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

LBA4507 Background: Bone metastases from hormone-refractory (castration-resistant) prostate cancer (CRPC) are associated with RANKL-mediated osteoclast activation resulting in bone destruction and skeletal-related events (SRE). Denosumab is a fully human monoclonal antibody against RANKL. This phase III, randomized, double-blind, active-controlled trial compared the efficacy and safety of denosumab vs. zoledronic acid (ZA) in patients with metastatic CRPC. Methods: Patients (n = 1,901) with CRPC and at least 1 bone metastasis, but no prior IV bisphosphonate use, received either SC denosumab 120 mg and IV placebo (n = 950), or SC placebo and IV ZA 4 mg (n = 951) adjusted for creatinine clearance every 4 weeks. All patients were instructed to take supplemental calcium and vitamin D. The primary endpoint was time to first on-study SRE, defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression. Results: Denosumab significantly delayed the time to first on-study SRE compared with ZA, (HR 0.82 ; 95% CI: 0.71, 0.95 ; p = 0.008.) The median time to first on-study SRE was 20.7 mo denosumab vs. 17.1 mo ZA, a difference of 3.6 months. Denosumab also significantly delayed the time to first and subsequent on-study SRE (multiple event analysis) (HR 0.82 ; 95% CI: 0.71, 0.94 ; p = 0.004). Greater suppression of the bone turnover markers uNTx and BSAP occurred in denosumab patients compared with ZA (p < 0.0001 for both). Overall, adverse event (AE) rates (97% each) and serious AEs (63% denosumab, 60% ZA) were similar, irrespective of potential relationship to study drugs. AEs of hypocalcemia were reported in 13% and 6% of denosumab and ZA patients. Osteonecrosis of the jaw occurred in 22 (2.3%) denosumab compared with 12 (1.3%) ZA patients (p = 0.09). Overall survival (HR 1.03 ; 95% CI: 0.91, 1.17 ; p = 0.65) and time to cancer progression (HR 1.06; 95% CI: 0.95, 1.18; p = 0.30) were similar between treatment arms. Conclusions: Denosumab demonstrated superiority over ZA in delaying or preventing SREs in patients with bone metastases from CRPC. Adverse events were consistent in both treatment groups with those previously reported in advanced cancer populations. [Table: see text]