 36 48 60 72 84

ZA

No ZA

54

83

No. of Events Hazard ratio (95% CI) events vs no ZA, P Value

0.643 (0.46 to 0.91), P = .011

0

20

40

60

80

100

90

70

50

30

10

0 12 24 36 48 60 72 84

Secondary Endpoints: ZA Vs No ZASecondary Endpoints: ZA Vs No ZA

Gnant M, et al. ASCO 2008. Abstract LBA4.

Time since randomization, months

Ov

era

ll s

urv

iva

l, %

No. of Events Hazard ratio (95 % CI)

ZA 16 0.595 (0.32 to 1.11), P = .101

No ZA 26

events vs No ZA, P Value

899

904 838

851 744

735 565

573

441

434 270

265 161

131

60

59

OS

899

904 832

846 730

714 538

555

403

414 257

241 145

123

47

54

Number at riskNo ZA

ZA

0

20

40

60

80

100

90

70

50

30

10

Time since randomization, months

Re

cu

rre

nc

e-f

ree

su

rviv

al,

%

0 12 24 36 48 60 72 84

No. of Events Hazard ratio (95 % CI)

ZA 54 0.653 (0.46 to 0.92), P = .014

No ZA 82

events vs No ZA, P Value

RFS

ZA-Mediated Mechanisms Contributing to ZA-Mediated Mechanisms Contributing to Improved Disease-Free SurvivalImproved Disease-Free Survival

Gnant M, et al. ASCO 2008. Abstract LBA4.

Direct antitumor activity Immune activation

Bone mets recurrence

Non-bone mets recurrence

Contralateralrecurrence

Locoregionalmets recurrence

Disease-free survival

ZA-Mediated Mechanisms Contributing to ZA-Mediated Mechanisms Contributing to Improved Disease-Free SurvivalImproved Disease-Free Survival

Gnant M, et al. ASCO 2008. Abstract LBA4.

• Chemo-induced OFChemo-induced OF– 50-70% of women50-70% of women

• Increasing ageIncreasing age• Distinct from Distinct from

amenorrhea that amenorrhea that reverses reverses

• No standard definitionNo standard definition

• Bone loss due to Bone loss due to estrogen deprivationestrogen deprivation

Shapiro CL, et al. ASCO 2008. Abstract 512.

None

Horm OnlyChem Only

Both

0.0

0.2

0.4

0.6

0.8

1.0

25 40 50 55

Age at DiagnosisE

stim

ated

Pro

bab

ility

453530

CALGB 79809 Study Rationale: Chemotherapy CALGB 79809 Study Rationale: Chemotherapy Decreases Bone DensityDecreases Bone Density

Effect of Zoledronic Acid on BMD: CALGB 79809 Effect of Zoledronic Acid on BMD: CALGB 79809 Trial DesignTrial Design

ZA 4 mg IV Q3MosCalcium/Vit D

ZA 4 mg IV Q3MosCalcium/Vit D

Calcium/ Vit D

Calcium/Vit D

Mos 1 12 24 36

“Early”

“Late”

StratificationsStageTamoxifen

Shapiro CL, et al. ASCO 2008. Abstract 512.

Premenopausal women

≤40 yrs; stages I-III;

last menstrual period ≤ 6 mos prior to entry

Randomize

Shapiro CL, et al. ASCO 2008. Abstract 512.

Control-TAM

9.5

4.3

-12

-10

-8

-6

-4

-2

0

2

4

ZA-TAM

ZA

Control

2.0 2.2

% ∆

CALGB 79809 Mean Percent Change in BMD +/- CALGB 79809 Mean Percent Change in BMD +/- Tamoxifen at 12 MonthsTamoxifen at 12 Months

Distant Disease-Free Survival by Vitamin D Level Distant Disease-Free Survival by Vitamin D Level in EBCin EBC

DeficienDeficientt

< 50 < 50 nmol/Lnmol/L

n = 192n = 192

InsufficiInsufficientent

≥ ≥ 50-72 50-72 nmol/Lnmol/L

n = 197n = 197

SufficieSufficientnt

72 72 nmol/Lnmol/L

nn

n = 123n = 123

HRHR

(95% (95% CI)CI)

1.941.94

(1.16-(1.16-3.25)3.25)

1.371.37

(0.80-(0.80-2.33)2.33)

1.01.0

5 Yr5 Yr 82%82% 85%85% 88%88%

10 Yr10 Yr 69%69% 79%79% 83%83%

Goodwin PJ, et al. ASCO 2008. Abstract 511.

