FDA Grants Talazoparib Priority Review for BRCA+ Breast Cancer

Mace Rothenberg, MD

The FDA has granted a priority review to a new drug application (NDA) for talazoparib for the treatment of patients with germline BRCA mutation—positive, HER2-negative locally advanced or metastatic breast cancer, according to Pfizer, the manufacturer of the PARP inhibitor.

The NDA is based on the III EMBRACA trial, in which talazoparib reduced the risk of disease progression or death by 46% versus chemotherapy in patients with BRCA-positive advanced breast cancer. At a median follow-up of 11.2 months, the median progression-free survival (PFS) was 8.6 months (95% CI, 7.2-9.3) with talazoparib compared with 5.6 months (95% CI, 4.2-6.7) with physician’s choice of therapy (HR, 0.54; 95% CI, 0.41-0.71; P <.0001). The objective response rate (ORR) was 62.6% (95% CI, 55.8-69.0) versus 27.2% (95% CI, 19.3-36.3), respectively (odds ratio, 4.99; 95% CI, 2.9-8.8; 2-sided P value <.0001).

Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision on the NDA by December 2018. Pfizer also reported that the European Medicines Agency has accepted an application for the use of talazoparib in the same patient population.

“Women with a hereditary BRCA mutation are typically diagnosed with breast cancer at a younger age than the overall breast cancer population and have limited treatment options when they develop advanced disease,” Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a statement.

“Today’s filing acceptances are just the latest example of the success of Pfizer’s precision medicine approach to drug development, in this case targeting the faulty DNA damage repair process associated with BRCA mutations. We are now one step closer to offering a potential alternative to chemotherapy for these patients,” added Rothenberg.

The international, open-label EMBRACA trial accrued 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 (n = 287) or physician’s choice of therapy (n = 144), which included capecitabine (received by 44% of patients), eribulin (40%), gemcitabine (10%), and vinorelbine (7%).

Patient characteristics were mostly well balanced between the 2 arms, with a few variations of note. In the talazoparib arm, 63.4% of patients were aged <50 years, compared with 46.5% of patients in the control arm. Fifteen percent of patients receiving the PARP inhibitor had a history of CNS metastasis, compared with 13.9% in the chemotherapy group. In the talazoparib group, 37.6% of patients had a disease-free interval (initial diagnosis to advanced breast cancer) of under 12 months versus 29.2% in the chemotherapy arm.

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 primary reasons for discontinuation in the talazoparib arm were adverse events (AEs; 4.5% vs 5.6% in the physician’s choice arm), progressive disease (68.6% vs 60.4%, respectively), subject withdrawal (1.0% vs 18.8%), and physician decision (3.5% vs 9.0%). Long-term follow-up was ongoing in 57.8% and 45.1% 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.

Among patients with measurable disease, the complete response (CR) rate in the talazoparib arm was 5.5%, the partial response (PR) rate was 57.1%, and the stable disease rate was 21.0%. The corresponding rates in the physician’s choice arm were 0, 27.2%, and 31.6%, respectively.

The median duration of response was 5.4 months (95% CI, 4.2-6.3) with talazoparib and 3.1 months (95% CI, 2.8-5.6) with chemotherapy (HR, 0.43; 95% CI, 0.27-0.70; P = .0005). The 1-year probability of sustained response was 23% vs 0%, respectively.

The OS data are not yet mature; however, an interim OS analysis found a positive trend favoring talazoparib, with a 24% reduction in the risk of death. The median OS was 22.3 months (95% CI, 18.1-26.2) with the PARP inhibitor versus 19.5 months (95% CI, 16.3-22.4) with chemotherapy (HR, 0.76; 95% CI, 0.54-1.06; P = .105).

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 AEs in the talazoparib group included anemia (38.5% vs 4.0% with chemotherapy), neutropenia (17.8% vs 19.8%, respectively), thrombocytopenia (11.2% vs 1.6%), and lymphopenia (3.1% vs 0).

In the talazoparib arm, grade 4 hematologic AEs included anemia (0.7% vs 0.8% with chemotherapy), neutropenia (3.1% vs 15.1%, respectively), thrombocytopenia (3.5% vs 0), and febrile neutropenia (0.3% vs 0.8%).

The most common grade 3 nonhematologic AEs with talazoparib included vomiting, back pain, and dyspnea, at 2.4% each. There were no grade 4 nonhematologic AEs in either arm. Grade 3/4 serious AEs occurred in approximately 25% of patients in each arm.

The investigators also examined QoL using the EORTC QLQ-C30 questionnaire, which was completed by 262 patients receiving the PARP inhibitor and 114 patients receiving chemotherapy.

The results showed that in patients receiving talazoparib, there was a statistically significant improvement from baseline in estimated overall mean change in global health status (GHS)/QoL: 3.0 (95% CI, 1.2-4.8) versus -5.4 (95% CI, -8.8 to -2.0) in patients receiving physician’s choice of therapy (P <.0001).

The results also found a significant delay in the median time to clinically meaningful deterioration in GHS/QoL with talazoparib versus chemotherapy: 24.3 months (95% CI, 13.8 to not reached) versus 6.3 months (95% CI, 4.9-12.2; HR, 0.38; 95% CI, 0.26-0.55; P <.0001).

In January 2018, olaparib (Lynparza) became the first PARP inhibitor approved for breast cancer. The agency specifically approved the drug for the treatment of patients with germline BRCA—positive, HER2-negative metastatic breast cancer who have previously received chemotherapy. Additionally, HR-positive patients should have prior endocrine therapy or not be considered appropriate for such treatment.

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. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-07.

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The PFS benefit with talazoparib was observed across all predetermined patient subgroups. “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,” lead author Jennifer Litton, MD, associate professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, said in a press release during the 2017 San Antonio Breast Cancer Symposium, where the data were presented.