In patients with BRCA-positive advanced breast cancer, talazoparib reduced the risk of disease progression or death by 46% vs chemotherapy, according to the phase III EMBRACA trial presented at the 2017 San Antonio Breast Cancer Symposium.¹

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.

— Jennifer Litton, MD

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“We are very pleased that the 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, of The University of Texas MD Anderson Cancer Center, Houston.

Talazoparib is an oral investigational inhibitor of poly ADP-ribose polymerase (PARP) that has a dual mechanism of action. Talazoparib has the potential to induce tumor cell death by blocking PARP enzyme activity and trapping PARP on the sites of DNA damage. It is currently being evaluated in advanced BRCA-mutated breast cancer and some other cancer types. 

EMBRACA Details

The international, open-label EMBRACA trial enrolled 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 receive oral talazoparib at 1 mg daily or physician’s choice of therapy, which included capecitabine (44%), eribulin (Halaven, 40%), gemcitabine (10%), and vinorelbine (7%).

Aside from two factors, patient characteristics were well balanced between the arms. In the talazoparib arm, more patients were younger than 50 years, slightly more had a history of brain metastases, and more had a short disease-free interval (< 12 months).

At the time of the data cutoff, treatment was ongoing in 64 patients in the talazoparib arm, compared with 7 patients in the chemotherapy arm. The median duration of treatment was 6.1 vs 3.9 months, respectively. 

Primary Endpoint Met

After a median follow-up of 11.2 months, median progression-free survival was 8.6 months with talazoparib compared with 5.6 months with physician’s choice of therapy (hazard ratio [HR] = 0.54, P < .0001). The objective response rate was 62.6% vs 27.2%, respectively (odds ratio = 4.99; P < .0001), including complete responses in 5.5% with talazoparib and none with chemotherapy. Median duration of response was 5.4 months and 3.1 months (HR = 0.43, P = .0005), with a 1-year probability of sustained response of 23% vs 0%, respectively. 

“The curves separated early, and the separation continues…. I am intrigued by the tail of these curves and the complete and long-term responders,” Dr. Litton said. “Our correlative studies will seek to identify the extraordinary responders, understand the mechanisms of resistance to talazoparib, and evaluate combinations that will enhance the drug’s effect and expand its use.” 

For overall survival, an interim analysis showed a positive trend favoring talazoparib, with a 24% reduction in the risk of death. Median survival was 22.3 months with the PARP inhibitor vs 19.5 months with chemotherapy (HR = 0.76, P = .105). At the 24-month landmark analysis, the survival probability was 45% for talazoparib arm vs 37% for physician’s choice of therapy.

“The hazard ratio [0.76] does not reach statistical significance, but the curves do separate at the end, so it will be important to follow this as the data mature,” she commented.

Subset Analyses

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. “In key subgroup analyses, outcomes remain consistent, with all favoring talazoparib and only patients with prior platinum therapy having a confidence interval that passes 1,” she said. 

Dr. Litton also emphasized that hormone receptor–positive patients “had a robust response,” with a hazard ratio of 0.47—better than the 0.60 hazard ratio seen in the triple-negative subset. She explained that the presence of BRCA mutations is not restricted to triple-negative tumors, especially BRCA2. “Ongoing research will look at combinations that could bring this agent beyond germline or somatic BRCA mutations,” she added. 

Tolerability and Quality of Life

Talazoparib was well tolerated overall. Grade 3 hematologic adverse events with talazoparib, vs chemotherapy, included anemia (38.5% vs 4.0%), neutropenia (17.8% vs 19.8%), thrombocytopenia (11.2% vs 1.6%), and lymphopenia (3.1% vs 0%). Grade 4 hematologic adverse events were anemia (0.7% vs 0.8%), neutropenia (3.1% vs 15.1%), thrombocytopenia (3.5% vs 0%), and febrile neutropenia (0.3% vs 0.8%). Nonhematologic adverse events grade ≥ 3 were uncommon. Alopecia occurred in approximately 25% of both arms and was mostly grade 1. 

“The most common toxicity related to talazoparib was anemia, and this was managed clinically. Only two patients were removed from the study for this. Neutropenia was more frequent with physician’s choice of therapy, and the rate of febrile neutropenia was low in both arms,” she said. 

Quality-of-life benefits were also observed with talazoparib. On the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire, patients receiving talazoparib had a statistically significant improvement from baseline in estimated overall mean change in global health status (+3.0 vs –5.4 for chemotherapy, P <. 0001). Treatment with talazoparib was also associated with a significant delay in the time to clinically meaningful deterioration in quality of life: 24.3 vs 6.3 months (HR = 0.38, P <. 0001).

“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,” Dr. Litton said. ■

DISCLOSURE: Dr. Litton conducts research with funding to her institution from multiple companies and has served on advisory boards for Pfizer and AstraZeneca with no compensation.

REFERENCE

1. Litton JK, Rugo HS, Ettl J, et al: A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a germline BRCA mutation. 2017 San Antonio Breast Cancer Symposium. Abstract GS6-07. Presented December 8, 2017.