Enhancing outcomes in mCRPC: The impact of androgen receptor inhibitor sequencing before ¹⁷⁷Lu-PSMA-617 therapy.

e17068 Background: Prostate-specific membrane antigen (PSMA) is a key therapeutic target in metastatic castration-resistant prostate cancer (mCRPC). Elevated PSMA expression predicts the efficacy of ¹⁷⁷Lu-PSMA-617 radioligand therapy. Enzalutamide, an androgen receptor pathway inhibitor (ARPi), has been shown to upregulate PSMA expression. This study evaluates the impact of prior ARPi selection on treatment outcomes, including PSMA expression, progression-free survival (PFS), and overall survival (OS), in patients receiving ¹⁷⁷Lu-PSMA-617 therapy. Methods: A retrospective cohort analysis was conducted at six cancer centers in Turkey, involving 214 mCRPC patients treated with ¹⁷⁷Lu-PSMA-617 between 2015 and 2025. Patients were grouped based on prior ARPi therapy: enzalutamide or abiraterone acetate (AA). Exclusion criteria included non-sequential ARPi-¹⁷⁷Lu-PSMA-617 treatments or incomplete survival data. PFS and OS were assessed using Kaplan-Meier and Cox regression methods. Results: Among 103 patients receiving ARPi prior to ¹⁷⁷Lu-PSMA-617, 59 (57%) were treated with enzalutamide and 44 (43%) with AA. Median PFS was 7.6 months for enzalutamide vs. 5.3 months for AA (p = 0.068), while median OS was significantly longer for enzalutamide (12.8 vs. 6.9 months, p = 0.021). Patients with ECOG PS 0–1 had a much longer OS (27.6 vs. 6.9 months for PS 2–3, p < 0.0001). Among 67 patients with detectable PSMA SUVmax, 42 had SUVmax > 20; 69% had prior enzalutamide and 31% AA. Median OS was five months longer with enzalutamide (19.7 vs. 14.7 months, p = 0.164). Multivariate analysis identified ARPi type (HR: 2.59, p = 0.009) and ECOG PS (HR: 5.28, p < 0.0001) as independent OS predictors. Conclusions: Enzalutamide prior to ¹⁷⁷Lu-PSMA-617 significantly improves OS and enhances PSMA expression compared to AA, highlighting its critical role in optimizing sequencing strategies for mCRPC. These findings warrant prospective studies to refine treatment pathways and maximize patient outcomes.