Fu, Wei

PURPOSE 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 BRCA1/ 2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied. METHODS We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/ 2-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 BRCA1- versus BRCA2-altered mCRPC. RESULTS A total of 123 patients (13 BRCA1 and 110 BRCA2) 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. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA 50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively ( P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity. CONCLUSION PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.

PURPOSE In prostate cancer, inactivating CDK12 mutations lead to gene fusion–induced neoantigens and possibly sensitivity to immunotherapy. We aimed to clinically, pathologically, and molecularly characterize CDK12-aberrant prostate cancers. METHODS We conducted a retrospective multicenter study to identify patients with advanced prostate cancer who harbored somatic loss-of-function CDK12 mutations. We used descriptive statistics to characterize their clinical features and therapeutic outcomes (prostate-specific antigen [PSA] responses, progression-free survival [PFS]) to various systemic therapies, including sensitivity to poly (ADP-ribose) polymerase and PD-1 inhibitors. RESULTS Sixty men with at least monoallelic (51.7% biallelic) CDK12 alterations were identified across nine centers. Median age at diagnosis was 60.5 years; 71.7% and 28.3% were white and nonwhite, respectively; 93.3% had Gleason grade group 4-5; 15.4% had ductal/intraductal histology; 53.3% had metastases at diagnosis; and median PSA was 24.0 ng/mL. Of those who underwent primary androgen deprivation therapy for metastatic hormone-sensitive disease (n = 59), 79.7% had a PSA response, and median PFS was 12.3 months. Of those who received first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer (mCRPC; n = 34), 41.2% had a PSA response, and median PFS was 5.3 months. Of those who received a first taxane chemotherapy for mCRPC (n = 22), 31.8% had a PSA response, and median PFS was 3.8 months. Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none had a PSA response (median PFS, 3.6 months). Nine men received a PD-1 inhibitor as fourth- to sixth-line systemic therapy (pembrolizumab [n = 5], nivolumab [n = 4]); 33.3% had a PSA response, and median PFS was 5.4 months. CONCLUSION CDK12-altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors. A proportion of these patients may respond favorably to PD-1 inhibitors, which implicates CDK12 deficiency in immunotherapy sensitivity.