Background: Bone metastases from castrate-resistant prostate cancer (CRPC) are associated with osteoclast-mediated bone destruction and skeletal-related events (SREs). Denosumab is a fully human monoclonal antibody against RANKL, a key mediator of osteoclast formation, function, and survival. Previous results from a phase III trial showed denosumab was superior to zoledronic acid (ZA) in delaying or preventing SREs (pathologic fracture, radiation or surgery to bone, or spinal cord compression) in patients with bone metastases from CRPC. This analysis assesses the effect of denosumab vs ZA treatment among patients with earlier stage CRPC ‑ those with no prior SRE or no/mild pain at baseline. Methods: Patients with CRPC and ≥1 bone metastasis and no prior IV bisphosphonate use were randomized to receive either SC denosumab 120 mg + IV placebo or SC placebo + IV ZA 4 mg (adjusted for creatinine clearance) every 4 weeks. Patients also were instructed to take calcium and vitamin D supplements. Time to 1^st on-study SRE (primary endpoint) and time to 1^st and subsequent SRE (multiple event analysis) were evaluated in patients with no prior SRE or no/mild pain. The Brief Pain Inventory – Short Form (BPI) was used to assess worst pain scores at baseline. A score of 0 to 4 on the BPI indicates no or mild pain. Results: Of the 1901 patients enrolled (n = 950 denosumab; n = 951 ZA), 1438 were in the subgroup of patients with no prior SRE and 1045 were in the subgroup with no/mild pain (BPI score 0 to 4) at baseline. As compared with ZA, denosumab treatment significantly delayed the time to 1^st SRE for the overall population (HR = 0.82 [0.71, 0.95]; P = 0.008), as well as in both subgroups of patients with earlier disease: no prior SRE (HR = 0.80 [0.67, 0.95]; P = 0.011) or no/mild pain at baseline (HR = 0.77 [0.63, 0.95]; P = 0.014). Similar results also were noted with denosumab vs ZA treatment for the time to 1^st and subsequent SREs (P ≤ 0.007 for all groups). Conclusions: Denosumab treatment in patients with earlier stage CRPC significantly reduced SREs.