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.
Author(s): Yardley DA(1), Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN, Klein PM,
Cruickshank S, Miller KD, Lee MJ, Trepel JB.
Affiliation(s): Author information:
(1)Sarah Cannon Cancer Center, 250 25th Avenue North, Suite 100, Nashville, TN
37203, USA. dyardley@tnonc.com
Publication date & source: 2013, J Clin Oncol. , 31(17):2128-35
PURPOSE: 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.
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