Chidamide Plus Exemestane for Postmenopausal Patients with Hormone-Receptor-Positive Advanced Breast Cancer (ACE Study): A Randomised, Double-Blind, Placebo-Controlled Phase 3 Trial

Abstract

Background: Chidamide is an oral subtype-selective histone deacetylase (HDAC) inhibitor that demonstrated encouraging anti-tumour activity when combined with exemestane in hormone-receptor (HR)-positive advanced breast cancer patients. The current study aimed to assess the efficacy and safety of chidamide plus exemestane in postmenopausal patients with advanced, HR-positive breast cancer. Methods: In this phase 3 trial, we compared chidamide and exemestane versus placebo and exemestane in 365 postmenopausal patients (randomised as a 2:1 ratio) with HR-positive, human epidermal growth factor receptor 2-negative advanced breast cancer who had relapsed or progressed after previous endocrine therapy. The primary end point was progression-free survival, as assessed by the investigators. Secondary end points included overall survival, objective response, clinical benefit rate, and safety. Findings: The median progression-free survival on the basis of investigator assessment was 7·4 months (95% CI 5·5-9·2) in the chidamide group versus 3·8 months (95% CI 3·7-5·5) in the placebo group (HR 0·75, 95% CI 0·58-0·98; p=0.034). The median progression-free survival was 9.2 months and 3.8 months, respectively, according to central assessment (HR 0·71, 95% CI 0·53-0·96; p=0.024). Objective response rates were 18% and 9% (p=0·026), and clinical benefit rates were 47% and 36% (p=0·034) in the chidamide group and placebo group, respectively. The most common grade 3 or 4 adverse events in the chidamide group were neutropenia (51% vs. 3% in the placebo group), thrombocytopenia (27% vs. 3%), and leucopenia (19% vs. 3%). Serious adverse events occurred in 51 (21%) patients in the chidamide group and 7 (6%) patients in the placebo group. No treatment related death was reported. Interpretation: This is the first phase 3 trial to demonstrate that a selective HDAC inhibitor plus endocrine blockade improves progression-free survival in patients with HR-positive advanced breast cancer progressing after prior endocrine therapy. Trial Registration Number: This study is registered with ClinicalTrials.gov, number NCT02482753. Funding: Chipscreen Biosciences Declaration of Interest: ZN and XP are employees of Chipscreen Biosciences Ltd. The other authors declare no competing interests. Ethical Approval: The Ethics Committee at each participating centre approved the study which was conducted in accordance with the principles of Good Clinical Practice, the Declaration of Helsinki and the regulations of China.