Outcomes of radium-223 therapy in combination with enzalutamide for metastatic castration-resistant prostate cancer: A multicenter retrospective analysis in Japan.

66 Background: The PEACE-3 trial demonstrated improved radiographic progression-free survival (rPFS) with radium-223 (Ra-223) plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (mCRPC). This study evaluated real-world outcomes and safety of the combination in a multicenter Japanese cohort. Methods: We retrospectively analyzed patients with metastatic castration-resistant prostate cancer (mCRPC) who received radium-223 (Ra-223) between January 2020 and December 2023 at 84 Japanese institutions. Eligible cases included those treated with Ra-223 plus androgen-deprivation therapy (ADT) with enzalutamide (ADT+ENZ) or Ra-223 with ADT alone (ADT-only). Patients receiving other systemic therapies were excluded. Propensity score matching balanced baseline factors. Primary endpoints were time to progression and overall survival (OS); secondary endpoints were 6-cycle completion, pain non-deterioration rate (PNDR), radiologic response, symptomatic skeletal events (SSE), and safety. Results: A total of 386 patients were analyzed after matching. The median age was 74 years; 82% had ECOG PS 0–1, and 74% had ≤EOD2 disease. Prior ARSI exposure during the CRPC phase was higher in the ADT+ENZ group (111.4% vs. 90.2%; multiple responses allowed), whereas prior chemotherapy was less common (30.2% vs. 51.5%). Over 70% of patients in both groups completed at least 6 cycles. The median time to progression was longer with ADT+ENZ (6 vs. 5 months, p=0.01), and there were fewer PSA progressions (71.1% vs. 81.5%, p=0.03). No significant differences were observed in radiologic response, PNDR, or new pain. Grade ≥3 toxicities were uncommon (anemia 6.1%, neutropenia 5.2%). In the ADT+ENZ group, the absence of bone-modifying agents was linked to a higher risk of SSE (RR 3.09, p=0.0015). OS and cancer-specific survival were similar (32 vs. 36; 35 vs. 37 months). Conclusions: This nationwide retrospective analysis found that Ra-223 combined with enzalutamide improved PFS with comparable safety and no OS difference. These findings support PEACE-3 and underscore the role of bone-modifying agents in reducing SSE risk. Progression-free survival and reasons for progression after Ra-223 initiation. Variable ADT+Enzalutamide (n = 192) ADT monotherapy (n = 194) p-value Progression status at data cut-off Progressed 149/192 (77.6%) 157/194 (80.9%) χ² p=0.42 Not progressed (censored at cut-off) 43/192 (23.4%) 37/194 (19.1%) Progression-free survival from Ra-223 initiation (months) 6 (5 - 10) 5 (4 - 8) 0.01 Reasons for PD determination after Ra-223 initiation* Radiographic progression 74/149 (49.7%) 81/157 (51.6%) 0.73 PSA elevation 106/149 (71.1%) 128/157 (81.5%) 0.03 Onset or worsening of clinical symptoms 30/149 (20.1%) 32/157 (20.4%) 0.96 Other 6/149 (4.0%) 10/157 (6.4%) 0.44 *Multiple responses allowed.