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

Abstract

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. <b>Methods:</b> 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. <b>Results:</b> Seventy-two patients were included. Patients with <i>TP53</i>/<i>PTEN/RB1</i> mutations demonstrated inferior overall survival, even after adjustment for age and race. <i>TP53/PTEN/RB1</i>, <i>BRCA1/2</i>, and <i>CHEK2/PALB2/ATM</i> 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. <b>Conclusion:</b> <i>TP53, PTEN</i>, and <i>RB1</i> 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.