Distant Disease-Free Survival

Pro

po

rtio

n d

ista

nt

dis

ease

-fre

e

Yrs since diagnosis

0 2 4 6 8 10 120.0

0.2

0.4

0.6

0.8

1.0

DeficientInsufficient

Sufficient

P = .02

ZO-FAST DesignZO-FAST Design

1065 pts in 128 centers in Asia Pacific, Central and South America, Egypt, and Europe

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

Stratification:Adjuvant CTT scoreEstablished vs recent postmenopausal

Letrozole 2.5 mg/d

Add zoledronic acid if:BMD T score below 2 or clinical

or asymptomatic fracture at 36 months

5 years

Zoledronic acid 4 mg IV q6mo

Letrozole 2.5 mg/d

IMMEDIATE

DELAYED†

RANDOMI ZE

ZO-FAST Study Objectives

• Primary objective – Percent change in lumbar spine (L2-L4) BMD at

12 m

• Key secondary objectives – Incidence of fractures at 3 years – Time to disease recurrence/relapse– Overall survival– General safety of the two treatment arms

ZO-FAST Primary EndpointZO-FAST Primary EndpointMean Change in BMD from BaselineMean Change in BMD from Baseline

Lumbar SpineLumbar Spine HipHipP<0.0001P<0.0001 P<0.0001P<0.0001

Mean Percent Change in BMD from Baseline to 36 MonthsMean Percent Change in BMD from Baseline to 36 Months

-3.52

1.894.39

-4.9

-6

-4

-2

0

2

4

6

Immediate

Delayed

BM

D c

hang

e (%

)B

MD

cha

nge

(%)

-3.52

1.89

4.39

-4.9

Shift in LS T Score Distribution at 36 Months in Patients with Baseline BMD between -1 and -2 (Osteopenic)

Immediate(N=146)

Delayed(N=139)

Pat

ien

ts (

%)

P<0.001

44.5 % in the immediate arm and 38.1 % in the delayed arm had missing data due to early discontinuations at month 36 or missing central reader BMD values at baseline

0

20

40

60

80

100 T Score > -1 T Score -1 to -2 T Score < -2

All Fractures at 36 MonthsAll Fractures at 36 Months

Immediate groupImmediate group:: 26 patients (5.0%)*26 patients (5.0%)* Clinical: 24 (4.6%)Clinical: 24 (4.6%) Radiological Fx detected at Month 36 X-ray: 3 (0.6%)Radiological Fx detected at Month 36 X-ray: 3 (0.6%)

Delayed groupDelayed group: : 32 patients (6.0%)^32 patients (6.0%)^ Clinical: 26 (4.9%)Clinical: 26 (4.9%) Radiological Fx detected at Month 36 X-ray: 8 (1.5%)Radiological Fx detected at Month 36 X-ray: 8 (1.5%)

Fisher’s exact test for difference between arms; p=0.502

*Patient 661-00002 had both a clinical and radiographic fx^Patients 0152-00009 and Patient 0304-00022 had both a clinical and radiographic fx

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30 35

Dis

ease

-Fre

e S

urv

ival

(%

)

Study Month

Upfront ZOL

Delayed ZOL

ZO-FAST 36-mo : Disease-Free Survival

Upfront zoledronic acid significantly

decrease the risk of DFS events by 41%

(HR= 0.588, P= 0.0314)

Sites of Disease Recurrence at Month 36Sites of Disease Recurrence at Month 36

ImmediateImmediate

N=532N=532

No. of Patients (%)No. of Patients (%)

Delayed Delayed

N=532N=532

No. of Patients (%)No. of Patients (%)

LocalLocal 2 (0.4)2 (0.4) 10 (1.9)10 (1.9)

Distant*Distant*

BoneBone

BrainBrain

Lymph nodeLymph node

LiverLiver

LungLung

SkinSkin

OtherOther

20 (3.8)20 (3.8)

