Background: Radium-223 chloride (Ra-223), a targeted alpha-emitter, targets bone metastases (mets) with high-energy alpha-particles of short range (<100 µm). ALSYMPCA, a phase III double-blind, randomized, multinational study, compared Ra-223 plus best standard of care (BSC) vs placebo plus BSC in CRPC patients (pts) with bone mets. In a planned interim analysis (n = 809), based on 314 events, Ra-223 significantly improved overall survival (OS) vs placebo (median 14.0 mo vs 11.2 mo, respectively; HR = .695; 95% CI, .552-.875; 2-sided p = .00185). Secondary endpoints were met and Ra-223 safety was favorable. An updated analysis was conducted prior to the crossover to further assess the effect of Ra-223 on the primary endpoint (OS), secondary endpoints including skeletal-related events (SREs), and safety. Methods: Eligible pts had confirmed symptomatic CRPC with ≥ 2 bone mets; no known visceral mets; and were post-docetaxel, unfit for docetaxel, or had declined docetaxel. Pts were randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wks or matching placebo. An updated descriptive analysis of OS, based on 528 events, was performed including data from all randomized pts prior to implementing crossover to Ra-223 for placebo pts. Results: 921 pts (Ra-223, n = 614; placebo, n = 307) were randomized from 6/2008-2/2011. Ra‑223 significantly improved OS vs placebo (median 14.9 mo vs 11.3 mo, respectively; HR = .695; 95% CI, .581-.832; p = 0.00007), and time to first SRE was significantly prolonged (median 15.6 mo vs 9.8 mo, respectively; HR = 0.658; 95% CI, 0.522-0.830; p = 0.00037). Safety and tolerability of Ra-223 remained favorable, with low myelosuppression (e.g., gr 3/4 neutropenia in 2.2% and 0.7% and gr 3/4 thrombocytopenia in 6.3% and 2% of the Ra-223 and placebo groups, respectively). Conclusions: On updated analysis, the median OS benefit for Ra-223 increased from 2.8 to 3.6 months, with a hazard ratio of 0.695 (i.e., 30.5% reduction in risk of death). Ra-223 is an effective therapy that improves OS and time to first SRE with a highly favorable safety profile, and may provide a new standard of care for CRPC pts with bone mets.