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ZOLEDRONIC ACID(ZOMETAR)
FOR BONE METASTASES OFSOLID TUMOURS
By Joan Fabbro
BSc Pharm
BCCA- Fraser Valley Center
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Outline
•Bone metastases and cancer
•Bisphoshphonates in cancer
•Zoledronic acid
Hypercalcemia
Bone metastases
•Cost comparison
•Summary
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Bone Remodelling in Healthy
vs. Cancer Patients osteoclast = bone resorbing cells => osteolysis
osteoblast = bone forming cells => osteogenesis
Healthy bone “remodelling”: osteoclast = osteoblast activity
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Cancer Bone “remodelling”
Osteolytic
Osteoclast > Osteoblast Net bone resorbtion
Release of growth factors => tumour growth
Release mediators => stimulate osteoclast activity
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Osteogenic
Osteoblast > Osteoclast
Net bone formation
Osteoclast activity
osteolysis
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The Impact of Metastatic Bone Disease Advanced
Breast
Cancer
Multiple
Myeloma
Prostate
Cancer
Lung
Cancer
Renal
Cancer
%
Incidence
of Bone
Metastases
65 – 75 95 - 100 65 -75 30 - 40 25 - 30
5 yr
survival
median
survival
20%
24 months
10 %
20 months
25 %
40 months
<2%
to<5%
< 6 months
**
<9 months
ClassificationMixed
Osteolytic
>
Osteogenic
Mostly
Osteolytic
Mixed
Osteogenic
>>
Osteolytic
Mostly
Osteolytic
Mostly
Osteolytic
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Bisphosphonates in cancer
1) hypercalcemia
2) bone metstreatment
prevention-mixed evidence
Available in Canada :
Clodronate(BonefosR )…oral/IV
Pamidronate(ArediaR
)…IV Alendronate(FosamaxR )..oral
Etidronate(DidronelR , DidrocalR )..oral
Risendronate(ActonelR )….oral
Zoledronic Acid(ZometaR )…IV
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Bisphophonates - Mechanism of Action
•clinical benefit takes several days
vs. osteoclast:
•inhibit hyperactivity
•inhibit maturation
•inhibit attachment to bone site
•decrease cytokine production
vs. tumour activity:•inhibit tumour cell invasion, proliferation &
adhesion to bone
•induce apoptosis
•reduce tumour cell proliferation
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Properties of bisphosphonates
Absorption
• Low oral bioavailability
• dose = side effects
• Food
Elimination
• renal
• bound to bone
Side Effects
• flu-like symptoms
• bone pain• GI complaints
• dyspnea
• lower limb edema
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Zoledronic Acid
• New highly potent 3rd generation
bisphosphonate
• Heterocyclic nitrogen-containingmolecule with:
– A core bisphosphonate moiety
– An imidazole-ring side chaincontaining 2 critically positioned
nitrogen atoms
Green JR, et al. J Bone Miner Res . 1994;9:745-751.
Green JR, et al. Pharmacol Toxicol . 1997;80:225-230.
