Background: In ALSYMPCA, Ra-223, a first-in-class α-emitter, improved overall survival and delayed time to first symptomatic skeletal event vs placebo (pbo). This post hoc analysis evaluated safety and efficacy of Ra-223 plus EBRT. Methods: Pts had symptomatic (recent EBRT for bone pain or any regular analgesic use) CRPC with ≥ 2 bone and no visceral mets; best standard of care; and prior docetaxel (pD) or were unfit for or declined docetaxel (no pD). Pts were stratified by pD use (yes/no), baseline total alkaline phosphatase level (tALP; < 220 U/L or ≥ 220 U/L), and current bisphosphonate (bp) use (yes/no) and randomized 2:1 to 6 Ra-223 injections (50 kBq/kg IV q 4 wk) or pbo. EBRT for bone pain was permitted within 12 weeks prior to randomization and during study. Baseline pain by prior EBRT, time to first on-study EBRT use for bone pain, and adverse events (AEs) by concomitant EBRT (cEBRT) were analyzed. Results: Pts with no prior EBRT had less pain at baseline; a WHO pain score ≤ 1 (no opioid use) was present in 46% (355/724) of pts with no prior EBRT vs 36% (53/147) of pts with prior EBRT. Ra-223 vs pbo significantly reduced EBRT use in the overall population (HR = 0.67, P = 0.001) and in pts with ≤ 20 bone mets (HR = 0.49, P < 0.001), current bp use (HR = 0.47, P = 0.004), tALP < 220 U/L (HR = 0.66, P = 0.008), and no pD (HR = 0.65, P = 0.038). At 6 months, the percentage of Ra-223 pts requiring EBRT was similar for prior and no prior EBRT subgroups (24% vs 20%), increasing at 12 months (38% vs 29%). cEBRT did not affect Ra-223 safety, and myelosuppression was low (Table). Conclusions: cEBRT did not adversely affect Ra-223 hematologic safety. Ra-223 significantly reduced risk of EBRT use. In Ra-223 pts, prior EBRT did not appear to affect later EBRT use. Clinical trial information: NCT00699751