Dr. Peng Yuan: In the Post-CDK4/6i Era, Entinostat Offers New Hope for Patients with HR+/HER2− Advanced Breast Cancer

Breast cancer remains one of the most prevalent malignancies among women worldwide, and its hormone receptor-positive, HER2-negative (HR+/HER2⁻) subtype accounts for nearly 70% of all cases. In recent years, the combination of CDK4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) has become the gold standard for first-line treatment in metastatic settings. However, once progression occurs on CDK4/6i-based regimens, the optimal path forward is less clearly defined, presenting a persistent challenge in clinical decision-making. The recent approval of entinostat, a histone deacetylase inhibitor (HDACi), marks a significant advancement in this space. Now officially available across China—with initial prescriptions issued in key regions such as Beijing and Guangdong—entinostat offers a novel, biomarker-agnostic therapeutic option that may help reshape the post-CDK4/6i treatment landscape for HR+/HER2⁻ metastatic breast cancer (MBC).

To better understand the implications of this development, Oncology Frontier spoke with Dr. Peng Yuan, a leading oncologist at the Cancer Hospital Chinese Academy of Medical Sciences. In this exclusive conversation, Professor Yuan explores the evolving treatment strategies in the post-CDK4/6i era, highlights clinical considerations in therapy selection, and offers insights into the efficacy and safety of entinostat based on the latest evidence.

01. Unmet Needs Remain in HR+/HER2⁻ MBC

Oncology Frontier: Breast cancer is the most frequently diagnosed malignancy among women globally. Approximately 70% of cases are classified as HR+/HER2⁻. In the metastatic setting, endocrine therapy remains the cornerstone of treatment for HR+ disease. Could you briefly summarize the current treatment landscape for HR+/HER2⁻ MBC?

Dr. Peng Yuan: Indeed, breast cancer is the most common cancer affecting women worldwide. In 2020 alone, there were approximately 416,000 new cases of breast cancer and 117,000 deaths reported in China. Among newly diagnosed patients, 3–10% present with distant metastases at diagnosis, and roughly 30% of early-stage patients eventually progress to advanced disease [¹].

The HR+/HER2⁻ subtype accounts for around 70% of all breast cancer cases. For these patients, endocrine therapy is a key treatment modality [²]. In the advanced setting, CDK4/6 inhibitors combined with ET have become the standard first-line option for patients without visceral crisis. However, treatment resistance remains an inevitable issue, and currently there is no universally accepted standard of care following progression on CDK4/6i therapy.

02. Post-CDK4/6i Progression: Navigating Treatment Options and Decision-Making

Oncology Frontier: CDK4/6i plus ET has become the standard first-line treatment for HR+/HER2⁻ MBC. However, after progression, there is no established second-line standard. What treatment strategies can be considered for patients who progress on CDK4/6i?

Dr. Peng Yuan: For HR+/HER2⁻ MBC patients who progress on CDK4/6i-based therapy, a number of options exist—though the variety itself reflects the absence of a clearly superior approach. Traditional chemotherapy remains a treatment option, but its efficacy is modest, with a median progression-free survival (PFS) of about 5 months, and it is often associated with considerable toxicity [³]. Many patients are therefore reluctant to pursue this route.

One potential approach is switching to an alternative CDK4/6 inhibitor for continued CDK4/6i therapy. While the Phase III postMONARCH trial [⁴] showed positive results for abemaciclib plus fulvestrant in this setting, the median PFS was only 6 months, and overall survival (OS) data remain immature. Thus, cross-line CDK4/6i treatment may not be the optimal solution.

The DB-06 trial [⁵], presented at this year’s ASCO meeting, generated considerable attention. It demonstrated that in HR+/HER2-low or ultra-low expression MBC patients—who either progressed within 6 months of starting CDK4/6i+ET therapy or had received at least two prior lines of endocrine therapy—trastuzumab deruxtecan (T-DXd) offered superior PFS compared to physician’s choice of chemotherapy. However, this approach requires HER2 status testing before administration.

Other post-CDK4/6i options target the PI3K/AKT/mTOR pathway, including mTOR inhibitors, PI3K inhibitors, and AKT inhibitors. Everolimus, an mTOR inhibitor, was one of the earliest agents in this category. While it offers some PFS benefit when combined with endocrine therapy, it predates the widespread use of CDK4/6i and does not align well with current clinical paradigms. The BYLieve trial [⁶] showed that patients harboring PIK3CA mutations may benefit from alpelisib (a PI3K inhibitor) combined with ET after progression on CDK4/6i. Similarly, the CAPItello-291 trial [⁷] demonstrated that the AKT inhibitor capivasertib combined with fulvestrant significantly improved PFS in patients who failed prior aromatase inhibitors, including those previously treated with CDK4/6i (about 70% of the study population). However, these pathway-targeted therapies depend on the presence of specific genomic alterations, and genetic testing is essential.

