Syndax Pharmaceuticals announced that updated results from ENCORE 301, a randomized, placebo-controlled Phase 2 study of exemestane with and without entinostat in estrogen receptor positive metastatic breast cancer demonstrated improvement in overall survival for patients treated with exemestane plus entinostat. At median follow up of 25 months, treatment with the combination resulted in an 8.3 months improvement in overall survival (an exploratory endpoint) corresponding to a 41% reduction in the risk of dying (P=0.04).   

ENCORE 301 (ENtinostat Combinations Overcoming REsistance) was a multicenter, double-blind, Phase 2 study of exemestane with and without entinostat in 130 post-menopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer, progressing on treatment with the non-steroidal aromatase inhibitors anastrozole or letrozole.  The study hit the primary endpoint of progression-free survival and preliminary analysis indicated an overall survival benefit. Pharmacodynamic analysis in a subset of patients linked for the first time a readout of histone deacetylase inhibitor activity with clinical outcome.

Previously reported results indicated the study met the designated primary endpoint of progression-free survival (PFS) (4.28 months vs. 2.27 months, respectively; hazard ratio (HR=0.73; P=0.06).  Additionally, in the subset of patients assessed for the pharmacodynamic marker of protein lysine acetylation in peripheral blood cells, acetylation in entinostat-treated patients was associated with prolonged progression-free survival to over six months across all peripheral mononuclear cell types analyzed.                 

Entinostat is a novel, oral small molecule inhibitor of class I histone deacetylases, key enzymes that alter the structure of chromatin to control gene expression. 

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