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, combined with exemestane, significantly improved progression-free survival (PFS) in patients with advanced hormone receptor-positive (HR+) breast cancer, with a manageable safety profile. This analysis presents the long-term safety data and overall survival (OS) outcomes.

Methods: The ACE study is a randomized, double-blind, placebo-controlled, phase 3 trial comparing tucidinostat 30 mg twice weekly plus exemestane 25 mg daily versus placebo plus exemestane 25 mg daily in postmenopausal patients with advanced HR+ breast cancer. The primary endpoint was PFS, while OS served as a secondary endpoint.

Results: Of the 365 patients enrolled between July 2015 and June 2017, 244 were assigned to the tucidinostat plus exemestane group, and 121 to the placebo plus exemestane group. Baseline characteristics were well balanced between the groups. The median follow-up from randomization to the data cutoff (February 25, 2021) was 26.5 months (range, 13.9-45.5 months). A total of 231 deaths (63.3%) occurred across the 365 patients, 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 in both groups were consistent with those previously reported, with no new safety concerns identified during the extended follow-up. Grade 3 or 4 neutropenia occurred in 51.6% of patients in the tucidinostat group and 2.5% in the placebo group. Adverse events (AEs) leading to treatment discontinuation occurred in 28 (11.5%) patients in the tucidinostat group and 4 (3.3%) in the placebo group.

Conclusions: While tucidinostat combined with exemestane resulted in a clinically meaningful and statistically significant improvement in the primary endpoint of PFS, the ACE study did not demonstrate an improvement in OS for the tucidinostat combination regimen. Ongoing studies are exploring potential patient subpopulations that may benefit most from tucidinostat combination therapies in advanced HR+ breast cancer.