ctDNA biomarker PD1 efficacy on melanoma

Talazoparib Superior to Chemotherapy in BRCA-Associated Metastatic Breast Cancer

Approximately 5% of patients with sporadic breast cancer harbor mutations in BRCA1 or BRCA2; genes that are involved in the DNA repair process. Several phase I/II clinical studies have shown activity of single agent poly(ADP-ribose) polymerase (PARP) inhibitors in patients with metastatic breast cancer (MBC) and BRCA1/2 mutations. Recently in the randomized phase III OlympiAD trial, the PARP inhibitor olaparib improved progression-free survival (PFS) by 2.8 months over standard chemotherapy in patients with human epidermal growth factor 2 (HER2)–negative MBC and germline BRCA mutations.

At the 2017 San Antonio Breast Cancer Symposium (SABCS), results from a phase III international trial evaluating the efficacy and safety of talazoparib were presented. Talazoparib is a novel, highly potent, dual mechanism PARP inhibitor that prevents DNA repair by both inhibiting the PARP enzyme and trapping PARP on single-stranded DNA breaks. The open label EMBRACA study is the largest randomized trial evaluating a PARP inhibitor in patients with hereditary breast cancer. The trial compared talazoparib (1 mg daily orally) to physician’s choice single agent chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) in 431 patients with HER2-negative BRCA1/2-mutated MBC.

Talazoparib significantly improved PFS by blinded central review (primary endpoint of the study) compared to physician’s choice therapy, resulting in a 45.8% reduction in the risk of disease progression (8.6 months vs 5.6 months; HR 0.54, P<.0001). Of note, in patients with central nervous system (CNS) metastases, talazoparib resulted in a 4.1-month improvement in PFS compared to chemotherapy (HR 0.32, P = .0016). Overall survival (OS) data are not yet mature, but preliminary analysis indicates a positive trend in favor of talazoparib.

The overall response rate (ORR) was also significantly higher with talazoparib compared to physician’s choice (62.6% vs 27.2%; HR 4.99, P<.0001). Twelve patients treated with talazoparib achieved complete response (CR), while there were no CRs among patients treated with chemotherapy. Responses to talazoparib were more durable than with chemotherapy (HR 0.43, P = .0005), with a one-year probability of sustained response for 23% of patients treated with talazoparib versus 0% of patients treated with chemotherapy. The benefit of talazoparib was consistent regardless of hormone receptor expression status, number of prior lines of therapy, and BRCA mutation type.

Similar rates of grade 3/4 serious adverse events (AEs) occurred in the talazoparib and chemotherapy arms (25.5% vs 25.4%). The primary grade 3/4 AE for talazoparib was anemia (39.2% vs 4.8%), which was clinically managed with dose delays, dose reductions, and blood transfusions. The rate of grade 3/4 neutropenia was higher in the chemotherapy arm, but the rate of febrile neutropenia was below 1%. Grade 3/4 nonhematologic AEs were rare in both arms. Importantly, talazoparib was associated with overall improvement in quality of life from baseline and a delay in the time to clinically meaningful deterioration (24.3 months vs 6.3 months; HR 0.38, P<.0001).

The presenter of the study, Jennifer Litton, MD (University of Texas MD Anderson Cancer Center, Houston, Texas, United States), concluded that talazoparib provides a significant benefit for patients with BRCA-mutated advanced breast cancer, noting the tolerable safety profile and impressive and durable response rate. While OS data are awaited, it appears that talazoparib may provide a highly effective treatment option for patients with breast cancer who carry BRCA mutations.