Real-world outcomes of radium-223 in the FRONTIER study: Impact of prior up-front therapy in mCRPC.

63 Background: The role of Radium-223 (Ra-223) after up-front therapies for metastatic castration-sensitive prostate cancer (mCSPC) remains unclear. Given their widespread adoption, assessing the impact on Ra-223 outcomes is clinically important. Methods: We retrospectively analyzed the FRONTIER database of mCRPC patients treated with Ra-223 at 84 Japanese institutions (2020–2023). Of 844 cases, 591 met eligibility criteria. Patients were grouped as: up-front therapy with docetaxel and/or ARSI (n=189) or ADT monotherapy (n=402). After multiple imputation and 1:1 propensity score matching, 377 patients were analyzed (189 vs. 188). Primary endpoints were OS and CSS; secondary endpoints included time to progression, treatment completion, radiologic response, pain non-deterioration, and skeletal events. Results: After matching, baseline features were well balanced. Six-cycle completion rates were similar (73.0% up-front vs. 68.1% ADT). Median time to progression was 5 months in both groups (p=0.9), with comparable radiologic response and pain outcomes. Disease progression was detected more frequently in the up-front group (86.8% vs. 77.1%, p=0.01). Among patients completing six cycles, median OS did not significantly differ (67 vs. 70 months, HR=0.97, p=0.87). CSS was also similar. Absence of bone-modifying agents was associated with a tripled SSE risk in the up-front group. Conclusions: Ra-223 demonstrated comparable efficacy and safety regardless of prior up-front therapy. Survival was not compromised, supporting its use after treatment intensification and underscoring the need for bone-modifying agents to prevent SSE. Treatment response and progression outcomes after radium-223. Variable Up front therapy(n=189) Vintage hormone therapy(n=188) p-value Radiographic treatment response to Ra-223 Complete response 7/159 (4.4%) 3/147 (2.0%) Partial Response 23/159 (14.5%) 13/147 (8.8%) Stable Disease 58/159 (36.5%) 74/147 (50.3%) Progressive Disease 71/159 (44.7%) 57/147 (38.8%) Not evaluable/Unknown 30 41 Overall distribution across CR/PR/SD/PD χ² p=0.06 Objective response rate (CR+PR) 30/159 (18.9%) 16/147 (10.9%) 0.07 Progression status at data cut-off Progressed 164/189 (86.8%) 145/188 (77.1%) χ² p=0.01 Not progressed (censored at cut-off) 25/189 (15.7%) 43/188 (22.9%) Progression-free survival from Ra-223 initiation (months) 5 ( 4-8 ) 5 ( 4-8 ) 0.9 Values are n (%) or median (IQR). Radiographic responses (CR/PR/SD/PD) are among evaluable patients; χ² for distribution; ORR=CR+PR (2×2; Fisher if needed). Progression status is descriptive; PFS by KM/log-rank and Cox. Reasons for PD: n/N (%) among progressed (164/145), multiple responses; 2×2 χ² except Other (Fisher); no multiplicity adjustment.