Talazoparib Outperforms Chemotherapy in BRCA+ Advanced Breast Cancer

For patients with advanced breast cancer who carry a germline mutation in BRCA1 or BRCA2, and are thus deficient in the repair mechanism for DNA double-strand breaks, treatment with a poly(adenosine diphosphase) polymerase (PARP) inhibitor is a highly effective therapeutic option. Talazoparib is a novel, highly potent PARP inhibitor that demonstrated promising responses among pretreated patients with advanced breast cancer and germline BRCA1/2 mutation in phase I and phase II trials. The randomized, phase III EMBRACA trial (N = 431) compared the safety and efficacy of talazoparib (1 mg daily) to physician’s choice of standard chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine) in patients with HER2-negative advanced breast cancer with a germline BRCA1/2 mutation.

Treatment with talazoparib resulted in a significant improvement in median progression-free survival (PFS), from 5.6 months with standard therapy to 8.6 months with talazoparib (HR 0.54, P<.001). At one year, 37% of patients in the talazoparib group were progression-free, compared to 20% in the standard therapy group. The benefit of talazoparib was seen across all prespecified patient subgroups, though it was less pronounced in patients who had received prior treatment with a platinum-containing regimen. At interim analysis, the median overall survival (OS) was 22.3 months in the talazoparib group, compared with 19.5 months in the standard therapy group (HR 0.76; P = .11). Significantly more patients responded to treatment with talazoparib (62.6% vs 27.2%; P<.001), with 12 (5.5%) complete responses in the talazoparib group and none in the standard therapy group.

The most common adverse events (AEs) associated with talazoparib were anemia, fatigue, and nausea. Hematologic grade 3/4 AEs occurred in 55% of patients receiving talazoparib and 38% of patients receiving standard therapy. There were similar rates of nonhematologic grade 3/4 AEs in the two treatment groups (32% and 38%). Discontinuation due to AEs was rare, occurring in 5.9% and 8.7% of patients receiving talazoparib and standard therapy, respectively. Of note, patient-reported outcomes favored talazoparib, with significant improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status-quality of life and breast cancer symptoms scales.

The investigators concluded that single-agent talazoparib is the second PARP inhibitor to show superiority over standard chemotherapy in patients with advanced breast cancer with BRCA1/2 mutations, with a manageable safety profile and meaningful improvements in quality of life. Future studies should compare talazoparib to platinum chemotherapy in patients who have not previously received platinum and evaluate best strategies for sequencing of platinum agents and PARP inhibitors.

N Engl J Med. 2018 August 15 [Epub ahead of print].
talazoparib-BRCA-breast-cancer

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