Background:

A potential mechanism of resistance to endocrine therapy in breast cancer involves changes in gene expression secondary to epigenetic modifications, which might be modulated with the use of histone deacetylase (HDAC) inhibitors such as entinostat. ENCORE 301, a phase II study evaluating the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with hormone receptor (HR)-positive advanced breast cancer who had experienced disease progression after a non-steroidal AI (NSAI), showed a significant improvement in progression-free survival (PFS), and overall survival (OS). Entinostat has been designated a Breakthrough Therapy by the FDA.

Methods:

E2112 is a multicenter randomized double-blind placebo-controlled phase III study (NCT02115282) enrolling patients with advanced HR-positive, HER2-negative breast cancer with prior disease progression on a NSAI (n=600). Patients receive exemestane 25mg po daily and entinostat/placebo 5mg po every week. Eligibility: Postmenopausal women and men, ECOG 0-1, locally advanced/metastatic invasive adenocarcinoma of the breast: ER/PR-positive, HER2-negative, measurable or non-measurable (20% cap) disease. Disease progression after NSAI use in the metastatic setting OR relapse while on or within ≤ 12 months of end of adjuvant NSAI therapy.

Statistics: Both PFS (central review) and OS are primary endpoints, and the study is designed to show an improvement in either PFS or OS. Secondary endpoints include: Safety and tolerability, objective response rate, changes in lysine acetylation status in peripheral blood mononuclear cells, patient-reported symptom burden and treatment toxicities, adherence. One-sided type 1 error 0.025 split between two hypotheses tests: 0.001 for PFS test and 0.024 for OS. PFS is tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS 4.1 to 7.1 months); OS is tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS 22 to 29.3 months).

E2112 was activated in March 2014 and accrual is anticipated to complete in 40 months.

Citation Format: Connolly R, Zhao F, Miller K, Tevaarwerk A, Wagner L, Lee M, Murray J, Gray R, Piekarz R, Zujewski JA, Sparano J. E2112: Randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-04.