Background: Radium-223 dichloride (Ra-223), a first-in-class alpha-emitting radiopharmaceutical targeting bone metastases (mets), reduced risk of death and delayed time to first symptomatic skeletal event (SSE) v placebo (pbo) in ALSYMPCA (Parker et al. NEJM 2013; Sartor et al. Lancet Oncol 2014). The favorable safety profile of Ra-223 supports combining it with other agents. Abiraterone acetate (Abi) improved radiologic progression-free survival (rPFS) and overall survival (OS) (Ryan et al. NEJM 2012) in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC); it has no overlapping toxicity with Ra-223. This study investigates efficacy and safety of Ra-223 + Abi v Abi alone in chemotherapy-naïve patients (pts) with mCRPC to bone. Methods: This phase 3, double-blind, pbo-controlled, multinational trial (NCT02043678) randomizes ~800 pts with asymptomatic or mildly symptomatic chemotherapy-naïve, bone-predominant mCRPC 1:1 to Abi (1000 mg daily, PO) and prednisone (5 mg bid, PO) + Ra-223 (50 kBq/kg IV) q 4 wk × 6 or matching pbo until SSE or death. Sample size is calculated based on the primary end point, SSE-free survival (SSE-FS). 389 events are required to detect a 39% increase in SSE-FS with ~90% power using a stratified log-rank test, at a 2-sided 0.05 level, assuming median SSE-FS is 29.2 mo for Ra-223 v 21.0 mo for pbo. Pts are stratified by geographic region, concurrent use of denosumab or bisphosphonate or none, and total alkaline phosphatase (tALP) < 90 U/L v tALP ≥ 90 U/L. Secondary end points are OS, time to opiate use for cancer pain, time to pain progression, time to cytotoxic chemotherapy, rPFS, and acute and long-term safety. Pts are assessed at each treatment visit for efficacy, safety, and health-related quality of life. Pts who complete all study treatment and have no SSE enter active follow-up. Long-term follow-up begins after pts have an SSE and ends up to 7 years after last Ra-223 dose or at death, loss to follow-up, or withdrawal. As of January 19, 2016, 415 pts were randomized. Clinical trial information: NCT02043678