SABCS 2017: Phase III EMBRACA Trial Meets Primary Endpoint
Patients with advanced HER2-negative breast cancer with germline BRCA mutations had significantly prolonged progression-free survival when treated with the poly(ADP-ribose) polymerase (PARP) inhibitor talazoparib, compared with those who received chemotherapy of physician’s choice, according to data from the phase III EMBRACA trial, presented at the 2017 San Antonio Breast Cancer Symposium (Abstract GS6-07) by Litton et al.
“We are very pleased that the phase III 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,” said Jennifer Litton, MD, Associate Professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston.
Talazoparib is a dual-mechanism PARP inhibitor that inhibits the PARP enzyme and also traps PARP on DNA, thus preventing DNA damage repair, leading to death in BRCA1/2-mutated cells, Dr. Litton explained. Prior studies had shown that talazoparib’s unique structural properties make it more effective in trapping PARP-DNA complexes. This agent had yielded promising results in preclinical studies and previous phase I and II clinical trials.
“In EMBRACA, talazoparib demonstrated superior clinical benefit in all subsets of patients, regardless of receptor subtype (hormone receptor–positive or triple-negative breast cancer), number of prior lines of chemotherapy, BRCA mutation type, and central nervous system metastasis,” noted Dr. Litton.
The U.S. Food and Drug Administration has approved three PARP inhibitors so far—olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula)—to treat certain ovarian cancers, including those with BRCA gene mutations.
Study Details
EMBRACA is an open-label, randomized, phase III trial to compare the efficacy and safety of talazoparib at 1 mg/d with standard single-agent physician’s choice of therapy (capecitabine, eribulin [Halaven], gemcitabine, or vinorelbine) in patients with advanced breast cancer and a germline BRCA1/2 mutation. Patients were randomly assigned (2:1) to talazoparib (n = 287) or physician’s choice of therapy (n = 144).
The primary objective was progression-free survival, assessed by blinded independent central review, and secondary objectives were overall survival, overall response rate and clinical benefit rate at 24 weeks, and safety. Patient-reported outcomes were also measured.
The median progression-free survival was 8.6 months for patients in the talazoparib arm, vs 5.6 months for those in the physician’s-choice arm, and this difference was statistically significant (hazard ratio [HR] = 0.542, P < .0001). Patients in the talazoparib arm were 45.8% less likely to have disease progression, compared with those in the physician’s-choice arm.
Overall response rate and clinical benefit rate at 24 weeks showed a statistically significant improvement for those in the talazoparib arm compared with those in the physician’s-choice arm: The overall response rate was 62.6% for patients in the talazoparib arm, vs 27.2% for those in the physician’s-choice arm (HR = 4.99, P < .0001). Twelve complete responses were observed in the study, all in the talazoparib arm. The clinical benefit rate at 24 weeks was 68.6% for patients in the talazoparib arm, vs 36.1% for those in the physician’s-choice arm.
An interim analysis of overall survival was also conducted; although data are not yet mature, a positive trend favoring talazoparib was observed, with a 24% reduction in the risk of death. Survival data will continue to be monitored and final overall survival estimates reported once the data mature, Dr. Litton said.
Quality-of-life measurements revealed that in the talazoparib arm, patients had a significant delay in the time to deterioration in health compared with patients in the physician’s-choice arm, using the EORTC QLQ-C30 questionnaire.
“Most notable for this study was not only the improvement to date of [progression-free survival], but the time to clinical deterioration, which was 24.3 months for patients on talazoparib, vs 6.3 months for those on standard-of-care chemotherapy,” Dr. Litton noted.
Safety Profile
About 55% of patients in the talazoparib arm experienced grade 3-4 hematologic adverse events, vs 39% of those in the physician’s-choice arm. Talazoparib was associated with fewer grade 3-4 gastrointestinal disorders and skin/subcutaneous tissue disorders than physician’s choice of therapy. Grade 3-4 serious adverse events were observed in 26% and 25% of patients in talazoparib and physician’s-choice arms, respectively. Adverse events resulting in death occurred in 2.1% and 3.2% of patients in the talazoparib and physician’s-choice arms, respectively.
“Overall, once-daily oral talazoparib was well tolerated in comparison to chemotherapy, with improvements in progression-free survival and clinical responses, providing a significant option for patients with BRCA mutations and metastatic breast cancer. We look forward to following the [overall survival] results as those data mature,” said Dr. Litton.
Disclosure: The EMBRACA study was funded by Pfizer. Dr. Litton receives research funding from EMD Serono, AstraZeneca, Pfizer, Genentech, and GlaxoSmithKline and serves on advisory boards for Pfizer and AstraZeneca, all uncompensated.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
