Association between DNA damage repair alterations and outcomes to ¹⁷⁷Lu-PSMA-617 in advanced prostate cancer

Background: ¹⁷⁷Lu-prostate-specific membrane antigen (PSMA)-617 (LuPSMA) is a radionuclide therapy approved for patients with PSMA-avid metastatic castrate-resistant prostate cancer (mCRPC). We evaluated whether alterations in the DNA damage repair (DDR) pathway were associated with outcomes to LuPSMA.

Patients and methods: We identified an institutional cohort of men (n = 134) treated with ≥2 cycles of LuPSMA who had panel-based germline and/or tumor genomic sequencing. Mutations or two-copy losses in any of BRCA1, BRCA2, ATM, CDK12, PALB2, RAD51, and MSH2 were considered DDR defects. The primary outcome was a ≥50% reduction in the prostate-specific antigen (PSA) level during LuPSMA therapy (PSA50); secondary outcomes were PSA progression-free survival (PSA-PFS) and overall survival (OS). Models were adjusted for age, number of prior systemic therapies, sites of metastasis, and log-transformed PSA at cycle 1.

Results: Thirty-four patients (25%) harbored DDR alterations, most commonly in BRCA2 and ATM (both n = 13). The presence of a DDR defect was not associated with PSA50 [adjusted odds ratio 0.48 (0.20-1.09), P = 0.08], PSA-PFS [adjusted hazard ratio (HR) 1.29 (0.79-2.10), P = 0.30], or OS [adjusted HR 1.42 (0.74-2.72), P = 0.29], with a non-significant trend toward poorer outcomes among DDR-altered patients.

Conclusions: DDR alterations were not associated with outcomes following LuPSMA. This has implications for treatment sequencing in mCRPC, particularly in patients with DDR alterations.