Enhancing Outcomes in mCRPC: The Impact of Androgen Receptor Inhibitor Sequencing Before 177Lu-PSMA Therapy

Abstract

Background Prostate-specific membrane antigen (PSMA) is a key target in metastatic castration resistance prostate cancer (mCRPC). Enzalutamide, an androgen receptor pathway inhibitor (ARPi), increases PSMA expression, potentially enhancing 177Lu-PSMA-617 radioligand therapy. This study evaluates the impact of prior ARPi (enzalutamide vs abiraterone acetate [AA]) on PSMA expression, PFS, and OS. Materials and Methods A retrospective analysis of 214 mCRPC patients treated with 177Lu-PSMA-617 across six Turkish centers (2015-2025) was conducted. Patients were grouped by prior ARPi therapy. PFS and OS were analyzed using Kaplan-Meier and Cox regression methods. Results Among 103 patients receiving ARPi before 177Lu-PSMA-617, 59 (57%) had enzalutamide and 44 (43%) AA. Median PFS was 7.6 months for enzalutamide versus 5.3 months for AA (P = .068). Median OS was significantly longer with enzalutamide (12.8 vs 6.9 months, P = .021). Patients with Eastern Cooperative Oncology Group Performance Scores (ECOG PS) 0-1 had significantly longer OS (27.6 vs 6.9 months for PS 2-3, P < .0001). Higher PSMA SUVmax (>20) correlated with longer OS (15.1 vs 7.8 months, P = .016). Among 86 patients with detectable PSMA SUVmax, 53 had SUVmax > 20; 66% had prior enzalutamide and 34% AA. Median OS was four months longer with enzalutamide (18.1 vs 13.9 months P = .120). Multivariate analysis identified ARPi type (HR: 2.24, P = .033) and ECOG PS (HR: 5.22, P < .0001) as independent OS predictors. Conclusion Enzalutamide prior to 177Lu-PSMA-617 significantly improves OS and enhances PSMA expression compared to AA. These findings highlight the importance of treatment sequencing in mCRPC and warrant further prospective studies.