Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer

Abstract

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. PSA50 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.

Emerging Biomarker-Guided Therapies in Prostate Cancer

“…Other PARP inhibitors, such as talazoparib and niraparib, are also being investigated [ 75 , 76 ]. Interestingly, there seems to be a class effect whereby PARP inhibitors seem to have increased activity in patients with BRCA2 mutations compared to BRCA1 [ 77 , 78 ]. A meta-analysis of PARP inhibitors in mCRPC demonstrated that BRCA mutations and HRR mutations were effective biomarkers in predicting response to PARP inhibitors in mCRPC [ 79 ].…”

Integrative Genomic Tests in Clinical Oncology

“…Another issue is the varying functional impact of HR gene alterations. Even BRCA1 , which is obviously associated with the HRD phenotype in breast or ovarian cancer, does not necessarily undergo second-hit inactivation in pancreatic or prostate carcinomas [ 51 , 52 ]. The efficacy of olaparib in prostate cancer is primarily attributed to the presence of the BRCA2 gene within the NGS-HRR panel, while many other genes included in the above list do not render sensitivity to this drug [ 47 , 49 ].…”

Implications of DNA damage repair alterations for the management of prostate cancer

“…Retrospective analyses suggest a diminished efficacy of PARPi in BRCA1 compared with BRCA2 mCRPC patients [54 ▪ ,55]. This difference might be related to BRCA1 alterations being more often monoallelic [10] and to the co-occurrence of other genomic events in the tumour, such as TP53 mutations [55]. Patients with ATM alterations seem to get limited benefit from PARPi in monotherapy [47 ▪ ,52 ▪▪ ,56].…”

“…All the aforementioned studies have consistently reported that patients with BRCA2 alterations are the ones that benefit the most from PARPi in monotherapy [ 55]. This difference might be related to BRCA1 alterations being more often monoallelic [10] and to the co-occurrence of other genomic events in the tumour, such as TP53 mutations [55] ]. Less frequent HRR alterations may also predict response to PARP inhibitors; however, these are underrepresented in the trials reported to date and the data currently available is insufficient to understand their value as predictors of response to PARPi.…”