Switch androgen receptor pathway inhibitor strategies in metastatic castration-resistant prostate cancer: A meta-analysis of randomized trials.

Abstract

198 Background: The optimal sequencing of therapy in metastatic castration-resistant prostate cancer (mCRPC) remains unclear. Real-world practice patterns show that over 50% of patients undergo sequential therapy with androgen receptor pathway inhibitors (ARPIs), and the ARPI switch serves as the control arm for multiple ongoing randomized controlled trials (RCTs). However, most existing reviews focus on the efficacy of individual agents, with limited attention to outcomes following ARPI-to-ARPI switch. This meta-analysis synthesizes randomized evidence comparing sequential ARPI therapy with alternative strategies to define efficacy, resistance, and the impact on survival. Methods: A systematic search, based on PRISMA 2020, for RCTs using switch ARPI strategies in mCRPC was completed in PubMed, Scopus, CINAHL, Ovid, and ASCO. A random effects model with a restricted maximum likelihood method was used for pooling medians and variance, utilizing R (4.3.3). Results: Eighteen studies comprising 7,514 patients were analyzed. Eight studies evaluated ARPI switch pre-taxane (Pre-T) chemotherapy, eight post-taxane (Post-T) exposure, and two included both. Nine studies evaluated abiraterone (ABI) to amide ARPI sequencing (enzalutamide, darolutamide, or apalutamide), two evaluated amide-to-ABI, and eight included pooled ARPI cohorts without sequence-level detail. The overall (OA) pooled PSA50 response rate was 20.0% (95% CI: 11-34%), with a median radiological progression-free survival (rPFS) of 5.08 months (4.24-5.92) and overall survival (OS) of 19.7 months (15.0-24.4). Stratified results are summarized in Table 1. In ARPI sequencing analyses among the Pre-T subgroup, OS was comparable between the ABI to amide and amide to ABI subgroups (22.6 vs 24.7 months, p=0.77). Conclusions: In the largest analysis to date, sequential ARPI therapy in mCRPC demonstrated limited benefit, consistent with existing evidence of cross-resistance among AR-targeted agents. Post-T outcomes were poor, reinforcing the limited clinical value of ARPI switching after initial progression. ARPI switch should be approached with caution; it should not be used as a control arm in large RCTs when alternative therapies are available with proven life-prolonging benefits. These findings underscore the need for alternative mechanisms and optimized sequencing strategies. Pooled outcomes by prior taxane exposure. Outcomes ARPI Cohorts No. of Studies No. of Patients (N or n/N) Pooled Value 95% CI I² (%) P-value PSA50 response (%) OA 9 258/1122 20 11-34 93.7 0.45 Pre-T 5 113/612 17 8-32 83.2 <0.05 Post-T 4 145/510 26 10-51 96.9 <0.05 Median rPFS (mo) OA 10 4401 5.08 4.24-5.92 70.5 <0.05 Pre-T 6 3191 5.54 4.35-6.73 81.4 <0.05 Post-T 4 1210 4.11 3.36-4.86 0 0.50 Median OS (mo) OA 7 2945 19.7 15.0-24.4 93.9 <0.05 Pre-T 5 1902 22.6 18.3-26.9 88.7 <0.05 Post-T 2 1043 12.7 9.2-16.3 82 <0.05