Histone deacetylase inhibitors (HDACi) have also emerged as a viable post-CDK4/6i treatment strategy. Unlike PI3K/AKT/mTOR inhibitors, HDACi therapies do not require biomarker testing, offering broader applicability. To date, at least two HDAC inhibitors have been approved in China. Among them, entinostat was investigated in a Phase III trial that closely mirrors real-world clinical scenarios. The study enrolled patients who had previously received CDK4/6i therapy and achieved significant clinical benefit [⁸].

03. Epigenetic Therapies on the Rise: HDAC Inhibitors Emerge as a Promising Option

Oncology Frontier: Could you provide an overview of the current landscape of epigenetic anti-cancer therapies, and specifically elaborate on the mechanisms by which HDAC inhibitors (HDACi) exert therapeutic effects in patients with HR+/HER2⁻ advanced breast cancer?

Dr. Peng Yuan: The development and progression of breast cancer are closely tied to epigenetic regulation, which is also intricately linked to endocrine therapy and treatment resistance. In recent years, research into epigenetic therapies for breast cancer has gained significant momentum, particularly in North America and the Asia-Pacific region. Among these, HDAC inhibitors are the most extensively studied class of in vitro agents, accounting for approximately 45.45% of all such drugs under investigation [⁹].

HDAC inhibitors exert anti-tumor effects through several key mechanisms:

  • Induction of apoptosis: HDAC inhibitors can activate both intrinsic and extrinsic apoptotic pathways in tumor cells.
  • Induction of autophagy: In addition to promoting apoptosis, HDAC inhibitors can induce caspase-independent autophagic cell death across various tumor cell types.
  • Induction of necrosis: HDAC inhibitors such as SAHA, TSA, and butyrate may trigger necrotic cell death through the generation and accumulation of reactive oxygen species (ROS), suggesting a potential mechanism of ROS-mediated necrosis regulation [¹⁰].

HDAC inhibitors also influence cancer cell death pathways by activating NF-κB transcription factors and promoting the release of pro-inflammatory cytokines. These changes suppress antioxidant defenses and trigger oxidative stress, leading to DNA damage. Concurrently, HDAC inhibitors downregulate proteins involved in base excision repair, impairing the cell’s ability to repair oxidative damage and causing mitochondrial membrane depolarization and further ROS accumulation—thus amplifying DNA injury [¹⁰].

Through modulation of key breast cancer-related genes and signaling pathways, HDAC inhibitors exhibit anti-tumor efficacy. However, due to genetic variation in breast cancer between populations, the therapeutic impact of HDAC inhibitors may differ across ethnic groups. Notably, Chinese patients are more likely to harbor mutations in common breast cancer-related genes and pathways, suggesting that HDAC inhibitors may offer enhanced efficacy in the Chinese population [¹¹,¹²].

04. Entinostat: The First HDACi with OS Beyond 38 Months, Delivering Safety, Adherence, and a New Option for HR+/HER2⁻ MBC

Oncology Frontier: Entinostat has recently been approved by the National Medical Products Administration (NMPA) and prescribed for the first time in China. Could you share insights on its clinical efficacy among Chinese patients and highlight its key therapeutic advantages?

Dr. Peng Yuan: To assess the efficacy and safety of entinostat in Chinese breast cancer patients, we conducted a Phase III clinical trial (EOC103A3101) [⁸]. This study enrolled patients aged 18–75 years with HR+/HER2⁻ locally advanced or metastatic breast cancer who had experienced recurrence or progression following prior endocrine therapy. Participants were randomized in a 2:1 ratio to receive either entinostat or placebo, both in combination with exemestane.

Results demonstrated a significantly longer median progression-free survival (PFS) in the entinostat group compared to placebo (6.32 vs. 3.72 months), with a 24% reduction in the risk of progression or death (HR 0.76). Median overall survival (OS) in the entinostat group reached 38.39 months, exceeding the placebo group by over 9 months and reducing the risk of death by 17% (HR 0.83), indicating a notable survival benefit.

Among patients previously treated with CDK4/6 inhibitors, entinostat reduced the risk of progression by 43% (PFS HR 0.57). The combination of entinostat with exemestane showed an overall manageable safety profile. Subgroup analyses by ECOG performance status, presence of visceral metastasis, number of prior treatment lines, primary endocrine resistance, prior chemotherapy, prior use of CDK4/6 inhibitors, and prior treatment with fulvestrant were consistent with the overall study findings.

