Yardley, Denise A.Ismail-Khan, Roohi R.Melichar, BohuslavLichinitser, MikhailMunster, Pamela N.Klein, Pamela M.Cruickshank, ScottMiller, Kathy D.Lee, Min J.Trepel, Jane B.2017-03-272017-03-272013-06-10Yardley, D. A., Ismail-Khan, R. R., Melichar, B., Lichinitser, M., Munster, P. N., Klein, P. M., … Trepel, J. B. (2013). 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. Journal of Clinical Oncology, 31(17), 2128–2135. http://doi.org/10.1200/JCO.2012.43.72511527-7755https://hdl.handle.net/1805/12123PURPOSE: 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.en-USPublisher PolicyAndrostadienestherapeutic useAntineoplastic Combined Chemotherapy ProtocolsBreast Neoplasmsdrug therapyArticle