Randomized Phase 3 Trial of Endocrine Therapy plus Entinostat in Patients with HR-Positive Advanced Breast Cancer

In patients with advanced breast cancer, endocrine therapy resistance remains a significant clinical problem that may be approached therapeutically with use of histone deacetylase inhibitors such as entinostat (Syndax). Previously, a randomized phase 2 study called ENCORE 301 reported an improvement in overall survival (OS) and progression-free survival (PFS) with the addition of entinostat to the steroidal aromatase inhibitor exemestane (Aromasin) in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.

This phase 3, multicenter, randomized, double-blind, placebo-controlled study enrolled men and women with HR-positive, HER2-negative advanced breast cancer who experienced disease progression while receiving a nonsteroidal aromatase inhibitor in the adjuvant or metastatic setting. To be included in the study, participants were also required to have an Eastern Cooperative Oncology Group performance status 0-1 with measurable or nonmeasurable disease. One previous chemotherapy for metastatic disease and previous treatment with fulvestrant and a cyclin-dependent kinase (CDK)4/6 inhibitor was also permitted, but not required.

The study participants were treated with exemestane 25 mg orally daily and entinostat or exemestane alone (placebo) 5 mg orally every week.

Primary end points were PFS and OS. Secondary end points were safety and objective response rate and changes in a protein found in peripheral blood mononuclear cells.

Between March 2014 and October 2018, a total of 608 participants were randomized to receive either exemestane and entinostat (N = 305) or placebo (N = 303). Patient median age was 63 years, 99% were female, and 95% were postmenopausal. Eighty-four percent of patients had disease that was resistant to aromatase inhibitors in the metastatic setting, with 78% having measurable disease and 60% having visceral disease.

Previous treatment included CDK4/6 inhibitor (35%), chemotherapy (60%), everolimus (3%), and fulvestrant (30%). Median previous lines of therapy were 1 for chemotherapy and 2 for endocrine therapy. In patients treated with exemestane and entinostat, grade 3/4 side effects included anemia (8%), diarrhea (4%), fatigue (4%), decreased neutrophil count (20%), hypophosphatemia (14%), decreased platelet count (3%), and decreased white blood cell count (6%).

No differences in median PFS (approximately 3.2 months), OS (approximately 22 months), or objective response rate (approximately 4.4%) were observed between treatment arms.

The investigators concluded that the combination of exemestane and entinostat did not improve survival in aromatase inhibitor–resistant, HR-positive, HER2-negative advanced breast cancer although there was inhibition of the target.