Differential Response to ¹⁷⁷ Lu-PSMA-617 in Patients with Tumor Suppressor Gene–Mutated Metastatic Castration-Resistant Prostate Cancer

Genomic alterations are common in metastatic castration-resistant prostate cancer (mCRPC), but limited data exist on the response to ¹⁷⁷Lu-PSMA-617 (LuPSMA) in patients with these aberrations. We aimed to characterize oncologic outcomes of patients with mCRPC and germline or somatic aberrations after treatment with LuPSMA. Methods: The medical record was surveyed for all patients with mCRPC treated with LuPSMA between October 2022 and October 2024. All patients who had received at least 1 cycle of LuPSMA and underwent either germline or somatic testing were included. Results: Seventy-two patients were included. Patients with TP53/PTEN/RB1 mutations demonstrated inferior overall survival, even after adjustment for age and race. TP53/PTEN/RB1, BRCA1/2, and CHEK2/PALB2/ATM were not associated with inferior progression-free survival. No individual mutation was significantly associated with changes in the percentage decline in prostate-specific antigen levels from baseline. Conclusion: TP53, PTEN, and RB1 mutations were linked to inferior overall survival in LuPSMA-treated patients and may serve as prognostic biomarkers. Prospective validation is required to establish their predictive value.