Purpose <p>Several clinical and preclinical studies showed that ARPI medication such as enzalutamide increases the expression of PSMA in mCRPC patients and may potentially act as a sensitizer for PSMA RLT. In this study we aim to provide insight into the efficacy and safety profile of concurrent treatment with [¹⁷⁷Lu]Lu-PSMA-617 RLT and enzalutamide and draw a comparison to [¹⁷⁷Lu]Lu-PSMA-617 alone.</p> Methods <p>In total <i>n</i> = 63 mCRPC patients received [¹⁷⁷Lu]Lu-PSMA-617 RLT alongside medication with enzalutamide and were compared with <i>n</i> = 62 mCRPC patients receiving [¹⁷⁷Lu]Lu-PSMA-617 without any ARPI medication. All patients participated in a prospective registry (REALITY Study, NCT04833517). The patients’ biochemical response and outcome (PFS; OS) to PSMA RLT were evaluated and compared between both groups. Adverse events were assessed according to CTCAE criteria.</p> Results <p>Patients treated with PSMA RLT in combination with enzalutamide achieved a significantly higher response rate (61.9% vs. 43.5%) and experienced a significantly longer PFS (6.1 months vs. 3.5 months). Statistically significant difference in OS between the groups was not reached (<i>p</i> = 0.097). The adverse event profiles between the treatment groups did not differ for renal toxicity, hematoxicities and xerostomia but a more frequent rate of low-grade fatigue in the enzalutamide group was observed. The combination of PSMA RLT and enzalutamide was both safe and overall well tolerated.</p> Conclusion <p>The results suggest that concurrent medication of enzalutamide during PSMA RLT may enhance response and clinical outcomes, underscoring the potential of this specific combination as a promising approach in mCRPC. Future studies, ideally in prospective setting with larger patient cohorts are warranted.</p>