Entinostat, a class I selective histone deacetylase inhibitor, plus exemestane for Chinese patients with hormone receptor-positive advanced breast cancer: An overall survival update and long-term safety from the randomised, double-blind, placebo-controlled, phase 3 trial.
Authors: Wang Jiani , Zhang Qingyuan , Hu Xichun , Li Qing , Sun Tao , Li Wei , Ouyang Quchang , Wang Jingfen , Tong Zhongsheng , Yan Min , Li Huiping , Zeng Xiaohua , Shan Changping , Wang Xian , Zhang Jian , Zhang Yue , Zhang Liang , Tian Ying , Shang Hongyan , Xu Binghe 
Published: May 2024

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Background: Entinostat, a synthetic benzamide derivative HDAC inhibitor, selectively targets Class I HDAC enzymes. In a randomized, double-blind, phase 3 trial, entinostat with exemestane demonstrated a statistically significant progression-free survival (PFS) benefit compared to placebo, with a median PFS of 6.32 months versus 3.72 months (HR 0.76, 95% CI 0.58-0.98, p=0.046; Binghe Xu, et al. Acta Pharm Sin B. 2023). This analysis focus on the results of overall survival (OS) and long-term safety. Methods: Patients eligible for this study had HR+/HER2– advanced breast cancer (ABC) with disease relapse or progression following at least one prior endocrine therapy (ET). They were randomly assigned in a 2:1 ratio to receive either entinostat (5mg, weekly) or placebo in combination with exemestane until disease progression or unacceptable toxicity. The primary endpoint of the study was PFS. Secondary endpoints included OS, objective response rate, clinical benefit rate and safety. Median OS was estimated using the Kaplan-Meier method and the HR and its 95% CI were calculated using the multivariate Cox proportional hazard regression model. Results: A total of 354 patients were randomized to receive either entinostat (n=235) or placebo (n=119). As of the data cutoff date (July 31, 2023), 196 (55.4%) OS events had occurred, with a median follow-up of 31.83 months. There were 127 (54.0%) deaths in the entinostat arm compared to 69 (58.0%) deaths in the placebo arm. The entinostat demonstrated improved OS compared to placebo, with a median OS of 38.39 months versus 29.18 months (HR 0.837, 95% CI 0.624-1.124, p=0.237) in the full analysis set (FAS). The results of the per-protocol analysis set (PPS) were consistent with those of the FAS, showing a median OS of 39.01 months versus 33.98 months (HR 0.796, 95% CI 0.588-1.079, p=0.142). Notably, 179 (76.2%) patients in the entinostat arm and 100 (84%) patients in the placebo arm received new anti-cancer regimens, including CDK4/6 inhibitors (14.5% vs 24.4%), chemotherapy (54.9% vs 63.9%), endocrine therapy (40.4% vs 42.9%), and herbal medicines (9.8% vs 3.4%). After adjusting for the imbalance in the use of CDK4/6 inhibitors and chemotherapy between the treatment arms, the HR for overall survival was 0.78 (95% CI 0.58-1.05, p=0.097). The updated safety results were generally consistent with the previous analysis. Conclusions: The combination of entinostat with exemestane has provided clinically meaningful OS benefit in addition to the previously observed PFS benefit over exemestane alone in patients with pre-treated, ET-resistant ABC. These findings further support entinostat as an effective and safe treatment option for the specific patient population. Clinical trial information: NCT03538171 .