The European Medicines Agency's Committee for Medicinal Products for Human Use has backed approval of talazoparib (Talzenna) for adult patients with HER2-negative locally advanced or metastatic breast cancer harboring germline BRCA1/2 mutations.
Chris Boshoff, MD, PhD
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has backed approval of talazoparib (Talzenna) for adult patients with HER2-negative locally advanced or metastatic breast cancer harboring germline BRCA1/2 mutations, according to Pfizer, the manufacturer of the PARP inhibitor.
If approved, the indication would stipulate that eligible patients must have prior treatment with an anthracycline and/or a taxane in the neoadjuvant/adjuvant locally advanced or metastatic setting. Further, eligible patients with HR-positive disease must first have received endocrine-based therapy. The European Commission will now be reviewing the application for a final approval decision.
“There is a pressing need for new, effective medicines that are specifically developed for patients with an inherited BRCA mutation who are often diagnosed at a younger age and have limited options for the treatment of advanced-stage disease,” Chris Boshoff, MD, PhD, Chief Development Officer, Oncology, Pfizer Global Product Development, said in a press release. “Results from the EMBRACA trial provide evidence supporting the use of Talzenna in these patients, and we look forward to working with the European Commission to potentially offer an alternative treatment option to chemotherapy.”
The CHMP recommendation is based on findings from the international, open-label phase 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. In the study, 431 patients with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer were randomized in a 2:1 ratio to receive 1 mg daily of oral talazoparib (n = 287) or physician’s choice of chemotherapy (n = 144), which included capecitabine (received by 44% of patients), eribulin (40%), gemcitabine (10%), and vinorelbine (7%).
To be eligible for enrollment, patients were required to have received no more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease. Moreover, patients must have received treatment with an anthracycline and/or a taxane, unless contraindicated, in the neoadjuvant, adjuvant, and/or metastatic setting. The primary endpoint was progression-free survival (PFS), as assessed by blinded independent central review. Secondary endpoints were overall survival (OS), safety, and overall response rate (ORR).
Results demonstrated that, at a median follow-up of 11.2 months, the median PFS was 8.6 months (95% CI, 7.2-9.3) in the talazoparib arm and 5.6 months (95% CI, 4.2-6.7) in the chemotherapy arms, respectively (HR, 0.54; 95% CI: 0.41-0.71; P <.0001). The 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). The PFS benefit with talazoparib was observed across all predetermined patient subgroups.
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.
The median duration of treatment was 6.1 months versus 3.9 months for talazoparib versus chemotherapy, respectively. Among patients with measurable disease, the complete response rate in the talazoparib arm was 5.5%, the partial response 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). Moreover, the 1-year probability of sustained response was 23% vs 0%, respectively.
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 safety population included 286 patients in the talazoparib arm and 126 patients in the chemotherapy arm. The most common grade 3 adverse events (AEs) in the talazoparib arm were anemia (38% versus 4% in the chemotherapy arm), neutropenia (18% versus 20%, respectively), and thrombocytopenia (11% versus 2%, respectively).
Grade 4 AEs occurring most often with talazoparib included anemia (1%), neutropenia (3%), and thrombocytopenia (4%). Discontinuation of treatment due to AEs occurred in 5% and 6% of the talazoparib and chemotherapy arms, respectively.
In October 2018, the FDA approved talazoparib for patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer. The approval was also based on findings from the EMBRACA trial.
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.