Addition of Entinostat to Exemestane in Aromatase Inhibitor–Resistant, HR-Positive, HER2-Negative Advanced Breast Cancer

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As reported in the Journal of Clinical Oncology by Roisin M. Connolly, MB, BCh, MD, and colleagues, the phase III ECOG-ACRIN Cancer Research Group E2112 trial showed no significant improvement in progression-free or overall survival with the addition of the histone deacetylase inhibitor entinostat to steroidal aromatase inhibitor (AI) therapy with exemestane in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer progressing after nonsteroidal AI treatment in the adjuvant or metastatic setting.

Roisin M. Connolly, MB, BCh, MD

Roisin M. Connolly, MB, BCh, MD

As stated by the investigators, “Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat.”

Study Details

In the double-blind trial, 608 patients from sites in the United States and South Africa were randomly assigned between March 2014 and October 2018 to receive entinostat at 5 mg (n = 305) or placebo (n = 303) once weekly in combination with 25 mg of exemestane once daily until disease progression or unacceptable toxicity. Overall, 84% of patients had experienced progression after nonsteroidal AI treatment in the metastatic setting. The primary endpoints were progression-free survival on central review and overall survival.

Progression-Free and Overall Survival

The progression-free survival analysis was performed after 249 progression-free survival events had been observed in the first 360 randomly assigned patients. Median progression-free survival was 3.3 months (95% confidence interval [CI] = 3.1–5.3 months) in the combination group vs 3.1 months (95% CI = 3.0–3.3 months) in the exemestane group (hazard ratio [HR] = 0.87, 95% CI = 0.67–1.13, P = .30). Median overall survival was 23.4 months (95% CI = 21.2–25.6 months) in the combination group vs 21.7 months (95% CI = 19.3–27.1 months) in the exemestane group (HR = 0.99, 95% CI = 0.82–1.21, P = .94). Subgroup analyses showed similar results in all subgroups for progression-free and overall survival. Objective response rates were 5.8% vs 5.6%.


  • The addition of entinostat to exemestane did not improve progression-free or overall survival.
  • Median overall survival was 23.4 vs 21.7 months in the combination vs control group.

Adverse Events

Grade ≥ 3 adverse events occurred in 51% of patients in the entinostat/exemestane group vs 16% of the placebo/exemestane group; the most common in the combination group were neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), and diarrhea (4%). Adverse events led to discontinuation of treatment in 16% vs 8% of patients (P = .002). Adverse events led to death in 15 patients in the combination group and 13 patients in the exemestane group; among these, 4 deaths were considered possibly related to treatment, with causes consisting of heart failure, pneumonitis, and hepatic failure in 1 patient each in the combination group and myocardial infarction in 1 patient in the exemestane group.

The investigators concluded, “The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.”

Dr. Connolly, of The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and University College Cork, Ireland, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit

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