Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study

Abstract

Background: Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer.

Methods: In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed.

Findings: 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9-18·5) for patients on denosumab and 11·2 months (IQR 5·6-17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8-24·9) with denosumab compared with 17·1 months (15·0-19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71-0·95; p = 0·0002 for non-inferiority; p = 0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 [2%] vs 12 [1%]; p = 0·09).

Interpretation: Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer.

Funding: Amgen.

Figure 1. Trial profile

*Most common reasons for exclusion were evidence of bone metastasis (n=124 patients), serum testosterone of 1·72 nmol/L or higher (n=54), and informed consent not given (n=52); two patients were excluded because they did not meet inclusion or exclusion criteria and because they did not enrol. †Includes six terms with less than 5% occurrence: miscellaneous, lost to follow-up, non-compliance, protocol deviation, ineligibility established, and administrative decision.

Figure 2. Kaplan-Meier estimates of time to first on-study skeletal-related event

Patients were assessed from baseline to the primary analysis cutoff date. HR=hazard ratio. *p values were adjusted for multiplicity.

Figure 3. Time to first and subsequent on-study skeletal-related events

Events occurred at least 21 days apart. *Adjusted for multiplicity.

Figure 4. Kaplan-Meier estimates of (A) overall survival and (B) time to disease progression

Patients who were no longer on study, but who were still in the survival follow-up, were included along with those remaining on study in the risk set for the survival analysis. HR=hazard ratio.

Figure 5. Median prostate-specific antigen concentrations during the study

Prostate-specific antigen was measured every 3 months in all patients remaining on study. Data are presented by visit months, where an assessment within each 3-month period was captured at the end of the window between visits.