Adding entinostat to exemestane did not improve survival in patients with endocrine-resistant, advanced breast cancer, according to results of the E2112 study published in the Journal of Clinical Oncology.1

The study authors noted that these results run counter to results from the phase 2 ENCORE301 trial.2 In that trial, adding entinostat, a histone deacetylase inhibitor, to exemestane, an aromatase inhibitor (AI), improved outcomes for patients with AI-resistant breast cancer.

The phase 3 E2112 trial ( Identifier: NCT02115282) enrolled 608 patients with hormone receptor-positive, HER2-negative, advanced breast cancer that had progressed after nonsteroidal AI treatment.

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The patients were randomly assigned to receive exemestane and entinostat (EE; 305 patients) or exemestane and placebo (EP; 303 patients).

At baseline, the patients’ median age was 63 years (range, 29-91 years). A majority of patients (84%) had progressive disease following non-steroidal AI in the metastatic setting, and 60% had visceral disease. Prior treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitors (35%).

The median progression-free survival was 3.3 months in the EE arm and 3.1 months in the EP arm, a nonsignificant difference (hazard ratio [HR], 0.87; 95% CI, 0.67-1.13; P =.30).

Likewise, there was no significant difference in median overall survival between the EE arm and the EP arm — 23.4 months and 21.7 months, respectively (HR, 0.99; 95% CI, 0.82-1.21; P =.94).

The objective response rate among patients with measurable disease was 5.8% in the EE arm and 5.6% in the EP arm.

Patients in the EE arm had a significantly higher increase in lysine acetylation by C1D15 in peripheral blood mononuclear cells. This confirms that entinostat was acting at the intended target, according to the study authors.

Grade 3 or higher adverse events (AEs) occurred in 51% of patients in the EE arm and 16% of those in the EP arm (P <.001).

In the EE arm, the most common grade 3-4 AEs were neutropenia (20%),  hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), and diarrhea (4%).

“In conclusion, the combination of entinostat and exemestane did not improve outcomes in patients with advanced endocrine-resistant breast cancer,” the study authors wrote. “Results from [an] ongoing correlative analysis and other clinical trials may clarify a role for histone deacetylase inhibitors in a biomarker-selected population or in other breast cancer settings.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


  1. Connolly RM, Zhao F, Miller KD, et al. E2112: Randomized phase III trial of endocrine therapy plus entinostat or placebo in hormone receptor–positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group. J Clin Oncol. Published August 6, 2021. doi:10.1200/JCO.21.00944
  2. Yardley DA, Ismail-Khan RR, Melichar B, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol. 2013;31(17):2128-35. doi:10.1200/JCO.2012.43.7251