Efficacy and safety of entinostat plus exemestane in hormone receptor-positive breast cancer: a systematic review meta-analysis of randomized controlled trials

Abstract

Background: Hormone receptor-positive (HR+) breast cancer continues to be a significant global challenge, as resistance to endocrine therapy (ET) often reduces its effectiveness. Entinostat (ENT), a novel and selective histone deacetylase inhibitor (HDACi), has been suggested to overcome the resistance. However, there is still ongoing debate regarding its efficacy and safety.

Objective: Our meta-analysis aims to assess the efficacy and safety of ENT plus exemestane (EXE) versus placebo (PL) plus EXE in patients with HR+ breast cancer.

Methods: Following PRISMA guidelines, a systematic search was conducted across PubMed, Web of Science, and Cochrane Library up to November 2024, resulting in the inclusion of four randomized controlled trials (RCTs) involving 1371 patients. The primary outcomes were progression-free survival (PFS) and overall survival (OS), while secondary outcomes were the objective response rate (ORR), clinical benefit rate (CBR), and adverse events (AEs). Our meta-analysis was prospectively registered in PROSPERO (registration number: CRD42024615056).

Results: Our Analysis showed that ENT + EXE significantly enhanced PFS in the overall HR+ population Hazard Ratio (HR) = 0.79 (95% CI 0.68-0.92; P = 0.003), particularly among human epidermal growth factor receptor-2 (HER2-) negative patients (HR = 0.80; 95% CI 0.68-0.95; P = 0.01) when compared to PL + EXE. However, no significant improvements were noted in OS (HR = 0.91; 95% CI 0.63-1.30; P = 0.60), ORR with relative risk (RR) = 1.37 (95% CI 0.90-2.07; P = 0.14), CBR (RR = 1.15; 95% CI 0.89-1.74; P = 0.29). Furthermore, our safety analysis demonstrated that patients receiving ENT + EXE experienced significantly higher rates of adverse events (AEs) of all grades, with a RR of 1.33 (95% CI 0.99-1.78) and a significant increase in grade ≥ 3 AEs (RR = 3.04; 95% CI 2.52-3.67).

Conclusion: The ENT + EXE combination demonstrates significant PFS benefits in HR + breast cancer patients compared to PL + EXE. However, no improvements were seen in OS, ORR, or CBR. In addition, the higher incidence of AEs, especially hematologic and gastrointestinal, highlights the need for careful patient selection and monitoring.

Keywords: Breast cancer; Entinostat; Exemestane; HDAC; Hormone receptor positive; Meta-analysis.