9 (1.7)9 (1.7)

4 (0.8)4 (0.8)

5 (0.9)5 (0.9)

5 (0.9)5 (0.9)

4 (0.8)4 (0.8)

00

7 (1.3)7 (1.3)

30 (5.6)30 (5.6)

17 (3.2)17 (3.2)

3 (0.6)3 (0.6)

3 (0.6)3 (0.6)

3 (0.6)3 (0.6)

6 (1.1)6 (1.1)

7 (1.3)7 (1.3)

12 (2.3)12 (2.3)

*Patient could have multiple sites reported

ZO-FAST (36 mo) : Recurrences at the Breast

102

30

20

3

5

0

5

10

15

20

25

30

35

40

45

50

Immediate Delayed

Local Distant Lymph Node

No

of P

atie

nts

(%)

(n = 532)(n = 532)

210

17

9

4

3

5

33

54

6

7

07

19

0

10

20

30

40

50

60

70

80

Immediate Delayed

Local Bone

Brain Lymph Node

Liver Lung

Skin Other

No

of P

atie

nts

(%)

(n = 532)(n = 532)

ZO-FAST (36 mo) : Sites of Disease Recurrences

AEs Occurring in > 10% of PatientsAEs Occurring in > 10% of Patients

AEAE

No. of Patients (%)No. of Patients (%)

Immediate Immediate

(N=524)(N=524)

Delayed Delayed

(N=536)(N=536)

ArthralgiaArthralgia 236 (45.1)236 (45.1) 228 (42.6)228 (42.6)

Hot flashesHot flashes 140 (26.8)140 (26.8) 153 (28.6)153 (28.6)

Fatigue Fatigue 90 (17.1)90 (17.1) 84 (15.7)84 (15.7)

Bone pain Bone pain 85 (16.3)85 (16.3) 59 (11.0)59 (11.0)

PyrexiaPyrexia 78 (14.9)78 (14.9) 16 (3.0)16 (3.0)

HeadacheHeadache 70 (13.4)70 (13.4) 53 (9.9)53 (9.9)

MyalgiaMyalgia 66 (12.6)66 (12.6) 67 (12.5)67 (12.5)

Pain in extremityPain in extremity 59 (11.3)59 (11.3) 63 (11.8)63 (11.8)

Back painBack pain 57 (10.9)57 (10.9) 67 (12.5)67 (12.5)

Weight increaseWeight increase 39 (7.4)39 (7.4) 54 (10.0)54 (10.0)

Safety Results

Renal disordersNo cases of renal impairment were related to study

drug administrationImmediate: 1 patient (not related, received 3 doses of

zoledronic acid prior to onset)Delayed: 3 patients (none had received any doses of

zoledronic acid)

Osteonecrosis of the jaw Immediate: 1 patient (0.2%)

(mandibular involvement; received 6 doses of zoledronic acid prior to onset)

Delayed: none

Keep in Mind:

• Immediate use of zoledronic acid (4 mg IV q6mo) prevents bone loss in women with early stage BC receiving adjuvant letrozole

• The difference in the number of fractures with immediate use of zoledronic acid versus delayed is not significant

• Disease free survival was significantly improved with the use of zoledronic acid upfront

• The safety results were as expected and consistent with the known safety profiles of each drug

• These results add to the growing body of evidence that zoledronic acid can provide anti-tumor effects and may prolong DFS in patients with early BC

Bisphosphonate Indications—Focus on PCBisphosphonate Indications—Focus on PC

IndicationIndication

Prevention of SREsPrevention of SREs

HCMHCMMultiple Multiple myelomamyeloma

Breast Breast cancercancer

Prostate Prostate cancercanceraa

Other Other solidsolid

tumorstumors

Clodronate Clodronate (oral)(oral) Pamidronate Pamidronate (IV)(IV) Zoledronic acid Zoledronic acid (IV)(IV) Ibandronate Ibandronate (oral and IV)(oral and IV)

= European Registration = Worldwide RegistrationPC, prostate cancer; SREs, skeletal-related events; HCM, hypercalcemia of malignancy; IV, intravenous.a In the United States, prostate cancer must have progressed despite hormone therapy.Prescribing information for pamidronate and zoledronic acid is available at: www.pamidronate.com and www.zometa.com. Further information for clodronate and ibandronate is available at www.bayer.nl/ebbsc/cms/nl/healthcare/bayer_schering_pharma and www.roche.com.

