Background: Bone metastases (mets), present in > 90% of patients (pts) with CRPC, may cause severe pain. In a phase 2 dose-response study with a single injection of Ra-223, pain response was seen in up to 71% of CRPC pts with painful bone mets (Nilsson 2012). In the phase 3 ALSYMPCA study, which included 921 CRPC pts with bone mets randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching placebo (Ra-223, n = 614; placebo, n = 307), Ra-223 significantly improved overall survival vs placebo (median 14.9 vs 11.3 mo; HR = 0.695) and was well tolerated. Post hoc analyses of pain parameters in ALSYMPCA are presented. Methods: The Cox proportional hazards model was used to analyze time to initial opioid use and time to EBRT. Pts with no opioid use at baseline were included in the pain analyses. All pts were included in the analysis for the prespecified endpoint time to EBRT. Concomitant opioid use was recorded from first study drug injection to 12 weeks after last injection. Pain-related QOL was analyzed based on the sum of 4 questions within FACT-P prostate cancer subscale (PCS) (Cella 2009) using ANCOVA. Results: Baseline pain characteristics were similar between the treatment groups (approximately 55% of pts had moderate to severe pain and opioid use based on WHO ladder for cancer pain). Time to EBRT was significantly longer with Ra-223 vs placebo (HR = 0.670; 95% CI, 0.525-0.854). Despite a longer observation time, fewer Ra-223 pts (50%) than placebo pts (62%) reported bone pain as an AE. At baseline, 269 Ra-223 pts and 139 placebo pts did not use opioids. Median time to initial opioid use was significantly longer in the Ra-223 group, with a risk reduction of 38%, compared to placebo (HR = 0.621; 95% CI, 0.456-0.846). Fewer Ra-223 pts (36%) than placebo pts (50%) required opioids for pain relief. The QOL pain score indicated reduced pain for Ra-223 pts relative to placebo pts at week 16 (P = 0.001). Ra-223 pts had significant pain reduction relative to baseline at weeks 16 (P < 0.001 ) and 24 (P = 0.001). Conclusions: These results provide consistent evidence that, in addition to prolonging survival, Ra-223 reduces pain and opioid use in CRPC pts with bone mets. Clinical trial information: NCT00699751.