Breast cancer remains one of the leading malignancies threatening women’s health worldwide. Among its various subtypes, hormone receptor-positive (HR⁺) breast cancer is the most prevalent, comprising about 70% of all cases. While the advent of CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) has become the gold standard for first-line treatment of HR⁺/HER2⁻ advanced breast cancer (MBC), therapeutic strategies following progression on CDK4/6i remain a considerable challenge. The introduction of the histone deacetylase inhibitor (HDACi) entinostat has brought a new horizon of hope for patients in this therapeutic gap. Recently, entinostat prescriptions were issued across major cities in China, such as Beijing and Guangdong, marking a pivotal moment in the treatment landscape. Oncology Frontier invited Dr. Xiaojia Wang from Zhejiang Cancer Hospital to delve deeper into the current status of HR⁺/HER2⁻ MBC treatment, strategies after CDK4/6i failure, and the efficacy and safety profile of entinostat.1. The Unrelenting Pursuit of Overall Survival (OS) in HR⁺ Advanced Breast Cancer
Breast cancer remains one of the most diagnosed cancers in China, with more than 350,000 new cases annually. Approximately 70% of these cases are HR⁺ breast cancers. As the survival rates for patients with advanced disease continue to rise, treatment challenges, particularly after first-line therapy failure, have become more apparent. For these patients, extending overall survival (OS) remains the central therapeutic objective. According to the 2022 edition of the Chinese Guidelines for the Standardized Diagnosis and Treatment of Advanced Breast Cancer, the primary goal is to control the disease, alleviate symptoms, and prolong survival while maintaining the patient’s quality of life. This principle is echoed by the 2024 Chinese Anti-Cancer Association Guidelines, which emphasize delaying disease progression, improving quality of life, and extending survival. In this context, OS extension has become a key treatment goal, particularly for patients whose disease progresses after initial treatment with CDK4/6i combined with ET.
2. Efforts to Enhance OS in Second-Line Therapy for HR⁺ MBC
Currently, there is no unified standard of care for second-line treatment after failure of CDK4/6 inhibitors and ET. The 2024 CSCO Breast Cancer Guidelines recommend a switch to a different CDK4/6 inhibitor combined with ET or the use of other targeted therapies in combination with endocrine treatment. Several promising strategies have emerged:
• PI3K/AKT/mTOR Pathway Inhibitors: In the Phase II BYLieve study, the combination of alpelisib (a PI3K inhibitor) with ET resulted in median PFS of 5.6–8.0 months and median OS of 20.7–29.0 months in PIK3CA mutation-positive patients who had progressed after CDK4/6 inhibitors.
• AKT Inhibitors: The Phase III CAPItello-291 trial demonstrated that capivasertib, an AKT inhibitor, combined with fulvestrant, significantly improved PFS in patients with PIK3CA, AKT1, or PTEN mutations (median PFS: 7.3 vs. 3.1 months). OS data are still being evaluated, but the 18-month OS rates were 73.2% vs. 62.9% (HR=0.69, 95% CI: 0.45–1.05).
• ESR1 Inhibitors: The Phase III EMERALD study showed that elacestrant improved PFS in patients with ESR1 mutations compared to standard therapy (3.8 vs. 1.9 months), with a 12-month OS rate of 82.6% vs. 73.6%.
Among HDAC inhibitors, the Phase III ACE trial demonstrated that chidamide plus exemestane improved PFS in postmenopausal HR⁺ advanced breast cancer patients (7.4 vs. 3.8 months). However, it did not show an OS benefit. In contrast, entinostat, in the Phase III EOC103A3101 trial, achieved an impressive median OS of 38.39 months, surpassing the performance of other HDAC inhibitors and marking a breakthrough in the treatment of HR⁺/HER2⁻ MBC.
