Talazoparib, a New PARP Inhibitor, Shows Significant Benefit in Patients with Breast Cancer and BRCA Mutation
Talazoparib, an oral investigational poly (ADP-ribose) polymerase (PARP) inhibitor, is currently being evaluated in advanced breast cancer with BRCA mutation and other cancer types. Talazoparib’s dual mechanism of action has the potential to induce tumor cell death by blocking PARP enzyme activity and trapping PARP on the sites of DNA damage. Researchers reported the results from a phase 3 study that compared the efficacy and safety of single-agent talazoparib with chemotherapy in women with advanced breast cancer and a germline BRCA1/BRCA2 mutation (Litton JK, et al. N Engl J Med. 2018;379:753-763).
EMBRACA was an open-label, randomized, international phase 3 trial of 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 1 mg once daily (N = 287) or to physician’s choice of therapy (N = 144), which included capecitabine (Xeloda; 44%), eribulin (Halaven; 40%), gemcitabine (Gemzar; 10%), or vinorelbine (Navelbine; 7%), in continuous 21-day cycles. The primary end point was progression-free survival (PFS). The secondary end points included overall survival (OS), objective response rate, the clinical benefit rate at 24 weeks, and duration of response.
After a median follow-up of 11.2 months, PFS was longer in the talazoparib group than in the standard chemotherapy group (8.6 months vs 5.6 months, respectively). A total of 37% of patients in the talazoparib group and 20% of the patients in the standard therapy group did not have disease progression or death at 1 year.
The median OS was 22.3 months in the talazoparib arm compared with 19.5 months in the standard therapy group. The objective response was also higher in patients treated with talazoparib versus standard therapy (62.6% vs 27.2%, respectively).
In an analysis of patient-reported outcomes, quality-of-life benefits were also observed with talazoparib. Results from the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire showed that 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 standard therapy).
Talazoparib was well-tolerated, with 55% of patients in the talazoparib group and 38% of patients in the standard group having grade 3 or 4 hematologic adverse events. The most common adverse events leading to dose modification in the talazoparib group were anemia, neutropenia, and thrombocytopenia.
The study limitations included the open-label design necessitated by the mix of oral and intravenous chemotherapy options, and more patients in the standard group withdrew consent before receiving treatment.
“In conclusion, talazoparib resulted in a significantly longer progression-free survival than standard-of-care chemotherapy,” the researchers noted. “Treatment-associated myelotoxicity was managed by dose modifications or delays. Improvements in patient-reported outcomes indicated that talazoparib had a good side-effect profile.”