Outcomes of [177Lu]Lu-PSMA-617 radioligand therapy with and without concurrent enzalutamide in metastatic castration-resistant prostate cancer: a single-center retrospective study.

PURPOSE: Concurrent enzalutamide may upregulate PSMA expression and enhance the efficacy of [177Lu]Lu-PSMA-617 radioligand therapy (PSMA-RLT). We evaluated outcomes of PSMA-RLT with and without concurrent enzalutamide in a real-world metastatic castration-resistant prostate cancer (mCRPC) cohort. METHODS: We retrospectively evaluated 208 mCRPC patients treated with [177Lu]Lu-PSMA-617 at a single institution between June 2015 and January 2026. Among them, 106 received concurrent enzalutamide and 102 without any concurrent androgen receptor pathway inhibitor. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), PSA50 response, pain response, and toxicity. RESULTS: Median OS was 20.0 months in the concurrent enzalutamide group versus 12.4 months in the no-ARPI group (log-rank p = 0.082). In multivariable Cox analysis, concurrent enzalutamide was not independently associated with OS (hazard ratio 1.15, 95% confidence interval 0.77-1.70; p = 0.493). This lack of independent association was confirmed in propensity-score adjusted analyses. PFS (7.1 vs. 6.1 months; p = 0.112), PSA50 response rates (57.5% vs. 47.1%; p = 0.130) and toxicity profiles were similar between groups. CONCLUSION: Concurrent enzalutamide during PSMA-RLT was not independently associated with improved OS or PFS in our cohort. The combination did not result in increased toxicity. Prospective studies are needed to further clarify the role of concurrent enzalutamide in this setting.