3. Entinostat: The First HDAC Inhibitor to Achieve Over 38 Months of OS, Reshaping the Treatment Landscape
On April 24, 2024, the National Medical Products Administration (NMPA) of China approved entinostat, a domestic HDAC inhibitor, in combination with an aromatase inhibitor (AI) for patients with HR⁺/HER2⁻ locally advanced or metastatic breast cancer who have relapsed or progressed after prior endocrine therapy. This approval stems from the Phase III EOC103A3101 trial, led by Academician Binghe Xu, which demonstrated both PFS and OS benefits in Chinese breast cancer patients. The EOC103A3101 study enrolled patients aged 18 to 75 with HR⁺/HER2⁻ advanced breast cancer who had relapsed or progressed after prior endocrine therapy, including those who had previously been treated with CDK4/6 inhibitors. Patients were randomized in a 2:1 ratio to receive either entinostat plus exemestane or placebo plus exemestane. The primary endpoint was PFS, as assessed by an independent review committee (IRC), with secondary endpoints including investigator-assessed PFS, OS, objective response rate (ORR), clinical benefit rate (CBR), and safety.
In this randomized, double-blind, placebo-controlled Phase III study conducted in China, the median follow-up duration reached 15.7 months. Results demonstrated that entinostat in combination with exemestane significantly prolonged progression-free survival (PFS) as assessed by independent review committee (IRC), compared to placebo plus exemestane (6.32 vs. 3.72 months). This translated to a 24% reduction in the risk of disease progression or death (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.58–0.98; P = 0.046).
PFS and OS Outcomes of Entinostat Plus Exemestane vs. Placebo Plus Exemestane
The combination of entinostat and exemestane achieved a median overall survival (mOS) of 38.39 months—more than 9 months longer than that observed with placebo plus exemestane—and reduced the risk of death by 17% (HR = 0.83). Entinostat is the first histone deacetylase inhibitor (HDACi) to show a trend toward overall survival benefit in this setting. In terms of safety, the most common adverse events associated with entinostat plus exemestane were neutropenia, thrombocytopenia, and leukopenia. Notably, the incidence of these hematologic toxicities was lower than that reported for other HDAC inhibitors.
Among second-line and later treatment options for HR⁺/HER2⁻ advanced breast cancer, the Chinese Breast Cancer Society (CBCS) Guidelines identify HDAC inhibitors as an important therapeutic option following progression on endocrine therapy or prior treatment with CDK4/6 inhibitors [⁴]. The 2024 CSCO Breast Cancer Guidelines further list HDAC inhibitors combined with endocrine therapy as a Grade II recommendation for patients with disease progression after endocrine therapy or CDK4/6i treatment [⁵]. With a median overall survival (mOS) of 38.39 months, entinostat marks a significant advancement in the second-line treatment landscape for HR⁺/HER2⁻ advanced breast cancer. This notable OS benefit may signal a paradigm shift in therapeutic strategy.
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PhD, Chief Physician (Second-Level), Doctoral and Postdoctoral Supervisor Department of Breast Medical Oncology, Zhejiang Cancer Hospital
- Vice President, Zhejiang Society for Immunology
- Deputy Director, Zhejiang Provincial Center for Intelligent Oncology Diagnostics and Molecular Technologies
- Deputy Director, Zhejiang Cancer Diagnosis and Treatment Quality Control Center; Chair, Breast Cancer Quality Control Expert Committee
- Vice Chair, Breast Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO)
- Standing Member, Breast Cancer Professional Committee and Medical Ethics Committee, Chinese Anti-Cancer Association (CACA)
- Member, Cardio-Oncology Working Group, Cardiovascular Disease Branch, Chinese Medical Association
- Chair, Medical Oncology Branch, Zhejiang Medical Association
- Chair, Breast Cancer Professional Committee, Zhejiang Anti-Cancer Association; Former Chair, Medical Oncology Committee; Honorary Chair, Cardio-Oncology Committee
- Vice President, Zhejiang Society for Translational Medicine; Chair, Precision Medicine Branch
