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

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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 2010
• Abstract LBA4507
• Reviewed by Dr. Lori Wood
• Date 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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STUDY DESIGN
Treatment A Denosumab 120 mg sc
q4wks Placebo N950
R
Treatment B Zoledronic Acid 4 mg i.v.
q4wks Placebo N951

• - 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 0.82 p0.0002 (Non-Inferiority) p0.008 (Superiority)
SRE 41 36
Toxicity Acute Phase Rxn Renal ONJ Hypocalcemia 17.8 16.2 1.3 (n12) 5.8 8.4 14.7 2.3 (n22) 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