Entinostat plus Exemestane Has Activity in ER⁺ Advanced Breast Cancer

Treatment with aromatase inhibitors, which block estrogen synthesis, is the standard of care for postmenopausal women with estrogen receptor-positive (ER⁺) breast cancer, but the clinical efficacy of these drugs is limited by acquired resistance. Preclinical studies have shown that histone deacetylase (HDAC) inhibitors such as entinostat, an oral class 1 HDAC inhibitor, enhance the sensitivity of ER⁺ breast cancer cells to antiestrogen therapy, suggesting that they may overcome hormone resistance. Based on these data, Yardley and colleagues performed a randomized, placebo-controlled phase II trial to evaluate the safety and efficacy of the combination of entinostat with the steroidal aromatase inhibitor exemestane in postmenopausal women with locally advanced or metastatic ER⁺ breast cancer. One hundred thirty patients who experienced disease progression during treatment with a nonsteroidal aromatase inhibitor were randomly assigned to receive exemestane plus either entinostat or placebo. Although no significant difference in overall response rate was observed, adding entinostat to exemestane prolonged median progression-free survival (PFS) compared with the placebo group (4.3 months vs 2.3 months). In addition, combined treatment with entinostat and exemestane resulted in enhanced median overall survival (28.1 months vs 19.8 months), even after adjusting for baseline factors. Combination treatment was associated with a higher frequency of dose modification (35% vs 6%) or discontinuation (11% vs 2%), with the most common adverse events being fatigue and neutropenia, but was generally considered well tolerated. Intriguingly, among patients receiving entinostat plus exemestane, increased protein lysine acetylation in peripheral blood cells was correlated with improved PFS, suggesting that this may be a useful biomarker for HDAC inhibitor activity. These findings suggest that the addition of HDAC inhibitors may be an effective strategy to overcome resistance in ER⁺ breast cancer and support additional studies of this therapeutic combination.

Yardley DA, Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN, Klein PM, et al. 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. J Clin Oncol 2013 May 6 [Epub ahead of print].