1. There was some progression-free survival benefit in adding veliparib to cisplatin in patients who had homologous recombination DNA repair deficiency (BRCA-like) triple-negative breast cancer, but no benefit for overall survival or objective response rate.
2. Adding veliparib to cisplatin increased grade 3 or higher levels of neutropenia, leukopenia, anemia, and thrombocytopenia.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Homologous recombination DNA repair deficiency (HRD) is common in triple-negative breast cancer (TNBC) and can be identified by mutations such as BRCA1/2. PARP inhibitors previously have shown efficacy in such patients however PARP inhibition has shown limited efficacy in breast cancers without germline BRCA mutations. This study evaluated if the addition of veliparib, a PARP inhibitor vs placebo to cisplatin can improve outcomes for patients with BRCA-wildtype metastatic triple-negative breast cancer that still exhibit HRD (BRCA-like). The primary outcome was progression-free survival (PFS) and secondary outcomes included overall survival (OS), toxicity due to treatment, objective response rate (ORR), and clinical benefit rate. This study found that for germline BRCA1/2 mutated patients, there was no PFS (HR 0.79 [95%CI 0.38-1.67], p=0.54), OS (HR 1.20 [95%CI 0.56-2.55, p=0.64), or ORR benefit (p=0.37). However, for BRCA-like patients, there was some PFS benefit (HR 0.57 [95%CI 0.37-0.88], p=0.010), but no OS (HR 1.20 [95%CI 0.56-2·55], p=0.64) or ORR benefit (p=1.00). There was no PFS, OS, or ORR benefit for the non-BRCA-like group. The most common grade 3 or worse adverse events included neutropenia (46% in the cisplatin plus veliparib group vs 20% in the cisplatin plus placebo group), leukopenia (27% vs 7%), anemia (23% vs 8%), and thrombocytopenia (19% vs 3%). The strengths of this study included using a biomarker panel to separate the groups into their respective BCRA status. Limitations of this study included a short follow-up time. Overall, this study showed that there is some PFS benefit in adding a PARP inhibitor to platinum-based chemotherapy in patients with HRD or BRCA-like metastatic triple-negative breast cancer.
In-Depth [randomized controlled trial]: This randomized, double-blind, placebo-controlled, multicenter, phase 2 trial, enrolled 320 patients with metastatic/recurrent TNBC as well as BRCA-associated breast cancer and divided them into three prespecified groups; germline BRCA1/2-mutated, BRCA-like, and non-BRCA-like based on germline and another DNA testing method. These patients were then randomized into cisplatin and veliparib (162 patients) vs cisplatin and placebo (158 patients). The median follow-up was 11.1 months. In the germline BRCA1/2 mutated group there was no difference in median PFS, 6.2 months in the cisplatin plus veliparib group and 6.4 months in the cisplatin plus placebo group (HR 0.79 [95%CI 0.38-1.67], p=0.54), no difference in median OS, 14.2 months vs 15.6 months (HR 1.20 [95%CI 0.56-2.55, p=0.64), and no statistical difference in ORR (45% vs 33%, p=0.37). In the BRCA-like group, PFS improved with cisplatin plus veliparib compared with cisplatin plus placebo, 5.9 months vs 4.2 months (HR 0.57 [95%CI 0.37-0.88], p=0.010) but had no difference in OS, 14.2 months vs 15.6 months (HR 1.20 [95%CI 0.56-2·55], p=0.64) nor in ORR, 55% vs 56%, p=1.00. In the non-BRCA-like group, veliparib did not provide a significant benefit for PFS, 4.0 months in the cisplatin plus veliparib group and 3.0 months in the cisplatin plus placebo group (HR 0.89 [95%CI 0.60-1.33], p=0.57), nor did it provide benefit for OS, 10.9 months vs 11·1 months (HR 1.14 [95%CI, 0.76-1.71], p=0.53) nor in ORR 17% vs 19%, p=1.00. There was a fourth unclassified biomarker group with either no samples or samples that were unable to be assessed, and that group found no difference in PFS or OS between the two arms. A subgroup analysis of the BRCA-like group which involved patients with a high genomic instability score showed a statistically significant improvement in PFS, 6.1 months in the cisplatin plus veliparib group and 4.2 months in the cisplatin plus placebo group (HR 0.57 [95%CI 0.35-0.95]). The most common grade 3 or worse adverse events were neutropenia (46% in the cisplatin plus veliparib group vs 20% in the cisplatin plus placebo group), leukopenia (27% vs 7%), anemia (23% vs 8%), and thrombocytopenia (19% vs 3%). Overall this study showed that there is some PFS benefit in adding veliparib to cisplatin in patients with BRCA-like metastatic triple-negative breast cancer.
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