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

Abstract

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.