ZOLEDRONIC ACID (ZOMETAR)

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ZOLEDRONIC ACID (ZOMETAR)

• FOR BONE METASTASES OF SOLID 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 gt
osteolysis osteoblast bone forming cells gt
osteogenesis Healthy bone remodelling
osteoclast osteoblast activity
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Cancer Bone remodellingOsteolyticOsteoclas
t gt Osteoblast

• Net bone resorbtion

• Release of growth factors gt tumour growth

Release mediators gt stimulate osteoclast
activity
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Osteogenic Osteoblast gt Osteoclast
Net bone formation
Osteoclast activity
osteolysis
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The Impact of Metastatic Bone Disease
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• Bisphosphonates in cancer
• 1) hypercalcemia
• 2) bone mets
• treatment
• 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
C

• New highly potent 3rd generation
  bisphosphonate
• Heterocyclic nitrogen-containing molecule with
• A core bisphosphonate moiety
• An imidazole-ring side chain containing 2
  critically positioned nitrogen atoms

Green JR, et al. J Bone Miner Res.
19949745-751.Green JR, et al. Pharmacol
Toxicol. 199780225-230.
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Efficacy in Hypercalcaemia of Malignancy
C
87 P .015
82.6 P .005
70
Complete responders ()
64
45
33
Major, P et al. JCO ,200119 558-567
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Phase III Trials With Zoledronic Acid in Patients
With Metastatic Bone Disease
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Protocol 010
Rosen L S, et al. Zoledronic Acid versus
pamidronate in the treatment of skeletal
metastases in patients with breast cancer or
osteolytic lesiona of multiple myeloma 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 90 mg
  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
p 0.052
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

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Protocol 010 Breast Cancer and Multiple Myeloma
time to first SRE
14
010 PTF 9.2-1p4 CSR 010 T9-3
Median time, days
Zoledronic Acid 4 mg 373 Pamidronate 90 mg 363
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• Study 010 Comments (at 25 months)
• 12 month extension N606 (lt40) and gt50
  completion
• patients - one SRE (not HCM) Z4mg 47Pam90mg
  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
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 acidchemo
  vs. chemo preventing SRE
• 25 completed trial

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Protocol 011 Solid tumors (not PC BC)
proportion () of patients with an SREtime to
first SRE
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P .127
N 257
N 250
Median time,
days
P-value Zoledronic Acid 4 mg 230
.023 Placebo 163
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Protocol 039
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 acidchemo
  vs chemo preventing SRE
• 40 completed trial

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Proportion of protocol 039 patients with
skeletal-related events (SRE)
0.8
0.7
0.6
0.5
Proportion of patients
p 0.021
0.4
0.3
44.2
0.2
33.2
0.1
0
All patients
Saad F, et al. Journal of the National Cancer
Institute. 2002 94 1458 - 1468.
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Protocol 039 Time to first skeletal-related
event
Median Time Zoledronic Acid 4 mgNR Placebo
321 days
100 90 80 70 60 50 40 30 20 10 0
Percent of patients without event
P-value 0.011
0 50 100 150 200 250 300 350 400 450 500 550
Time after start of therapy (days) NR not
reached
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
• delaying onset of SRE in renal Ca patients

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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 20017 27 - 33
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• Summary
• cancer mets to bone gt 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