The now-published results from the EMBRACA study confirm that talazoparib (Pfizer), a poly-adenosine diphosphate-ribose polymerase (PARP) inhibitor, prolongs progression-free survival (PFS) in patients with advanced BCRA-positive breast cancer compared with single-agent chemotherapy alone and that it also significantly improves quality of life(QoL)
This is the largest randomized trial in BRCA mutation carriers [ever undertaken] and demonstrates PARP efficacy," Jennifer Litton, MD, associate professor in the Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News in an email.
"I think what was striking was that patients felt better on [talazoparib] than on chemotherapy and the time to meaningful deterioration was significantly improved on talazoparib than on standard chemotherapy," she added.
"The next steps will be to look beyond BRCA mutation carriers with combinations that may expand who may benefit or prolong their activity," Litton said. The study was published online on August 15 in the New England Journal of Medicine.
The study has now been submitted in an approved application to the US Food and Drug Administration (FDA) and also the European Medicines Agency. The FDA recently granted a priority review designation to Pfizer for talazoparib for the treatment of BRCA-mutated, human epidermal growth factor receptor 2–negative, locally advanced or metastatic breast cancer.
EMBRACA Study Design
As previously reported by Medscape Medical News, 287 patients received talazoparib, at a dose of 1 mg a day, and 144 patients received single-agent chemotherapy of their physician's choice. The chemotherapy could consist of capecitabine (Xeloda, Genentech), eribulin (Halaven, Eisai), gemcitabine (Gemzar, Pfizer), or vinorelbine (Navelbine, Pfizer), given in continuous 21-day cycles.
The response rate to the PARP inhibitor was also numerically higher, at 62.6% compared with 27.2% for standard therapy. Also, 5.5% of patients treated with talazoparib but no patients in the standard therapy group achieved a complete response. The median duration of response was also longer in the talazoparib group than in the standard chemotherapy group: 5.4 months vs. 3.1 months.
At the time of the interim analysis, median overall survival was 22.3 months in the talazoparib group compared with 19.5 months in the standard therapy group; the difference between the groups was not statistically significant (P = .11).
Regardless of the subgroup analyzed, the hazard ratios (HRs) for disease progression or death were also in favor of talazoparib compared with single-agent chemotherapy.
Investigators also assessed patient-reported outcomes through the use of the European Organisation for Research and Treatment for Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) as well as the breast cancer-specific QLQ-BR23 at baseline, at the beginning of each treatment cycle and the end of treatment.
By the estimated overall mean change from baseline on the EORTC QLQ-C30 scale, patients treated with talazoparib had a significant improvement from baseline to treatment endpoint, with a score of 3.0, compared with a significant deterioration in the standard therapy group, at a score of –5.4 (P < .001).
"As compared with standard therapy, treatment with talazoparib resulted in a significant delay in the onset of clinically meaningful deterioration according to the global health status–quality-of-life scale," the study authors add. "The majority of nonhematologic adverse events in the talazoparib group were grade 1 in severity," they indicate.
As investigators explain, inhibition of the PARP enzyme in cells expressing the BRCA1/2 mutation causes cell death due to an accumulation of irreparable DNA damage.
"Several other PARP inhibitors have shown positive results, so I think the concept has been shown to work in some of these patients," Osborne said at the meeting. This includes olaparib (Lynparza, AstraZeneca), which was recently approved by the FDA as the first drug specifically indicated for use in BRCA-mutated breast cancer.
However, Osborne cautioned that investigators still need to identify which patients will respond best to PARP inhibitor therapy and to characterize mechanisms of PARP drug resistance because in some cases, "tumor cells can repair the BRCA mutation and if there is no longer any mutation, the drug is no longer going to work," he said.