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Entinostat in combination with exemestane is effective in patients with HR+/HER2- advanced breast cancer

A large randomised phase III clinical trial including HR-positive advanced breast cancer patients who progressed after prior endocrine therapy demonstrated that combining the selective oral histone deacetylase inhibitor entinostat with exemestane, results in a significant improvement in progression-free survival compared to placebo plus exemestane.

Entinostat is a novel, potent, orally bioavailable, class I selective histone deacetylase (HDAC) inhibitor that has to be taken once a week. In a previous phase II study, the combination of entinostat with exemestane showed significant improvement of overall survival in patients with advanced hormone receptor positive (HR+) breast cancer. To verify and further confirm the benefit of this HDAC inhibitor in combination with exemestane, Xu et al. conducted a randomised, controlled trial to assess the efficacy and safety in a large population of Chinese patients with advanced, HR+ breast cancer.

Study design

The presented randomised, double-blind, placebo-controlled, phase III trial was conducted at 35 sites in China and enrolled a total of 354 pre- or postmenopausal women with advanced HR+/HER2- breast cancer who progressed on previous endocrine therapy. All patients had at least one measurable lesion, adequate organ function and an ECOG performance status of 0 or 1. Patients were randomised (2:1) to entinostat (5 mg, once a week) plus exemestane (25 mg, daily) or placebo plus exemestane until disease progression or intolerable toxicity. Randomisation was stratified according to previous usage of CDK4/6 inhibitors, fulvestrant or chemotherapy, and the presence of visceral metastases. Furthermore, pre- and perimenopausal women also received a goserelin injection (3.6 mg) on day 1 of each cycle. The primary endpoint of the study was progression-free survival (PFS) as assessed by an independent radiographic committee (IRC).


The baseline patient characteristics were well balanced between both treatment arms. In total, 68.9% of patients had visceral metastases, 38.7% received prior chemotherapy and 31.9% were primary endocrine resistant. IRC-assessed median PFS in the full analysis set was 6.32 months in the entinostat group and 3.72 months in the placebo group (HR[95%CI]: 0.74[0.58-0.96], p=0.021). In the per protocol set, an even more pronounced benefit of entinostat was observed (HR[95%CI]: 0.70[0.53-0.91], p=0.009). The median overall survival (OS) was not yet reached in the placebo nor in the entinostat arm. However, there was a trend towards an OS benefit with entinostat (HR[95%CI]: 0.75[0.49-1.15]).

The objective response rate (15.7% vs. 10.1%, p=0.192) and clinical benefit rate (37.4% vs. 32.8%, p=0.413) as assessed by the IRC were both improved in the entinostat arm compared to placebo. The same analysis was also performed based on the investigator’s assessment, which demonstrated an even more pronounced benefit of entinostat, especially in terms of clinical benefit rate (45.1% vs. 31.9%, p=0.022). The median duration of response in the entinostat arm was not reached in the IRC assessment and was significantly improved in the investigator’s assessment (12.96 with entinostat addition compared to 5.56 months with placebo addition; p=0.013).

The most common grade 3-4 adverse events in the entinostat group vs. placebo group were neutropenia (43.8% vs. 0.8%), thrombocytopenia (8.5% vs. 0.8%), and leukopenia (6.4% vs. 0%). However, haematologic toxicities were mostly asymptomatic and manageable through supportive care.


Entinostat and exemestane combination treatment significantly improved PFS compared with exemestane alone in patients with advanced, HR+/HER2- breast cancer that progressed after previous endocrine therapy. In addition, the entinostat and exemestane combination was generally well tolerated and can offer meaningful clinical benefit in these patients with unmet medical need.


Xu B, Zhang Q, Hu X, et al. A randomized control phase III trial of entinostat, a once weekly, class I selective histone deacetylase inhibitor, in combination with exemestane in patients with hormone receptor positive advanced breast cancer. Presented at SABCS 2021; abstract GS1-06.

Speaker Binghe Xu

Binghe Xu

Binghe Xu, MD, PhD, Cancer Hospital Chinese Academy of Medical Sciences, Beijing, China


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