Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer: a long-term safety and overall survival update from the randomised, double-blind, placebo-controlled, phase 3 trial

Background: The ACE study previously demonstrated that tucidinostat (chidamide), a subtype-selective histone deacetylase (HDAC) inhibitor, plus exemestane significantly improved progression-free survival (PFS) in advanced hormone receptor-positive (HR⁺) breast cancer patients with a manageable safety profile. The analysis of long-term safety and overall survival (OS) is presented here. Methods: ACE is a randomized, double-blind, placebo-controlled, phase 3 trial comparing tucidinostat 30 mg/twice weekly plus exemestane 25 mg/day versus placebo plus exemestane 25 mg/day in postmenopausal patients with advanced, HR⁺ breast cancer. The primary endpoint was PFS, and OS was the secondary endpoint. Results: Of the 365 patients enrolled between July 2015, and June 2017, 244 were assigned to tucidinostat plus exemestane (tucidinostat group) and 121 to placebo plus exemestane group (placebo group). Baseline characteristics were well balanced between groups. The median follow-up from randomization to data cut-off (February 25, 2021) of this analysis was 26.5 months (range, 13.9-45.5 months). A total of 231 deaths (63.3%) from 365 patients occurred, including 155 deaths (63.5%) in the tucidinostat group and 76 deaths (62.8%) in the placebo group. The median OS was 30.3 months (95% CI, 26.7-36.7) in the tucidinostat group and 30.3 months (95% CI, 24.8-38.1) in the placebo group. The safety profiles of both tucidinostat and placebo groups remained consistent with those previously reported, and no new safety signals were observed with longer follow-up. Neutropenia of grade 3 or 4 occurred in 51.6% of the patients in the tucidinostat group and 2.5% of the patients in the placebo group. Adverse events (AEs) that led to treatment discontinuations from any cause occurred in 28 (11.5%) patients in the tucidinostat group and 4 (3.3%) in the placebo group. Conclusions: Although tucidinostat in combination with exemestane had produced a clinically meaningful and statistically significant improvement in the primary endpoint PFS, the ACE study did not show a prolongation of the secondary endpoint OS in the tucidinostat combination regimen. Ongoing studies have been considered in terms of potential identification of what patient subpopulations could benefit most from the tucidinostat combination regimens in advanced HR⁺ breast cancer.