Association of Prior PARP Inhibitor Exposure with Clinical Outcomes after 177Lu-PSMA-617 in Men with Castration-resistant Prostate Cancer and Mutations in DNA Homologous Recombination Repair Genes.

Background and objective: The prostate-specific membrane antigen (PSMA) radioligand ¹⁷⁷Lu-PSMA-617 (LuPSMA) is approved for treatment of metastatic castration-resistant prostate cancer (mCRPC). PARP inhibitors (PARPi) are approved for patients with mCRPC and mutations in homologous recombination repair (HRR) pathway genes. Both modalities induce DNA damage and therefore may share mechanisms of resistance. We investigated whether PARPi exposure would reduce the subsequent efficacy of LuPSMA.

Methods: This retrospective study included 100 patients with a PARPi-qualifying HRR alteration treated with LuPSMA. Clinical outcomes on LuPSMA, including PSA₅₀ response, PSA progression-free survival (PFS), and overall survival (OS), were compared between those who had not previously received PARPi (PARPi-N) and those who had (PARPi-T). Subgroup analyses were performed for the most frequent HRR alterations (BRCA2 and ATM).

Key findings and limitations: PSA₅₀ responses on LuPSMA were similar between PARPi-N (n = 47) and PARPi-T (n = 53), although PSA PFS was longer in the PARPi-N group (9.1 vs 4.8 mo; p = 0.037). Among patients with BRCA2 alterations, the PARPi-N group had a better PSA₅₀ response rate (89% vs 35%; p = 0.009), PSA PFS (14 vs 2.9 mo; p = 0.026), and OS (19 vs 5.3 mo; p = 0.10). PARPi exposure did not influence LuPSMA outcomes among patients with ATM alterations. Limitations include the retrospective design and differences in prior lines of therapy between the groups.

Conclusions and clinical implications: PARPi exposure is associated with inferior LuPSMA outcomes, particularly for patients with BRCA2 alterations. These findings suggest potential cross-resistance and underscore the need for prospective studies assessing the optimal sequencing of these agents.