Differential Activity of PARP Inhibitors in <i>BRCA1</i>- Versus <i>BRCA2</i>-Altered Metastatic Castration-Resistant Prostate Cancer.

Abstract

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 <i>BRCA1</i>/<i>2</i> mutations, but the relative efficacy of PARP inhibition in <i>BRCA1</i>- versus <i>BRCA2</i>-altered mCRPC is understudied. We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with <i>BRCA1</i>/<i>2</i>-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 <i>BRCA1</i>- versus <i>BRCA2</i>-altered mCRPC. A total of 123 patients (13 <i>BRCA1</i> and 110 <i>BRCA2</i>) 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. <i>BRCA1</i> patients were more likely to have metastatic disease at presentation (69% <i>v</i> 37%; <i>P</i> = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% <i>v</i> 46%; <i>P</i> = .78) in both groups. <i>BRCA1</i> patients had more monoallelic (56% <i>v</i> 41%; <i>P</i> = .49) and concurrent <i>TP53</i> (55% <i>v</i> 36%; <i>P</i> = .32) mutations. PSA₅₀ responses in <i>BRCA1</i>- versus <i>BRCA2</i>-altered patients were 23% versus 63%, respectively (<i>P</i> = .01). <i>BRCA2</i> patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; <i>P</i> = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; <i>P</i> = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; <i>P</i> = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent <i>TP53</i> mutation were associated with PARP inhibitor sensitivity. PARP inhibitor efficacy is diminished in <i>BRCA1</i>- versus <i>BRCA2</i>-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent <i>TP53</i> alterations in the <i>BRCA1</i> group.