The phase 3 EMBRACA clinical trial has found no statistically significant overall survival (OS) benefit for patients with metastatic human epidermal growth factor receptor 2 (HER2)-negative breast cancer and mutations in the BRCA 1 and 2 genes. However, the research did confirm earlier studies that found talazoparib improved patient-reported quality-of-life measures and had a tolerable safety profile.

The FDA approved talazoparib in 2018, following the EMBRACA primary analysis, which found that patients treated with the drug had significantly prolonged progression-free survival compared with patients treated with chemotherapy.

The final OS analysis was performed using the intent-to-treat population after 324 deaths were observed. Patients receiving talazoparib had a median follow-up of 44.9 months whereas those receiving chemotherapy had a median follow-up of 36.8 months.

Mutations in the BRCA1/2 genes account for between 5% and 10% of all breast cancers, according to a news release from MD Anderson. They cause defects in normal DNA damage repair, and PARP inhibitors block an additional DNA repair pathway. Because of this, the anti-tumor effects of PARP inhibitors can be more intense in patients with these mutations.

The international phase 3 clinical trial enrolled 431 patients with locally advanced or metastatic and hereditary BRCA1/2 gene mutations. Due to the availability of approved targeted therapies for HER2-positive disease, patients with HER2-positive breast cancer were excluded.

The trial randomized 431 patients 2:1 to receive either talazoparib or the physician’s choice of treatment of single-agent therapy (capecitabine, eribulin, gemcitabine, or vinorelbine). In total, 54% had hormone receptor-positive disease and 46% had triple negative breast cancer, while 45% had BRCA1 mutations and 55% had BRCA2 mutations.

Nearly 50% of patients administered talazoparib also received a subsequent PARP inhibitor or platinum therapy, compared with nearly 60% of patients who received chemotherapy. 

After the follow-up periods, 216 patients in the talazoparib group and 108 patients in the chemotherapy group had died.

Despite this lack of a statistically significant OS benefit, the researchers noted that the OS analysis underestimated the treatment benefit of talazoparib. Patient-reported quality-of-life measures reported an average of 26.3 months until deterioration of overall health among the talazoparib arm, compared with just 6.7 months for the chemotherapy arm.

“Talazoparib remains an option for patients with advanced breast cancer and a germline BRCA mutation due to its improvements in progression free survival,” said Jennifer Litton, MD, professor of breast medical oncology, in a statement. “Other advantages include it being an oral once-daily option, as well as the demonstrated improvements in quality of life for metastatic breast cancer patients.”

Grade 3-4 hematological adverse events occurred in 56.6% of patients receiving talazoparib compared with 38.9% of those receiving chemotherapy. Most of those events reported in the talazoparib group were hematologic and most were successfully managed.

Correlative studies and analysis are underway using the EMBRACA population to research the effects of tumor BRCA zygosity and genomic loss-of-heterozygosity on efficacy outcomes.

REFERENCE
Patients with advanced BRCA-mutated breast cancer found no overall survival benefit with talazoparib [news release]. MD Anderson Cancer Center; April 26, 2020. https://www.mdanderson.org/newsroom/study-finds-no-overall-survival-benefit-but-improved-quality-of-life-with-talazoparib-in-advanced-BRCA-mutated-breast-cancer.h00-159381156.html. Accessed April 28, 2020.