NEW YORK – The addition of AbbVie's investigational PARP inhibitor veliparib to a chemotherapy doublet of carboplatin and paclitaxel could prolong progression-free survival in patients with HER2-negative advanced breast cancer harboring germline BRCA1 or BRCA2 mutations, according to results from the randomized Phase III BROCADE3 trial recently published in The Lancet Oncology.
The clinical trial, which was conducted across 147 hospitals in 36 countries, randomized a total of 509 patients with confirmed BRCA1 or BRCA2 mutations — as assessed by Myriad Genetics' BRACAnalysis CDx assay — to receive either the chemo doublet plus veliparib or the chemo doublet plus a placebo. Crossover was allowed for patients in the placebo group who experienced disease progression during treatment with the chemotherapy. Specifically, these patients could go on to receive single-agent veliparib treatment.
Among the patients randomized to the three-agent arm, the median progression-free survival was 14.5 months compared to 12.6 months for the control group. After three years, progression-free survival was 25.7 percent and 10.7 percent for the veliparib and control groups, respectively. Median overall survival was 33.4 months and 28.2 months in the veliparib and control groups, respectively, though at the time of the overall survival analysis, 44 percent of patients who had been randomly assigned to the control group had received veliparib monotherapy upon disease progression, meaning that overall survival comparisons could not isolate the benefit of the PARP inhibitor quite as clearly as progression-free survival.
While other PARP inhibitors, including olaparib (AstraZeneca/Merck's Lynparza) and talazoparib (Pfizer's Talzenna) have demonstrated benefit in treating patients with breast cancer harboring BRCA1 or BRCA2 mutations — and have garnered regulatory approvals for these indications — the study authors of the BROCADE3 trial results highlighted what they saw as potential unique benefits of veliparib over these other PARP inhibitors. Specifically, they wrote that veliparib is "more suitable than other PARP inhibitors to be administered in combination with platinum-based chemotherapy," because veliparib selectively inhibits PARP without substantially trapping PARP protein onto DNA damage repair intermediates, a phenomenon that has been associated with bone marrow suppression. The ability to combine the agent with platinum-based chemo safely and tolerably, the authors later wrote, could potentially "be a rational strategy to allow patients to benefit from both agents before developing cross-resistance."
AbbVie is also evaluating veliparib as a treatment for patients with ovarian cancer and non-small cell lung cancer.