established benefits of bisphosphonates; focus on breast and prostate cancers
DESCRIPTION
Established Benefits of 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, 13 th ,2009”. Bone as a Dynamic Structure: Normal Turnover. RANKL. - PowerPoint PPT PresentationTRANSCRIPT
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
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bla
sti
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bla
sti
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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