Patients with advanced or metastatic HER2-negative breast cancer and germline BRCA1/2 mutations may benefit from talazoparib, according to data from a phase III trial. Compared with chemotherapy, the investigational PARP inhibitor induced some complete responses, prolonged progression-free survival, and improved patients' overall quality of life.

Findings from the global phase III EMBRACA study indicate that patients with advanced or metastatic HER2-negative breast cancer and germline BRCA1/2 mutations may benefit from the investigational PARP inhibitor talazoparib (Pfizer). The data were presented by Jennifer Litton, MD, of The University of Texas MD Anderson Cancer Center in Houston, during the 2017 San Antonio Breast Cancer Symposium, held December 5–9 in Texas.

To date, EMBRACA is “the largest randomized trial evaluating a PARP inhibitor in this patient population,” Litton said. A total of 431 patients were randomized 2:1 to receive talazoparib or physician's choice of therapy (PCT)—capecitabine, eribulin (Halaven; Eisai), gemcitabine, or vinorelbine.

Litton reported that the study met its primary endpoint, with a median progression-free survival (PFS) of 8.6 months for patients who received talazoparib, versus 5.6 months in the control arm. Key subgroup analyses—by hormone receptor status, for instance—“also showed a PFS trend that consistently favored talazoparib,” she said.

The objective response rate (ORR) to talazoparib was 62.6%, including 12 complete responses; by comparison, the ORR among patients given PCT was 27.2%. The median duration of response was 5.4 months and 3.1 months, respectively.

Overall survival data are still immature, Litton said, but as with PFS, the trend appears to favor talazoparib. In an interim analysis, the estimated survival probability at 24 months was 45% for those treated with the PARP inhibitor and 37% for the PCT arm.

Talazoparib was generally well tolerated, with the most common toxicity being anemia—“a class effect of PARP inhibitors,” Litton noted. Other side effects included fatigue, nausea, and headache. Importantly, she added, based on patient-reported quality-of-life outcomes, those in the talazoparib cohort “had an improved global health status and a significant delay in their time to clinical deterioration”—24.3 months versus 6.3 months.

Currently, the three commercially available PARP inhibitors—olaparib (Lynparza; AstraZeneca), rucaparib (Rubraca; Clovis Oncology), and niraparib (Zejula; Tesaro)—are approved for ovarian cancer only. Olaparib could become the first in this class to have an expanded indication, having been granted Priority Review by the FDA in October for treating germline BRCA1/2-mutant, HER2-negative metastatic breast cancer.

Like its counterparts, talazoparib is effective in suppressing PARP's enzymatic activity. Where these drugs differ is in their ability to also trap PARP on damaged DNA, creating a large protein moiety that blocks DNA replication and transcription, inducing greater cytotoxicity than that of catalytic inhibition alone. Preclinically, talazoparib appears to be as much as 100-fold more potent when it comes to trapping PARP–DNA complexes, compared with rucaparib and olaparib. Whether this potency could translate to superior clinical efficacy remains an open question, however, Litton said, because none of these agents have been compared head to head.

Kent Osborne, MD, director of Baylor College of Medicine's Cancer Center, also in Houston, observed that “Doctors would look at [EMBRACA] and say, ‘This is great, we're seeing some activity,’ but patients may think a 3-month prolongation of their time to progression is not much of an advantage.” He suggested identifying resistance mechanisms that need to be overcome, as well as exploring combinations with other drugs.

Litton agreed that combinations are “absolutely” a next step in evaluating PARP inhibitors for breast cancer. “I’m also intrigued by the patients who responded completely or very durably [to talazoparib]—in several cases, as long as 33 months,” she added. “We're trying to identify and better understand the characteristics of these extraordinary responders.” –Alissa Poh