Overall survival following enzalutamide resistance in metastatic castration-sensitive versus metastatic castration-resistant prostate cancer.

e17043 Background: Enzalutamide (ENZA), an androgen receptor signaling inhibitor (ARSI), significantly prolongs overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). We define castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT) failure as CRPC 1.0 and after ARSI progression as CRPC 2.0. Whether OS following CRPC 2.0 differs based on whether ENZA was initiated for mCSPC or mCRPC 1.0 remains unclear. This study aimed to evaluate OS from CRPC 2.0 among patients with synchronous mCSPC or mCRPC treated with ENZA as first-line ARSI therapy. Methods: This retrospective study included men diagnosed with synchronous metastatic prostate cancer at two Japanese university hospitals (June 2014–May 2024). Patients received ENZA as initial systemic therapy for mCSPC or mCRPC. Those with prior use of other ARSIs (abiraterone, apalutamide, or darolutamide) before CRPC were excluded. Baseline characteristics (age, Gleason score, PSA levels, ECOG performance status) were recorded. CRPC 2.0 was defined as progression during or after ENZA. OS from CRPC 2.0 was analyzed using Kaplan-Meier methods and log-rank tests. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models. Institutional review board approval was obtained at both sites, and p < 0.05 was considered statistically significant. Results: Among 160 patients (59 mCSPC, 101 mCRPC), 15 (mCSPC) and 86 (mCRPC) developed resistance to ENZA, necessitating treatment changes. Most received taxane-based chemotherapy or alternative ARSIs; fewer than 10% received radionuclide therapy or PARP inhibitors. Median ENZA duration was longer in mCSPC (62.0 months) than mCRPC (11.2 months) (HR 0.21, 95% CI 0.14–0.31; p < 0.001). Median OS from initial diagnosis was similar for mCSPC (62.0 months) and mCRPC (52.0 months) (HR 0.84, 95% CI 0.44–1.59; p = 0.77). Similarly, OS from CRPC 2.0 did not differ significantly between mCSPC (13.3 months) and mCRPC (15.3 months) (HR 1.16, 95% CI 0.62–2.16; p = 0.13). At final follow-up, 10 (mCSPC) and 48 (mCRPC) patients had died. Conclusions: After ENZA resistance (CRPC 2.0), both mCSPC and mCRPC groups showed similarly poor prognosis, with median OS under 18 months. While taxane-based chemotherapy and alternative ARSIs were commonly used as subsequent treatments, only a small proportion received radionuclide therapy or PARP inhibitors. These findings highlight the urgent need for novel approaches to improve survival in CRPC 2.0. Prospective studies are warranted to validate new therapeutic strategies.