Test drug N Results Reference

Etidronate 57 Transient pain reduction Smith 1989, J Urol

Clodronate 75 Only transient Elomaa 1992,symptomatic benefit Int Urol Nephrol

Placebo-Controlled Studies

Clodronate 311 No significant benefit Dearnaley 2003, JNCI

Pamidronate 378 No significant benefit Small 2003, JCO

Clodronate 209 No significant benefit Ernst 2003, JCO

Zoledronic acid 643 Significant objective and Saad 2002-4, JNCIdurable benefits

Bisphosphonates in the TreatmentBisphosphonates in the Treatmentof Bone Metastases From Prostate Cancerof Bone Metastases From Prostate Cancer

Zoledronic Acid Reduced All Types of SREs at 2 Years Zoledronic Acid Reduced All Types of SREs at 2 Years in Patients With Bone Metastases From PCin Patients With Bone Metastases From PC

SRE, skeletal-related event; PC, prostate cancer; HCM, hypercalcemia of malignancy.

Adapted from Saad F, et al. Poster presented at: 19th EAU Congress; March 24-27, 2004; Vienna, Austria. Poster 615.

P = .028

38

26

17

46

20

49

33

25

8 74

10

10

20

30

40

50

60

Any SRE Radiationto Bone

Fractures Spinal CordCompression

Change inAntineoplastic

Therapy

Surgeryto Bone

HCM

Zoledronic acid 4 mg (n = 214) Placebo (n = 208)

Pat

ien

ts W

ith

SR

E,

%

Time on Study, Months

Mea

n C

han

ge

Fro

m B

asel

ine

in B

PI P

ain

Sco

re

Meann baseline BPI

Zoledronic acid 4 mg 214 2.0

Placebo 208 2.1

0

0.2

0.4

0.6

0.8

1

1.2

0 3 6 9 12 15 18 21 24

*

* *

*

Zoledronic Acid Resulted in Better Control of Pain Zoledronic Acid Resulted in Better Control of Pain Versus Placebo Over 2 Years in Patients With PCVersus Placebo Over 2 Years in Patients With PC

PC, prostate cancer; BPI, Brief Pain Inventory.*P < .05.

With Perrmission from Saad F, et al. BJU Int. 2006;96:964-969.

Prostate Cancer—ZOL Reduced the RiskProstate Cancer—ZOL Reduced the Riskof SREs Regardless of Prior SRE Historyof SREs Regardless of Prior SRE History

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2

.028

P value

0.603

0.670.027No prior SRE

40%

33%

Prior SRE

Risk ratio (zoledronic acid 4 mg versus placebo)

In favor of zoledronic acid In favor of placebo

Riskreduction

.0020.640

36%Overall trialpopulation

ZOL, zoledronic acid; SRE, skeletal-related event.

Data from Saad F, et al. J Natl Cancer Inst. 2004;96(11):879-882.

Before study entry

Zoledronic Acid Significantly Reduced the Risk Zoledronic Acid Significantly Reduced the Risk of SREs Across All Tumor Types Versus Placeboof SREs Across All Tumor Types Versus Placebo

SRE, skeletal-related event; RCC, renal cell carcinoma; ZOL, zoledronic acid.

1. Kohno N, et al. J Clin Oncol. 2005;23(15):3314-332; 2. Saad F, et al. J Natl Cancer Inst. 2004;96(11):879-882;3. Rosen LS, et al. Cancer. 2004;100(12):2613-2621; 4. Lipton A, et al. Cancer. 2003;98(5):962-969.

Risk Risk reductionreduction

PP valuevalue

41%41% .019.019

36%36% .002.002

31%31% .003.003

32%32% .016.016

58%58% .010.010

In favor of ZOL In favor of placebo

Prostate2

Solid tumors3

Lung cancer3

RCC4

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2Relative risk of SRE

Breast1