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

Purpose: Entinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor-positive (ER+) breast cancer. This randomized, placebo-controlled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone.

Patients and methods: Postmenopausal women with ER+ 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.

Results: One hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 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 = .055; two-sided P = .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 = .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.

Conclusion: Entinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ 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.

Trial registration: ClinicalTrials.gov NCT00676663.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

CONSORT diagram. (*)One patient received no study drug and was excluded from the safety set. ITT, intention-to-treat.

Fig 2.

Kaplan-Meier estimates of (A) progression-free survival (PFS) and (B) overall survival (OS). (A) Vertical tick marks represent the PFS time of patients without progressive disease. (B) Vertical tick marks represent the survival time of patients alive or lost to follow-up as of the last contact.

Fig 3.

Forest plot of progression-free survival for key subgroups. EE, exemestane plus entinostat; EP, exemestane plus placebo; NSAI, nonsteroidal aromatase inhibitor.

Fig 4.

Kaplan-Meier estimates of progression-free survival (PFS) in exemestane plus entinostat (EE) –treated acetylation subset. HA+, percent change in protein lysine acetylation at cycle 1 day 15 greater than the study derived median (hyperacetylation +). HA−, patients with percent change in protein lysine acetylation at cycle 1 day 15 less than the study derived median (hyperacetylation −). Vertical tick marks represent the PFS time of patients without progressive disease.