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

Abstract

A B S T R A C T PurposeEntinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor-positive (ERϩ) breast cancer. This randomized, placebocontrolled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone. Patients and MethodsPostmenopausal women with ERϩ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor were randomly assigned to exemestane 25 mg daily plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). The primary end point was progression-free survival (PFS). Blood was collected in a subset of patients for evaluation of protein lysine acetylation as a biomarker of entinostat activity. ResultsOne hundred thirty patients were randomly assigned (EE group, n ϭ 64; EP group, n ϭ 66). Based on intent-to-treat analysis, treatment with EE improved median PFS to 4.3 months versus 2.3 months with EP (hazard ratio [HR], 0.73; 95% CI, 0.50 to 1.07; one-sided P ϭ .055; two-sided P ϭ .11 [predefined significance level of .10, one-sided]). Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P ϭ .036). Fatigue and neutropenia were the most frequent grade 3/4 toxicities. Treatment discontinuation because of adverse events was higher in the EE group versus the EP group (11% v 2%). Protein lysine hyperacetylation in the EE biomarker subset was associated with prolonged PFS. ConclusionEntinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ERϩ advanced breast cancer in this signal-finding phase II study. Acetylation changes may provide an opportunity to maximize clinical benefit with entinostat. Plans for a confirmatory study are underway.

The Intestinal Epithelial Cell Differentiation Marker Intestinal Alkaline Phosphatase (ALPi) Is Selectively Induced by Histone Deacetylase Inhibitors (HDACi) in Colon Cancer Cells in a Kruppel-like Factor 5 (KLF5)-dependent Manner

“…This finding is also important because although the clinical utility of butyrate is limited by its rapid metabolism, MS-275 (entinostat) is undergoing clinical testing for anti-tumor activity and was recently shown to improve overall survival in post-menopausal women with ER ϩ advanced breast cancer, when combined with the aromatase inhibitor exemestane (24).…”

Treatment with Entinostat Heals Experimental Cholera by Affecting Physical and Chemical Barrier Functions of Intestinal Epithelia

“…Entinostat in combination with other drugs has also been found safe and efficacious in phase II trials (42,43). In rat liver, no significant histopathological changes were shown after the administration of as much as 49 mg entinostat/kg of body weight for 7 days (44).…”

Global histone post-translational modifications and cancer: Biomarkers for diagnosis, prognosis and treatment?

“…Due to their great successes in many studies, HDACi romidepsin and vorinostat have been approved by FDA as the treatment regime of cutaneous T-cell lymphoma, and romidepsin also for the treatment of relapsed peripheral T-cell lymphoma [84] . Since then many other HDACi have been under study of phase Ⅰ and/or Ⅱ trials as monotherapy, including belinostat, panobinostat, entinostat, chidamide, SB939 and LAQ824 in various cancers like ovarian, lung, soft tissue carcinoma, nonsmall-cell lung and breast [114][115][116][117][118][119][120][121] . However, unlike that of earlier success in treatment of lymphomas the majority of the results among solid tumor patients have been disappointing.…”