The PARP inhibitor talazoparib significantly increased progression-free survival (PFS) over physician’s choice of therapy in a randomized phase III trial of patients with advanced breast cancer and a germline BRCA mutation.
“Talazoparib is a highly potent, dual-mechanism PARP inhibitor. It prevents the repair of DNA damage, and results in cell death,” said Jennifer K. Litton, MD, of the University of Texas MD Anderson Cancer Center in Houston. A previous phase II study showed encouraging efficacy with the agent in patients with BRCA1/2 mutations, which led to the new EMBRACA trial. Litton presented results of the trial at the 2017 San Antonio Breast Cancer Symposium (SABCS), held December 5–9.
The trial included 287 patients randomized to talazoparib, and 144 to physician’s choice (capecitabine, eribulin, gemcitabine, or vinorelbine). Because the various therapies have differing delivery methods, the study was open-label.
Patients were well-balanced between the groups, though the talazoparib group had a slightly younger median age (45 vs 50 years), and more of them had a disease-free interval (diagnosis to advanced breast cancer) of less than 12 months (37.6% vs 29.2%). In the physician’s choice group, 12.5% did not receive any study drug, compared with only 0.3% in the talazoparib group; the median duration of treatment was 6.1 months with talazoparib and 3.9 months with physician’s choice.
After a median follow-up period of 11.2 months, the median PFS was 8.6 months with talazoparib and 5.6 months with physician’s choice, for a hazard ratio (HR) of 0.54 (95% CI, 0.41–0.71; P < .0001). Subgroup analyses showed significantly better PFS with talazoparib regardless of the number of prior cytotoxic regimens received, BRCA1 or 2 mutations, history of central nervous system metastasis, and other factors.
An interim overall survival analysis favored talazoparib as well, but did not reach significance. The median overall survival was 22.3 months with the study drug, compared with 19.5 months with physician’s choice, for an HR of 0.76 (95% CI, 0.54–1.06; P = .105). Litton noted that this analysis was done after only about half the survival events required for a final analysis, but the separation of the survival curves is encouraging. “It will be important to follow this,” she said.
The objective response rate was 62.6% with talazoparib and 27.2% with physician’s choice, for an odds ratio of 4.99 (95% CI, 2.9–8.8; P < .0001). The duration of response was 5.4 months with the study drug and 3.1 months with talazoparib.
Almost half of talazoparib patients (49.0%) had a grade 3 hematologic adverse event, compared with 23.0% of physician’s choice patients; 5.9% and 15.1%, respectively, had grade 4 hematologic adverse events. Anemia was more common with talazoparib, with 112 patients having a grade 3/4 event. A total of 91 talazoparib patients (31.8%) and 48 physician’s choice patients (38.1%) had any grade 3/4 nonhematologic event.
There was no clinically relevant cardiac or vascular toxicity observed in the talazoparib patients. Similar numbers of patients in each group had an adverse event resulting in permanent drug discontinuation: 7.7% of the talazoparib patients and 9.5% of the physician’s choice patients.
“EMBRACA is the largest randomized trial evaluating a PARP inhibitor in patients with advanced breast cancer and a germline BRCA1/2 mutation,” Litton said during a press conference. Kent Osborne, MD, of Baylor College of Medicine and a co-director of SABCS 2017, noted that the future of these drugs is likely in combinations with other agents, given their relatively limited absolute improvement in PFS as monotherapy.