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A Phase III, randomized, double-blind study of denosumab compared with zoledronic acid in the

treatment of patients with bone metastases from breast cancer

Presented by Dr. Alison StopeckAuthors: Sunil Verma

Date posted: September 28th, 2009

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R

Arm A:

Denosumab 120mg sc + Placebo IVevery 4 weeks

Arm B:

Zoledronic Acid 4 mg IV + Placebo SCevery 4 weeks

n=2046Med f/up=34m

MBC with Bone mets

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RESULTS

DenosumabZoledronic

Acid

Time to 1st on-study

SRENot reached 26,5 months

HR =0.82

p=0.01

OS No difference

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STUDY COMMENTARY

• 80% of MBC patients will develop bone metastases with significant clinical consequences

• RANK-L is a central mediator of bone destruction in metastatic cancer and activates osteoclasts. Denosumabe is a fully human monoclonal antibody that inhibits RANK-L

• Results from this study suggest that denosumab is superior to zoledronic acid by delaying the time to first skeletal related event

• There was no difference between the two agents in survival endpoints and pain scores

• Denosumab has a superior toxicity profile with fewer acute phase reactions and renal toxicity. The rates of Osteonecrosis of the Jaw (ONJ) were comparable in both arms.

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BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS

• It appears that RANK-L plays an important role in bone mets and denosumab has promising efficacy results for patients with metastatic breast cancer with bony metastases

• While denosumab does have superior activity when compared to zoledronic acid in SRE related endpoints, there were no differences between the two agents in breast cancer related outcome such as disease control and survival endpoints. ONJ rates were low but were seen with both agents

• We will soon have a new option for our patients with metastatic breast cancer with bony mets but it doesn’t necessarily change the standard of care.

•We still have a number of unanswered questions on the use of bisphosphonates in MBC– do we really need to give these agents on a monthly basis for all patients? Can we use bone turnover markers to better utilize these agents? Should we switch from one class/drug to another upon bone progression or development of a SRE ? And probably, most importantly we need to confirm if these agents have any anti-cancer effects beyond just supportive care.