BRCA1 Versus BRCA2 and PARP Inhibitors Efficacy in Solid Tumors:A Meta-Analysis of Randomized Controlled Trials

Abstract

BackgroundBRCA2 mutation has a more substantial impact on the homologous recombination and superior therapeutic response to platinum-based chemotherapy than BRCA1 mutation. Whether BRCA2-mutated patients could benefit more from PARPi than BRCA1-mutated patients remains unclear. We performed a meta-analysis to assess the efficacy difference of PARPi between BRCA1 mutation carriers and BRCA2 mutation carriers.MethodsPubmed, Embase, and Cochrane Library were comprehensively searched for randomized controlled trials (RCTs) of PARPi that had available hazard ratios (HRs) of progression-free survival (PFS) in both BRCA1-mutated population and BRCA2-mutated population. We calculated the pooled PFS HRs and 95%CI using randomized-effect models, and the difference between the two estimates was compared by interaction test.ResultsA total of 11 eligible RCTs of high quality were identified through search. Overall, 1544 BRCA1 mutation carriers and 1191 BRCA2 mutation carriers were included in the final analysis. The pooled PFS HR was 0.42 (95% CI: 0.35-0.50) in BRCA1-mutated patients who were treated with PARPi compared with patients in the control group. In BRCA2-mutated patients treated with PARPi, the pooled PFS HR compared with the control groups was 0.35 (95% CI: 0.24-0.51). The difference in efficacy of PARPi was not significant between the two subgroups (Pheterogeneity = 0.40, for interaction).ConclusionBRCA1-mutated patients and BRCA2-mutated patients could benefit from PARPi, and the efficacy is comparable. Currently, there is no evidence that BRCA2-mutated patients would benefit more from PARPi than BRCA1-mutated patients.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42020214582.

Efficacy of Poly(ADP-ribose) Polymerase Inhibitors by Individual Genes in Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer: A US Food and Drug Administration Pooled Analysis

“…Results of both PARPi plus ARPI and PARPi monotherapy trials were consistent and demonstrated a strong treatment effect of PARPi therapy. These results are consistent with the results of PARPi in other BRCA2m solid tumors 22. CDK12m subgroup, both rPFS and OS favored the PARPi arm.…”

“…The ORR in PARPi monotherapy group, and the increase in ORR by adding PARPi to ARPI, provides further supportive evidence of efficacy of PARPi in patients with BRCA1m mCRPC. Although the 95% CIs for rPFS and OS are wide because of small number of patients in this subgroup, overall, the results suggest a favorable treatment effect of PARPi in patients with BRCA1m mCRPC, consistent with results of PARPi trials across other tumors 22. BRCA2mBRCA2m was the largest subgroup in this pooled data set.…”

The BRCA Gene in Epithelial Ovarian Cancer

“…Even in the subgroup analyses performed according to the cancer types, study methodology and lines of therapy, no statistically significant differences in the efficacy of PARPi were found between the BRCA1- or 2-mutated patients. Both BRCA1 mutation carriers and 2 mutation carriers could significantly benefit from PARPi regardless of cancer types and therapeutic lines [ 37 ].…”

Expanding the Use of PARP Inhibitors as Monotherapy and in Combination in Triple-Negative Breast Cancer

“…Although a preclinical study identified a 2.3-fold enhanced sensitivity to PARPi in BRCA2-deficient in comparison to BRCA1-deficient cells [28], clinical trials have demonstrated mixed results. Indeed, a meta-analysis identified comparable efficacy of PARPi in BRCA1 MUT versus BRCA2 MUT solid cancers [94]. Since no trial has performed a back-to-back comparison of efficacy in BRCA1 MUT and BRCA2 MUT groups, we will describe the results of subgroup analysis from four randomized trials in breast cancer.…”