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Connolly RM , Zhao F , Miller KD , Lee MJ , Piekarz RL , Smith KL , Brown-Glaberman UA , Winn JS , Faller BA , Onitilo AA , Burkard ME , Budd GT , Levine EG , Royce ME , Kaufman PA , Thomas A , Trepel JB , Wolff AC , Sparano JA
E2112: Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor-Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group
J Clin Oncol. 2021 Oct 1;39(28) :3171-3181
PMID: 34357781    PMCID: PMC8478386     URL: https://www.ncbi.nlm.nih.gov/pubmed/34357781
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PURPOSE: Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. PATIENTS AND METHODS: E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. RESULTS: Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. CONCLUSION: The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.
1527-7755 Connolly, Roisin M Orcid: 0000-0003-0056-1070 Zhao, Fengmin Miller, Kathy D Lee, Min-Jung Piekarz, Richard L Orcid: 0000-0002-3591-7893 Smith, Karen L Orcid: 0000-0002-6687-0119 Brown-Glaberman, Ursa A Winn, Jennifer S Faller, Bryan A Onitilo, Adedayo A Orcid: 0000-0001-9185-0606 Burkard, Mark E Orcid: 0000-0002-4215-7722 Budd, George T Orcid: 0000-0002-1128-6185 Levine, Ellis G Orcid: 0000-0003-2300-0524 Royce, Melanie E Orcid: 0000-0002-7173-1295 Kaufman, Peter A Thomas, Alexandra Orcid: 0000-0001-9022-2229 Trepel, Jane B Wolff, Antonio C Orcid: 0000-0003-3734-1063 Sparano, Joseph A Orcid: 0000-0002-9031-2010 Journal Article United States J Clin Oncol. 2021 Aug 6:JCO2100944. doi: 10.1200/JCO.21.00944.