E2112: randomized phase iii trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer

Sri Lakshmi Hyndavi Yeruva,Robert J Gray,Roisin M Connolly,Joseph A Sparano,Lynne I Wagner,Fengmin Zhao,Kathy D Miller,Amye J Tevaarwerk

doi:10.1038/s41523-017-0053-3

Abstract

Endocrine therapies are effective in the treatment of hormone receptor (HR)-positive breast cancer, however, de novo or acquired treatment resistance is a significant clinical problem. A potential mechanism of resistance involves changes in gene expression secondary to epigenetic modifications, which might be reversed with the use of histone deacetylase (HDAC) inhibitors such as entinostat. The ENCORE 301 phase II randomized, placebo-controlled study demonstrated a significant improvement in progression-free survival (PFS) and overall survival (OS), with the addition of entinostat to exemestane in patients with HR-positive advanced breast cancer with disease progression after prior non-steroidal aromatase inhibitor (AI). These results prompted the development of E2112, a phase III registration trial which is investigating entinostat/placebo in combination with exemestane in patients with locally advanced or metastatic breast cancer who have experienced disease progression after a non-steroidal AI. E2112 aims to validate the preclinical and clinical findings supporting the role of HDAC inhibitors in overcoming resistance to endocrine therapy in breast cancer, and ultimately improve outcomes for patients with advanced breast cancer.

Highlights

Endocrine therapy is an important component of the adjuvant treatment paradigm for the majority of women with hormone receptor (HR)-positive breast cancer, which accounts for approximately two thirds of cases of breast cancer worldwide
The primary objective of E2112 is to determine whether the addition of entinostat to exemestane improves PFS and/or OS in patients with HR-positive and HER2-negative locally advanced or metastatic breast cancer who have progressed on prior nonsteroidal aromatase inhibitors (AIs)
- Preclinical studies suggest that the HDAC inhibitor entinostat can overcome resistance to non-steroidal AI therapy in breast cancer. - Phase II ENCORE301 randomized trial reported an 8 month OS benefit for addition of entinostat to exemestane

Summary

REVIEW ARTICLE

E2112: randomized phase iii trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. The ENCORE 301 phase II randomized, placebo-controlled study demonstrated a significant improvement in progression-free survival (PFS) and overall survival (OS), with the addition of entinostat to exemestane in patients with HR-positive advanced breast cancer with disease progression after prior non-steroidal aromatase inhibitor (AI). These results prompted the development of E2112, a phase III registration trial which is investigating entinostat/placebo in combination with exemestane in patients with locally advanced or metastatic breast cancer who have experienced disease progression after a non-steroidal AI. E2112 aims to validate the preclinical and clinical findings supporting the role of HDAC inhibitors in overcoming resistance to endocrine therapy in breast cancer, and improve outcomes for patients with advanced breast cancer

INTRODUCTION

SUMMARY OF TRIAL DESIGN

Entinostat and exemestane in breast cancer

Patient population

Findings

AUTHOR CONTRIBUTIONS