Jason M. Broderick
Jennifer Litton, MD
The PARP inhibitor talazoparib reduced the risk of disease progression or death by 46% versus chemotherapy in patients with BRCA
-positive advanced breast cancer, according to findings from the phase III EMBRACA trial presented at the 2017 San Antonio Breast Cancer Symposium.
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
“We are very pleased that the phase III 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,” 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.
The international, open-label EMBRACA trial accrued 431 patients with locally advanced or metastatic HER2-negative breast cancer and a germline BRCA1
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.
The PFS benefit with talazoparib was observed across all predetermined patient subgroups, according to Litton.
“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.”
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
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
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
“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 OS results as those data mature,” said Litton.
Several PARP inhibitor are approved by the FDA for the treatment of patients with ovarian cancer. In October, the FDA granted a priority review to the PARP inhibitor olaparib (Lynparza) for the treatment of patients with germline BRCA
-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy in the neoadjuvant, adjuvant, or metastatic settings.
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.