C
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C
o m p l e t e r e s p o n d e r s ( % )
Efficacy in Hypercalcaemia of
Malignancy
0
20
40
60
80
100
Day 0 Day 4 Day 7 Day 10
Zoledronic Acid 4mg
Pamidronate 90 mg (n = 99)
87%P = .015*
82.6%P = .005*
45%
33%
64%70%
C
Major, P et al. JCO ,2001;19: 558-567
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Phase III Trials With Zoledronic Acid in Patients With Metastatic
Bone Disease
•Zoledronic Acid4mg, 8mg or
placebo
•Prostate cancer with bonemetastases
stratification: Prostate Ca - no
mets; prostate Ca with mets
•Randomized, double-blind, placebo control
•Duration: 15 months
•039
•10 efficacy parameter: proportion of patients with at least one skeletal-related event (SRE)
• Adjustments: zoledronic acid infused over 15 min. 8mg dose => 4mg for renal complications
•Zoledronic Acid
4mg, 8mg or
placebo
•Lung and other cancers with bonemetastases
(excluding breast or prostate)
stratification: lung Ca; „other solid
tumours‟
•Randomized, double-
blind, placebo control
•Duration: 9 months
•011
•Zoledronic Acid
4mg, 8mg or
pamidronate 90mg
•Multiple myeloma or breast
cancer with bone metastases
stratification: myeloma;
breast Ca-chemo; breast Ca-hormonal
•Randomized, double-
blind, non-inferiority
•Duration: 12 months
•010
•Treatments•Patients•Design•Protocol
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Protocol 010
Completed trial
N = 353
Efficacy analysis: 561Safety analysis: 561
Zoledronic Acid 4 mg
N = 564
Completed trial
N = 313
Efficacy analysis: 524Safety analysis: 524
Zoledronic Acid 8/4 mg
N = 526
Completed trial
N = 338
Efficacy analysis: 555Safety analysis: 555
Pamidronate 90 mg
N = 558
RandomizedN = 1648
Rosen L S, et al. Zoledronic Acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesiona of multiplemyeloma: a phase III, double-blind commparative trial. Cancer J.2001; 7: 377-387
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Protocol 010
• Multicenter, double-blind, randomized, controlled,
phase III
• “inferiority” trial
• Zoledronic Acid 4mg, 8mg IV vs. pamidronate 90mg IV q 3-4 weeks x 12months
• multiple myeloma, breast Ca (chemo, hormonal)
• pamidronate 90 mg IV - standard• study objective: zoledronic acid non-inferior vs.
pamidronate preventing SRE
• 60% completed trial
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Breast Cancer and Multiple Myeloma
proportion (%) of patients in protocol
010 With an SRE
44%46%
0
10
20
30
40
50
P e r
c e n t o f p a t i e n t s
Zoledronic Acid4mgPamidronate90 mg
N = 561 555
Zoledronic Acid 4 mg versus pamidronate 90 mg: 95% CI ( –7.9%, 3.7%). The noninferiority
criterion, the upper boundary of the 95% CI, is below 8%
p= 0.052
14
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Protocol 010: Breast Cancer and
Multiple Myeloma time to first SRE
0
10
20
30
40
5060
70
80
90
100
0 60 120 180 240 300 360 420
Time after start of study drug, days
P e r c e n t w i t h o
u t e v e n t
Zoledronic Acid 4 mg 373
Pamidronate 90 mg 363
0 1 0 P T F 9 . 2 - 1 p 4 ; C S R 0
1 0 T 9 - 3
14
Median time,
days
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Study 010 Comments (at 25 months)
• 12 month extension N=606 (<40%) and >50% completion
• % patients - one SRE (not HCM); Z4mg 47%;Pam90mg 51%
• median time to first SRE - Z4mg 376 days;Pam90mg 356 days
• confirmed long-term safety, efficacy - ZoledronicAcid 4mg;
Pamidronate 90 mg
• subset group (breast Ca-hormonal) - further trials
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Protocol 011
Intent-to-treatN = 257
Zoledronic Acid 4 mgN = 257
Not included in analysis
Zoledronic Acid 8/4 mgN = 266
Intent-to -treatN = 250
PlaceboN = 250
Randomized
N = 773
Rosen L, Gordon D, Tchekmedyian S, et al. Zoledronic Acid versus placebo in the treatment of skeletal metastases in patients with lung
cancer and other solid tumours: A phase III, double-blind, randomized trial - the Zoledronic acid lung cancer and other solid tumours study group. JCO 21: 3150 - 3157, 2003.
