With the continuous advancement of pharmaceutical and medical technologies, novel therapies have steadily extended survival for breast cancer patients. Among them, the combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) has brought transformative improvements in outcomes for patients with hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer (MBC). Despite its establishment as the current standard first-line treatment, a significant number of patients still experience disease progression, and therapeutic options after CDK4/6i failure remain limited and without consensus.
Against this backdrop, entinostat—a histone deacetylase inhibitor (HDACi) with a distinct mechanism of action and demonstrated efficacy—has been formally approved by National Medical Products Administration (NMPA). The approved indication is its use in combination with an aromatase inhibitor (AI) for HR+/HER2− patients with locally advanced or metastatic disease who have relapsed or progressed following prior endocrine therapy. To further explore the treatment landscape and challenges in this setting, Oncology Frontier invited Dr. Yanxia Shi from Sun Yat-sen University Cancer Center to provide expert insights.

Treatment Landscape and Challenges for HR+/HER2− MBC in the Post-CDK4/6i Era

Breast cancer remains the most common malignancy among women, with approximately 70% of cases classified as HR+/HER2− [¹]. The development and clinical integration of CDK4/6 inhibitors—supported by the landmark PALOMA, MONARCH, MONALEESA, and DAWNA trials—have transformed the treatment paradigm for HR+/HER2− MBC, significantly improving patient survival. Today, CDK4/6i combined with ET is recommended by major international and Chinese clinical guidelines, including NCCN and CSCO, as the preferred first-line treatment [²–⁴]. However, data from the real-world YOUNG BC-9 study indicate that about 12.5% of patients experience rapid disease progression within six months of initiating CDK4/6i-based therapy [⁵]. For this subset, optimal second-line strategies are crucial, yet current guidelines offer no unified recommendations following CDK4/6i failure. Existing post-progression options remain suboptimal in terms of efficacy and tolerability.

  1. Cross-Line CDK4/6i Therapy: Using a different CDK4/6i following progression on initial CDK4/6i-based therapy has shown limited benefit. The postMONARCH study reported a median progression-free survival (PFS) of only 6 months with this approach, and overall survival (OS) data remain immature [⁶].
  2. Chemotherapy: As a conventional treatment modality, chemotherapy has demonstrated modest efficacy in this population. YOUNG BC-9 reported a median PFS of merely 5.6 months after CDK4/6i failure, along with a high rate of adverse events [⁵], underscoring the limitations of chemotherapy in this setting.
  3. PAM Pathway Inhibitors: Novel targeted agents against the PI3K/AKT/mTOR (PAM) pathway—such as everolimus and alpelisib—have shown efficacy in patients harboring pathway-specific mutations. However, these therapies are restricted to biomarker-positive populations and require genetic testing. Moreover, they are associated with distinctive side effects, including stomatitis and hyperglycemia, which require careful clinical management.

Given these limitations, there is an urgent need for effective, well-tolerated, and accessible treatment strategies for patients who have previously received CDK4/6i plus ET. Entinostat, with its epigenetic mechanism and clinical benefits demonstrated in late-line settings, is emerging as a valuable option for this unmet need.

Entinostat, a Novel HDAC Inhibitor, Offers Unique Advantages in Delaying Endocrine Resistance

Histone deacetylase inhibitors (HDACis) exert anti-tumor effects by modulating histone acetylation, thereby altering chromatin structure and gene transcription to suppress cancer cell growth and proliferation [⁷]. As a next-generation HDACi, entinostat selectively inhibits class I and IV HDACs, effectively correcting aberrant epigenetic states. It also enhances the expression of estrogen receptors (ER) and aromatase, restoring tumor cell sensitivity to non-steroidal aromatase inhibitors (NSAIs). Importantly, entinostat has demonstrated the ability to delay the onset of endocrine therapy resistance, providing a mechanistic rationale for its use in HR+/HER2− advanced breast cancer. Previous findings from a Phase I trial suggested that the combination of exemestane with entinostat demonstrated both tolerability and anti-tumor activity in patients with HR+ advanced breast cancer [⁸]. Building on this, a Phase III clinical study (EOC103A3101) led by Academician Binghe Xu at the Cancer Hospital, Chinese Academy of Medical Sciences, further validated the efficacy and safety of entinostat in Chinese breast cancer patients [⁹]. Results showed that the combination of entinostat and exemestane significantly prolonged median progression-free survival (PFS) compared to the placebo group (6.32 vs. 3.72 months), reducing the risk of disease progression or death by 24% (HR 0.76, P=0.046). Patients in the entinostat group achieved a median overall survival (OS) of 38.39 months, extending survival by more than nine months compared to the placebo group and reducing the risk of death by 17% (HR 0.83, P=0.184), indicating a favorable survival benefit. Notably, entinostat is currently the only HDAC inhibitor to demonstrate a median OS exceeding 38 months, offering patients a meaningful extension in survival outcomes. In terms of safety, entinostat demonstrated a manageable overall safety profile, with a relatively low incidence of grade ≥3 adverse events. The primary reasons for treatment discontinuation included neutropenia, elevated gamma-glutamyl transferase (GGT), and anemia. However, these adverse events were largely controllable. Compared to other HDAC inhibitors, entinostat showed a lower incidence of grade 3–4 hematologic toxicity, contributing to better tolerability and improved patient adherence. Entinostat’s pharmacological design is also noteworthy. With a prolonged half-life of 61.9 hours, it is administered orally once weekly—just one tablet per dose. This convenient regimen significantly reduces the burden of frequent medication intake, thereby enhancing treatment adherence and enabling patients to better integrate therapy into their daily lives, with minimal disruption to quality of life.

