Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial

Abstract

Background: Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer.

Methods: In this 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 ≤10·0 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. Randomisation 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. The 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. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov, number NCT00286091.

Findings: 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). Overall survival 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 adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo.

Interpretation: This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer.

Funding: Amgen Inc.

Figure 1

Patient Enrollment, Randomization, and Disposition ¹Patients were analyzed for safety according to their treatment received, regardless of treatment assigned; 4 patients randomized to placebo received denosumab in error. ²Patients who no longer participated in monthly assessments; patients who withdrew consent or were lost to follow up were not followed for survival ³Not in bone. ⁴Other = administrative decision, noncompliance, lost to follow-up, protocol deviation, ineligibility determined.

Figure 2

Kaplan-Meier Curves of Key Efficacy Endpoints Panel A shows the primary endpoint of bone metastasis-free survival. Panels B and C show the time to bone metastases (asymptomatic or symptomatic) and time to symptomatic bone metastasis, respectively. Panel D shows overall survival. Note: All curves were truncated when the combined risk sets dropped to below 3.5% of the total risk set (i.e., when there were 50 patients or less in the combined risk sets).

Figure 2

Kaplan-Meier Curves of Key Efficacy Endpoints Panel A shows the primary endpoint of bone metastasis-free survival. Panels B and C show the time to bone metastases (asymptomatic or symptomatic) and time to symptomatic bone metastasis, respectively. Panel D shows overall survival. Note: All curves were truncated when the combined risk sets dropped to below 3.5% of the total risk set (i.e., when there were 50 patients or less in the combined risk sets).

Figure 2

Kaplan-Meier Curves of Key Efficacy Endpoints Panel A shows the primary endpoint of bone metastasis-free survival. Panels B and C show the time to bone metastases (asymptomatic or symptomatic) and time to symptomatic bone metastasis, respectively. Panel D shows overall survival. Note: All curves were truncated when the combined risk sets dropped to below 3.5% of the total risk set (i.e., when there were 50 patients or less in the combined risk sets).

Figure 2

Kaplan-Meier Curves of Key Efficacy Endpoints Panel A shows the primary endpoint of bone metastasis-free survival. Panels B and C show the time to bone metastases (asymptomatic or symptomatic) and time to symptomatic bone metastasis, respectively. Panel D shows overall survival. Note: All curves were truncated when the combined risk sets dropped to below 3.5% of the total risk set (i.e., when there were 50 patients or less in the combined risk sets).