In a phase II trial (S1416) reported in The Lancet Oncology, Rodler et al found that the addition of the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib to cisplatin significantly improved progression-free survival in patients with germline BRCA1/2 wild-type advanced triple-negative breast cancer with a BRCA-like phenotype, but not among those without the BRCA-like phenotype.

Study Details

In the U.S. multicenter double-blind trial, 320 patients with recurrent or metastatic disease who had received up to one prior therapy for metastatic disease were randomly assigned between July 2016 and June 2019 to receive cisplatin at 75 mg/m² on day 1 plus either veliparib at 300 mg twice daily (n = 162) or placebo (n = 158) on days 1 to 14 in 21-day cycles.

Among the 320 patients, 247 had information available to allow classification into three biomarker groups:

• 37 had germline BRCA1/2-mutated disease (13 in the veliparib group vs 24 in the control group)
• 101 had BRCA-like disease (56 in the veliparib group vs 45 in control group)
• 109 had non–BRCA-like dsease (57 in the veliparib group vs 52 in control group).

BRCA-like status was based on presence of at least one of the following characteristics: genomic instability score (≥ 42), somatic BRCA1/2 mutations, BRCA1 promoter methylation, or non-BRCA1/2 homologous recombination repair germline mutations. The primary endpoint was investigator-assessed progression-free survival, analyzed separately for the three biomarker groups.

Progression-Free Survival

Median follow-up was 11.1 months (interquartile range = 5.6–20.8 months). In the germline BRCA1/2-mutated group, median progression-free survival was 6.2 months (95% confidence interval [CI] = 2.3–9.2 months) in the veliparib group vs 6.4 months (95% CI = 4.3–8.2 months) in the control group (hazard ratio [HR] = 0.79, 95% CI = 0.38–1.67, P = .54). In the BRCA-like group, median progression-free survival was 5.9 months (95% CI = 4.3–7.8 months) in the veliparib group vs 4.2 months (95% CI = 2.3–5.0 months) in the control group (HR = 0.57, 95% CI = 0.37–0.88, P = .010). In the non–BRCA-like group, median progression-free survival was 4.0 months (95% CI = 2.5–4.7 months) in the veliparib group vs 3.0 months (95% CI = 2.2–4.4 months) in the control group (HR = 0.89, 95% CI = 0.60–1.33, P = .57).

Adverse Events

Among 155 patients in the veliparib/cisplatin group and 147 in the placebo/cisplatin group in the safety population, the most common treatment-related grade ≥ 3 adverse events were neutropenia (46% vs 20%), leukopenia (27% vs 7%), anemia (23% vs 8%), and thrombocytopenia (19% vs 3%). Treatment-related serious adverse events occurred in 31% vs 36% of patients. Treatment-related adverse events led to death in one patient in the veliparib group (due to sepsis) and one patient in the control group (due to cisplatin-related acute kidney injury and heart failure from previous doxorubicin exposure).

The investigators concluded, “The addition of veliparib to cisplatin significantly improved progression-free survival in patients with BRCA-like metastatic triple-negative breast cancer, but not in patients with non–BRCA-like metastatic breast cancer. PARP inhibitors combined with platinum-based chemotherapy should be explored further in BRCA-like triple-negative breast cancer.”

Priyanka Sharma, MD, of the Department of Internal Medicine, University of Kansas Medical Center, Westwood, is the corresponding author for The Lancet Oncology article. 

Disclosure: The study was funded by the National Institutes of Health, National Cancer Institute, University of Kansas Cancer Center, AbbVie, and Myriad Genetics. For full disclosures of the study authors, visit thelancet.com.