Differential Activity of PARP Inhibitors in - Versus -Altered Metastatic Castration-Resistant Prostate Cancer.

UNLABELLED: Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring / mutations, but the relative efficacy of PARP inhibition in - versus -altered mCRPC is understudied.

METHODS: We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with /-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among - versus -altered mCRPC.

RESULTS: A total of 123 patients (13 and 110 ) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. patients were more likely to have metastatic disease at presentation (69% 37%; = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% 46%; = .78) in both groups. patients had more monoallelic (56% 41%; = .49) and concurrent (55% 36%; = .32) mutations. PSA responses in - versus -altered patients were 23% versus 63%, respectively ( = .01). patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent mutation were associated with PARP inhibitor sensitivity.

CONCLUSION: PARP inhibitor efficacy is diminished in - versus -altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent alterations in the group.