Comparison of mCRPC [¹⁷⁷Lu]Lu-PSMA-617 radioligand therapy with and without concurrent enzalutamide medication in a...

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.

In total n = 63 mCRPC patients received [¹⁷⁷Lu]Lu-PSMA-617 RLT alongside medication with enzalutamide and were compared with n = 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.

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 (p = 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.

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.