Addition of Standard Enzalutamide Medication Shows Synergistic Effects on Response to [(177)Lu]Lu-PSMA-617 Radioligand Therapy in mCRPC Patients with Imminent Treatment Failure—Preliminary Evidence of Pilot Experience

SIMPLE SUMMARY: In this study, we investigated co-medication with enzalutamide, a well-established newer androgen axis drug, as a potential re-sensitizer for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) in n = 10 patients with imminent treatment failure on standard (177)Lu-based PSMA-RLT. After the introduction of enzalutamide medication, all patients showed a PSA decrease (7/10 patients with partial remission). This pilot experience suggests the synergistic potential of adding enzalutamide to PSMA-RLT derived from the intra-individual comparison of (177)Lu-based PSMA-RLT ± enzalutamide. ABSTRACT: Well-received strong efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) does not prevent patients from either early or eventual disease progression under this treatment. In this study, we investigated co-medication with enzalutamide as a potential re-sensitizer for PSMA-RLT in patients with imminent treatment failure on standard (177)Lu-based PSMA-RLT. Ten mCRPC patients who exhibited an insufficient response to conventional [(177)Lu]Lu-PSMA-617 RLT received oral medication of enzalutamide 160 mg/d as an adjunct to continued PSMA-RLT. Prostate-specific antigen (PSA) and standard toxicity screening lab work-up were performed to assess the treatment efficacy and safety in these individuals. The mean PSA increase under PSMA-RLT before starting the re-sensitizing procedure was 22.4 ± 26.5%. After the introduction of enzalutamide medication, all patients experienced a PSA decrease, –43.4 ± 20.0% and –48.2 ± 39.0%, after one and two cycles of enzalutamide-augmented PSMA-RLT, respectively. A total of 70% of patients (7/10) experienced partial remission, with a median best PSA response of –62%. Moreover, 5/6 enzalutamide-naïve patients and 2/4 patients who had previously failed enzalutamide exhibited a partial remission. There was no relevant enzalutamide-induced toxicity observed in this small cohort. This pilot experience suggests the synergistic potential of adding enzalutamide to PSMA-RLT derived from the intra-individual comparison of (177)Lu-based PSMA-RLT ± enzalutamide.