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A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer (CRPC)

Authors: Fizazi K et al, ASCO 2010Abstract: LBA4507Reviewed by: Dr. Lori WoodDate posted: Jun 18 2010

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STUDY RATIONALE

• Bone metastases very common in Prostate Cancer• RANK Ligand (RANKL) is a central mediator of bone

destruction• RANKL is overexpressed in PCa and stimulates the

maturation and activation of osteoclasts• Denosumab is a monoclonal antibody to RANKL• To date, i.v. Zoledronic Acid is the only drug shown to

decrease SRE in CRPC• Safety profile of Denosumab shown to be good

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R

Treatment A: Denosumab 120 mg sc q4wksPlaceboN=950

Treatment B: Zoledronic Acid 4 mg i.v. q4wksPlaceboN=951

STUDY DESIGN

- CRPCa- Metastases to bone- Also given Vit D/calcium- Statistics: - designed with non- inferiority and superiority- Primary outcome: - time to first SRE

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RESULTS

ZA DENO HR P value

Time To First SRE 17.1m 20.7m 0.82p=0.0002 (Non-Inferiority)

p=0.008 (Superiority)

SRE 41% 36%

Toxicity:• Acute Phase Rxn• Renal• ONJ

• Hypocalcemia

17.8%

16.2%

1.3% (n=12)

5.8%

8.4%

14.7%

2.3% (n=22)

12.8%

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STUDY COMMENTARY

• Denosumab increased time to first SRE compared to Zoedronic Acid (20.7m vs. 17.1m) thus, meeting the primary endpoint of the study

• Originally felt very little renal toxicity but 14.7% compared to 16.2%. This will have to be further defined.

• Incidence of ONJ is not less (2.3% vs. 1.3%)

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BOTTOM-LINE FOR CANADIAN MEDICAL ONCOLOGISTS

• There is now another class of drugs that affect SRE in CRPC– Denosumab: a monoclonal antibody to RANKL

• The time to first SRE is longer with Denosumab compared to Zoledronic Acid– But will need further details on the number and types of SREs

• Unfortunately, it still does have toxicity including renal and ONJ• We still do not have good predictors of who benefits the most from

bone targeted agents (for example: urine bone turnover markers) and when patients should be started/continued/stopped– Hopefully this will come with more research

• Hard to know at this point how much Canadian practice will change based on this study