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Protocol 011
• Randomized, double-blind, multicenter, phase III
• placebo control trial
• zoledronic Acid 4mg, 8mg IV vs. placebo
q3weeks (daily calcium/vit D) x 9 months• bone metastases from solid tumours
• not breast or prostate
• study objective: efficacy- zoledronic acid+chemovs. chemo preventing SRE
• 25 % completed trial
12
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Protocol 011: Solid tumors (not PC &BC)
proportion (%) of patients with an SRE
time to first SRE
38
44
30
40
50
P e r c e n t o f p a t i e n
t s
Zoledronic Acid
Placebo
N = 257 N = 250
12
P = .127
0
10
2030
405060
70
8090
100
0 30 60 90 120 150 180 210 240Time after start of study drug, days
P e r c e n t w i t h o
u t e v e n t
Median time,
days P -value
Zoledronic Acid 4 mg 230 .023
Placebo 163
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Protocol 039
Completed Trial
N = 81
Efficacy analysis: 214
Safety analysis: 214
Zoledronic Acid 4mg
N = 214
Completed Trial
N = 62
Efficacy analysis : 221
Safety analysis: 218
Zoledronic Acid 8/4mg
N = 221
Completed Trial
N = 65
Efficacy analysis: 208
Safety analysis: 208
Placebo
N = 208
Randomized
N = 643
Saad F, et al. Journal of the National Cancer Institute. 2002; 94 : 1458 - 1468.
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Protocol 039
• Randomized, double-blind, multicenter, phase III• placebo control trial
• zoledronic acid 4mg, 8mg IV vs. placebo q 3
weeks (daily calcium/vit D)• 15 months
• prostate cancer - metastatic, PSA, hormonal
treatment
• study objective: efficacy zoledronic acid+chemo
vs chemo preventing SRE
• 40 % completed trial
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Proportion of protocol 039 patients
with skeletal-related events (SRE)
All patients
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
p = 0.021
P r o p o r t i o n o f p a
t i e n t s
Zoledronic Acid 4 mg
Placebo
Saad F, et al. Journal of the National Cancer Institute. 2002; 94 : 1458 - 1468.
33.2% 44.2%
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Protocol 039: Time to first skeletal-
related event
100
90
80
7060
50
40
30
20
10
0
0 50 100 150 200 250 300 350 400 450 500
550
P e r c e n t o f p a t i e
n t s
w i t h o u t e v e n
t
Time after start of therapy (days)
NR = not reached
P-value = 0.011
Median Time:
Zoledronic Acid 4 mg=NR
Placebo = 321 days
Saad F, et al. Journal of the National Cancer Institute. 2002
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Subset Analysis of Renal Cancer Patients from
Study 011
• N= 74 pt
• 10 endpoint - 74% placebo vs 37% Zoledronic Acid
• the time to SRE & morbidity rate - improved significantly
on the zoledronic acid 4mg arm.
• bone pain - placebo group
• subset group = lower numbers = lower power
• warrants investigation
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Cost Comparison Pamidronate vs Zoledronic Acid
Pamidronate 90 mg (monthly cost) $307.35
Zoledronic Acid 4mg (monthly cost) $564.63
• chair time shorter for Zoledronic acid (15 min vs 1-2 hours
infusion )
•time/motion study in USA - adapted to Canada
•Zoledronic Acid $9 more expensive to administer
•IV zoledronic acid vs. IV pamidronate = 1 hr extra chair time
Dranitsaris, G et al. Zoledronic Acid versus pamidronate as palliative therapy in cancer patients: A Canadian time and motion analysis. J Oncol Pharm Practice 2001;7: 27 - 33
S
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Summary
•cancer mets to bone => morbidity
• bisphosphonates provide clinical benefit
•Zoledronic Acid more effective than pamidronate in
hypercalcemia of malignancy and shorter infusion time
•study 010 suggests zoledronic acid 4mg IV effective in
patients with bone mets from breast cancer/multiple myeloma
•studies 011 and 039 support efficacy of zoledronic acid 4mg
IV vs. placebo in pts with bone mets from solid tumours
•renal subset analysis of study 011 numbers and power
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BCCA - Benefit
Current:
•multiple myeloma - pamidronate
• breast Ca + mets - clodronate
Future:
(PEC proposal)
• prostate Ca + mets - zoledronic acid
•renal Ca - zoledronic acid
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BCCA - Non benefit
Current:
•hypercalcemia - pamidronate
• palliative care - pamidronate- zoledronic acid
Future:
• prostate Ca osteoporosis
+ LHRH - zoledronic acid