Entinostat Offers New Hope for HR+/HER2– MBC Patients in the Post-CDK4/6i Era

For patients with HR+/HER2– metastatic breast cancer (MBC) who experience disease progression following CDK4/6 inhibitor therapy, treatment options remain limited. Entinostat, as a novel HDAC inhibitor, offers a new therapeutic strategy through its unique mechanism of action and demonstrated clinical benefit. Importantly, entinostat acts on common breast cancer-associated genes and signaling pathways and is not restricted by specific biomarkers, allowing broader application across the HR+/HER2– patient population. By promoting an epigenetic-based, biomarker-independent approach, entinostat has the potential to improve treatment outcomes and quality of life in patients with HR+/HER2– MBC. Its introduction not only brings renewed therapeutic hope to patients who have exhausted prior options but also represents a significant step forward in the personalization of breast cancer care. As clinical adoption of entinostat expands, it is poised to benefit a broader population of patients facing challenging treatment decisions.

References

1、国家肿瘤质控中心乳腺癌专家委员会, 中国抗癌协会乳腺癌专业委员会, 中国抗癌协会肿瘤药物临床研究专业委员会. 中国晚期乳腺癌规范诊疗指南(2022版)[J]. 中华肿瘤杂志, 2022, 44(12):1262-1287.

2、NCCN Clinical Practice Guidelines in Oncology:Breast Cancer(Version 4.2024).

3、中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会（CSCO）乳腺癌诊疗指南2024. 人民卫生出版社

4、中国抗癌协会乳腺癌专业委员会，中华医学会肿瘤学分会乳腺肿瘤学组. 中国抗癌协会乳腺癌诊治指南与规范（2024年版）［J］. 中国癌症杂志, 2023, 33 (12): 1092-1187.

5、Li, Yi et al. “A multicenter analysis of treatment patterns and clinical outcomes of subsequent therapies after progression on palbociclib in HR+/HER2- metastatic breast cancer.” Therapeutic advances in medical oncology vol. 13 17588359211022890. 11 Jun. 2021, doi:10.1177/17588359211022890

6、Garcia-Martinez, Liliana et al. “Epigenetic mechanisms in breast cancer therapy and resistance.” Nature communications vol. 12,1 1786. 19 Mar. 2021, doi:10.1038/s41467-021-22024-3

7、Garcia-Martinez, Liliana et al. “Epigenetic mechanisms in breast cancer therapy and resistance.” Nature communications vol. 12,1 1786. 19 Mar. 2021, doi:10.1038/s41467-021-22024-3

8、Masuda N, Tamura K, Yasojima H, Shimomura A, Sawaki M, Lee MJ,et al. Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer. BMC Cancer 2021;21:1269.

9、Xu, Binghe et al. “Entinostat, a class I selective histone deacetylase inhibitor, plus exemestane for Chinese patients with hormone receptor-positive advanced breast cancer: A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial.” Acta pharmaceutica Sinica. B vol. 13,5 (2023): 2250-2258. doi:10.1016/j.apsb.2023.02.001

Dr. Yanxia Shi Deputy Director, Department of Internal Medicine, Sun Yat-sen University Cancer Center

  • Board Member, Chinese Society of Clinical Oncology (CSCO)
  • Executive Member, Youth Committee of the Chinese Anti-Cancer Association
  • Chair, Breast Cancer Committee, China Association of Gerontology and Geriatrics
  • Vice Chair, Committee on Rare and Unknown Primary Tumors, Chinese Anti-Cancer Association
  • Standing Committee Member and Executive Deputy Chair of the Youth Committee, Committee on Clinical Chemotherapy, Chinese Anti-Cancer Association
  • Chair, Committee on Multiple and Unknown Primary Tumors, Guangdong Anti-Cancer Association
  • Secretary-General and Chair of the Youth Committee, Oncology Internal Medicine Branch, Guangdong Medical Association
  • Deputy Chair, Breast Cancer Branch, Thoracic Oncology Institute, Guangdong Province
  • Deputy Chair, Breast Cancer Branch, Guangdong Women Physicians Association
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Last updated on 2025.03.26