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Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: Results of a phase 3, randomised, placebo-controlled trial
The Lancet, 01/09/2012
Clinical Article
Smith MR et al. – This large randomized study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer.
Methods- Phase 3, double–blind, randomised, placebo–controlled study
- Men with non–metastatic castration–resistant prostate cancer at high risk of bone metastasis (prostate–specific antigen [PSA] ≥8·0 μg/L or PSA doubling time μ10·0 months, or both) were enrolled at 319 centres from 30 countries
- Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks
- Randomization was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer
- Patients, investigators, and all people involved in study conduct were masked to treatment allocation
- Primary endpoint was bone–metastasis–free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause
- Efficacy analysis was by intention to treat
- Masked treatment phase of trial has been completed
- 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo)
- Denosumab significantly increased bone–metastasis–free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4—33·3] vs 25·2 [22·2—29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73—0·98, p=0·028)
- Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5—38·0] vs 29·5 [22·4—33·1] months; HR 0·84, 95% CI 0·71—0·98, p=0·032)
- OS did not differ between groups (denosumab, 43·9 [95% CI 40·1—not estimable] months vs placebo, 44·8 [40·1—not estimable] months; HR 1·01, 95% CI 0·85—1·20, p=0·91)
- Rates of AE and serious AE were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia
- 33 (5%) patients on denosumab developed osteonecrosis of jaw versus none on placebo
- Hypocalcaemia occurred in 12 (2%) patients on denosumab and 2 (<1%) on placebo