Talazoparib improves PROs, but not OS, in germline BRCA1/2-mutated, HER2-negative advanced breast cancer

The oral PARP inhibitor talazoparib significantly improves patient-reported outcomes (PROs), but not overall survival (OS), compared with physician’s choice of chemotherapy (PCT) in patients with locally advanced or metastatic HER2-negative breast cancer with a germline BRCA1/2 mutation, final results of the phase III EMBRACA trial have shown.

The final analysis, reported after a median follow-up of 44.9 months in the talazoparib arm (n=287) and 36.8 months in the PCT arm (n=144), demonstrated a median OS of 19.3 months vs 19.5 months (hazard ratio [HR], 0.848; 95 percent confidence interval [CI], 0.670 to 1.073; p=0.17). [Litton JK, et al, AACR 2020 Virtual Annual Meeting I, abstract CT071]

“The OS results were consistent across subgroups of patients stratified by performance status, BRCA1 or BRCA2 mutation, hormone receptor status, prior platinum treatment, time from initial diagnosis of breast cancer to initial diagnosis of advanced breast cancer, and prior regimens of chemotherapy for advanced breast cancer,” reported Dr Jennifer K Litton of the University of Texas MD Anderson Cancer Center, Houston, Texas, US.

However, survival probability was higher in patients who received talazoparib at 24 months (0.42 [95 percent CI, 0.36 to 0.47] vs 0.38 [95 percent CI, 0.30 to 0.47] for PCT), 36 months (0.27 [95 percent CI, 0.22 to 0.33] vs 0.21 [95 percent CI, 0.14 to 0.29]) and 48 months (0.19 [95 percent CI, 0.14 to 0.25] vs 0.07 [95 percent CI, 0.02 to 0.15]).

In the trial, 48.4 percent of patients in the talazoparib arm and 59.7 percent of those in the PCT arm received subsequent PARP inhibitor therapy (4.5 percent vs 32.6 percent) or platinum chemotherapy (46.3 percent vs 41.7 percent).

“Adjusting for post-study use of PARP inhibitor therapy and/or platinum chemotherapy reduced the HR for OS and the upper bound of the 95 percent CI [HR, 0.756; 95 percent CI, 0.503 to 1.029], but the results still did not reach statistical significance,” said Litton.

“Patients in the PCT arm who did not receive subsequent PARP inhibitor or platinum chemotherapy had shorter OS than those who did,” she added. “A longer platinum-free interval before study entry was generally associated with a longer duration of survival.”

Consistent with previously reported PRO results, a significant overall improvement from baseline in global health status (GHS)/quality of life (QoL) was seen in the talazoparib vs PCT arm (p=0.001). Patients in the talazoparib arm also had a significantly longer time to definitive clinically meaningful deterioration in GHS/QoL (median, 26.3 months vs 6.7 months; HR, 0.385; 95 percent CI, 0.264 to 0.563).

Grade 3/4 serious adverse events (AEs) were reported in 28.3 percent of patients in the talazoparib arm vs 27.0 percent of those in the PCT arm, after a median study-drug exposure of 6.9 months and 3.9 months, respectively.

“Talazoparib was generally well tolerated, with no new safety signals reported. Grade 3/4 AEs reported in the talazoparib arm were mostly haematologic, and were manageable by supportive care and dose modifications,” said Litton. “Permanent drug discontinuation due to AEs were required by 7.7 percent vs 9.5 percent of the patients.”

Previously reported primary endpoint results of EMBRACA demonstrated a significant improvement in progression-free survival with talazoparib vs PCT (median, 8.6 months vs 5.6 months; HR, 0.542; 95 percent CI, 0.413 to 0.711; p<0.0001). [N Engl J Med 2018;379:753-763]

“The final results suggest that talazoparib is a favourable treatment option for patients with locally advanced or metastatic HER2-negative breast cancer with a germline BRCA1/2 mutation,” Litton concluded.