title: 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: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Sarah Cannon Cancer Center, 250 25th Avenue North, Suite 100, Nashville, TN 37203, USA. dyardley@tnonc.com
authors: Denise A
authors: DA
authors: Yardley
authors: Roohi R
authors: RR
authors: Ismail-Khan
authors: Bohuslav
authors: B
authors: Melichar
authors: Mikhail
authors: M
authors: Lichinitser
authors: Pamela N
authors: PN
authors: Munster
authors: Pamela M
authors: PM
authors: Klein
authors: Scott
authors: S
authors: Cruickshank
authors: Kathy D
authors: KD
authors: Miller
authors: Min J
authors: MJ
authors: Lee
authors: Jane B
authors: JB
authors: Trepel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D017698:Postmenopause; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D000730:Androstadienes; D047072:Aromatase Inhibitors; D001549:Benzamides; D014408:Biomarkers, Tumor; D011725:Pyridines; D011960:Receptors, Estrogen; C118739:entinostat; C056516:exemestane
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