Talazoparib, a PARP inhibitor is more effective than chemotherapy in reducing the risk of disease progression and death from BRCA-positive breast cancer.
Talazoparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, was tested against chemotherapy to see whether it significantly reduced the risk of disease progression or death. It did, beating out chemotherapy by 46 percent in patients with BRCA-positive advanced breast cancer, according to findings from the phase 3 EMBRACA trial presented at the 2017 San Antonio Breast Cancer Symposium.
At a median follow-up of 11.2 months, the median progression-free survival (PFS) was 8.6 months with talazoparib compared with 5.6 months with physician’s choice of therapy. The objective response rate (ORR) was 62.6 percent versus 27.2 percent, respectively.
“We are very pleased that the phase 3 EMBRACA trial—the largest randomized clinical trial conducted in this group of patients with hereditary breast cancer—met its primary efficacy endpoint of progression-free survival,” lead author Jennifer Litton, M.D., associate professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, said in a press release.
The international, open-label EMBRACA trial tested 431 patients with locally advanced or metastatic HER2-negative breast cancer and a germline BRCA1 or BRCA2 mutation. Patients were randomized in a 2:1 ratio to oral talazoparib at 1 mg daily or physician’s choice of therapy, which included capecitabine (received by 44 percent of patients), eribulin (40 percent), gemcitabine (10 percent), and vinorelbine (7 percent).
Patient characteristics were mostly well balanced between the two arms, with a few variations of note. In the talazoparib arm, 63.4 percent of patients were younger than age 50, compared with 46.5 percent of patients in the control arm. Fifteen percent of patients receiving the PARP inhibitor had a history of central nervous system (CNS) metastasis, compared with 13.9 percent in the chemotherapy group. In the talazoparib group, 37.6 percent of patients had a disease-free interval (initial diagnosis to advanced breast cancer) of under 12 months versus 29.2 percent in the chemotherapy arm.
At the time of the data cutoff, treatment was ongoing in 64 patients in the talazoparib arm compared with seven patients in the chemotherapy arm. The primary reasons for discontinuation in the talazoparib arm were side effects (4.5 percent vs 5.6 percent in the physician’s choice arm), progressive disease (68.6 percent vs 60.4 percent, respectively), subject withdrawal (1.0 percent vs 18.8 percent), and physician decision (3.5 percent vs 9.0 percent). Long-term follow-up was ongoing in 57.8 percent and 45.1 percent of the talazoparib and control arms, respectively.
The median duration of treatment was 6.1 months versus 3.9 months for talazoparib versus chemotherapy, respectively. PFS was the primary endpoint, with overall survival (OS), ORR, and safety as key secondary endpoints, and duration of response for responders and quality of life (QoL) as exploratory endpoints.
The PFS benefit with talazoparib was observed across all predetermined patient subgroups, according to Litton. “In EMBRACA, talazoparib demonstrated superior clinical benefit in all subsets of patients, regardless of receptor subtype (HR-positive or triple-negative breast cancer), number of prior lines of chemotherapy, BRCA mutation type, and central nervous system metastasis.”
Among patients with measurable disease, the complete response (CR) rate in the talazoparib arm was 5.5 percent, the partial response (PR) rate was 57.1 percent, and the stable disease rate was 21.0 percent. The corresponding rates in the physician’s choice arm were 0, 27.2 percent, and 31.6 percent, respectively.
The median duration of response was 5.4 months with talazoparib and 3.1 months with chemotherapy. The one-year probability of sustained response was 23 percent vs 0 percent, respectively.
The OS data are not yet mature; however, an interim OS analysis found a positive trend favoring talazoparib, with a 24 percent reduction in the risk of death. The median OS was 22.3 months with the PARP inhibitor versus 19.5 months with chemotherapy.
The investigators considered talazoparib to be well tolerated overall. The safety analysis included 286 patients from the talazoparib arm and 126 patients from the control arm.
Grade 3 hematologic side effects in the talazoparib group included anemia (38.5 percent vs 4.0 percent with chemotherapy), neutropenia (17.8 percent vs 19.8 percent, respectively), thrombocytopenia (11.2 percent vs 1.6 percent), and lymphopenia (3.1 percent vs 0).
In the talazoparib arm, grade 4 hematologic side effects included anemia (0.7 percent vs 0.8 percent with chemotherapy), neutropenia (3.1 percent vs 15.1 percent, respectively), thrombocytopenia (3.5 percent vs 0), and febrile neutropenia (0.3 percent vs 0.8 percent).