Background: The CARD NCT02485691 study reported superior rPFS and OS with CBZ vs abiraterone or enzalutamide in patients with mCRPC who progressed on docetaxel and within 12 months on a previous alternative androgen-signaling-targeted inhibitor (ARTA). This analysis evaluated changes in pain and HRQL associated with CBZ and ARTA during the CARD study. Methods: Pain response was defined as a decrease > 30% from baseline in BPI-SF pain intensity score with no increased analgesic use. HRQL was assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Patients were evaluable if they had received at least one dose of CBZ or ARTA and had a baseline FACT-P score plus at least one subsequent FACT-P measurement. A clinically meaningful improvement or deterioration of total FACT-P score was defined as a difference of ± 10 points from baseline. Clinically meaningful changes in HRQL and pain response were confirmed at two consecutive evaluations ≥ 3 weeks apart during the on-treatment period. Survival curves were generated by Kaplan–Meier estimates. Results: Of the 255 patients randomized, 172 (67.5%) had moderate to severe pain at randomization. Pain response and HRQL were evaluable for 111 (86.0%) and 108 (83.7%) for CBZ and 109 (86.5%) and 114 (90.5%) for ARTA. Pain response was 45.9% vs 19.3% for CBZ vs ARTA (p < 0.0001). The probability of not having pain progression after 12 months was 66.2% vs 45.3% CBZ vs ARTA (HR 0.55; 95% CI 0.32–0.97; p = 0.0348). An improvement in total FACT-P score from baseline was reported by 27 (25.0%) patients vs 26 (22.8%) for CBZ vs ARTA. FACT-P score was maintained or improved for 81 (75.0%) patients with CBZ and 86 (75.4%) patients with ARTA. A deterioration in FACT-P from baseline was reported by 22.2% with CBZ vs 24.6% with ARTA. Median time to FACT-P deterioration was 14.8 months for CBZ vs 8.9 months for ARTA (HR 0.72; 95% CI 0.44–1.20; p = 0.2072). Conclusions: CBZ was associated with a greater pain response and delayed pain progression vs ARTA. CBZ and ARTA were associated with similar trends in HRQL but time to FACT-P deterioration was longer with CBZ vs ARTA. Clinical trial information: NCT02485691