Therapeutic Advantages:

  • Prolonged survival: Entinostat is currently the only HDAC inhibitor that has demonstrated a median OS exceeding 38 months in HR+/HER2⁻ MBC patients.
  • Improved adherence: With a long half-life of 61.9 hours, entinostat requires only weekly dosing, significantly enhancing patient compliance.
  • Convenient administration: No biomarker testing is needed, the treatment interval is weekly, and the oral formulation offers ease of use.

Oncology Frontier: What are the most common adverse events associated with entinostat in Chinese patients, and how can they be prevented or managed?

Dr. Peng Yuan: As with other HDAC inhibitors, entinostat can cause adverse effects, but these are generally controllable. In the EOC103A3101 trial, the leading causes of treatment discontinuation included neutropenia, elevated γ-glutamyl transferase, and anemia—highlighting that hematologic toxicity is the primary concern.

Therefore, it is crucial to monitor for bone marrow suppression during treatment. We recommend weekly complete blood count monitoring during the initial treatment phase. If hematologic toxicity is manageable, the frequency of monitoring may be reduced under physician guidance.

Oncology Frontier: How do you envision entinostat shaping the treatment landscape for HR+/HER2⁻ MBC in the future, and what are your expectations for this drug?

Dr. Peng Yuan: In clinical practice, treatment decisions for HR+/HER2⁻ MBC patients are based on individual therapeutic needs, prior treatment history, tumor burden, and drug accessibility. Entinostat is the only HDAC inhibitor to demonstrate a significant OS benefit in this setting, making it a valuable addition to our therapeutic arsenal—particularly following CDK4/6i failure.

Its convenience (weekly dosing) and favorable safety profile further support its use. Entinostat is poised to become a key therapeutic option in the post-CDK4/6i era and is likely to drive a shift toward more individualized and precision-based treatment strategies for HR+/HER2⁻ metastatic breast cancer.

References

  1. National Cancer Quality Control Center Breast Cancer Expert Committee, Chinese Anti-Cancer Association Breast Cancer Committee, Chinese Anti-Cancer Association Clinical Oncology Drug Research Committee. Guidelines for the standardized diagnosis and treatment of advanced breast cancer in China (2022 Edition). Chin J Oncol. 2022;44(12):1262–1287. doi:10.3760/cma.j.cn112152-20221007-00680.
  2. National Cancer Quality Control Center Breast Cancer Expert Committee, Chinese Anti-Cancer Association Clinical Oncology Drug Research Committee. Expert consensus on clinical application of CDK4/6 inhibitors in hormone receptor-positive, HER2-negative breast cancer (2023 Edition). Chin J Oncol. 2023;45(12):1003–1017. doi:10.3760/cma.j.cn112152-20230428-00188.
  3. Ingrand I, Etienne A, Paillere C, et al. Serious adverse effects occurring after chemotherapy: a general cancer registry-based incidence survey. Br J Clin Pharmacol. 2020;86(4):711–722. doi:10.1111/bcp.14159.
  4. Kalinsky K, et al. Abemaciclib plus fulvestrant vs. fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: primary outcome of the Phase 3 postMONARCH trial. J Clin Oncol. 2024 ASCO Abstract LBA1001.
  5. Curigliano G, et al. Trastuzumab deruxtecan (T-DXd) vs physician’s choice of chemotherapy in HR+, HER2-low or ultra-low metastatic breast cancer after endocrine therapy: primary results from DESTINY-Breast06 (DB-06). J Clin Oncol. 2024 ASCO Abstract LBA1000.
  6. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22(4):489–498.
  7. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058–2070.
  8. Xu B, Zhang Q, Hu X, 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 Pharm Sin B. 2023;13(5):2250–2258. doi:10.1016/j.apsb.2023.02.001.
  9. Purja S, Sun X, Xie Y, et al. Breast cancer epigenetics: current and evolving treatment. Breast Cancer (Tokyo). 2024 Jun 11. doi:10.1007/s12282-024-01601-6.
  10. Chen H, He Y. Advances in the research of histone deacetylase inhibitors in tumor therapy. Chongqing Med J. 2017;46(30):4280–4282. (In Chinese)
  11. Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci. 2017;18(7):1414. doi:10.3390/ijms18071414.
  12. Li G, Jiang W, Hu Y, et al. The roles of histone deacetylases and their inhibitors in cancer therapy. Front Cell Dev Biol. 2020;8:576946. doi:10.3389/fcell.2020.576946.

Professor Yuan Peng

Chief Physician, Professor, Doctoral Supervisor National Cancer Center / Cancer Hospital Chinese Academy of Medical Sciences

  • Board Member, Chinese Anti-Cancer Association (CACA)
  • Chair, International Medical and Exchange Branch, CACA
  • Standing Committee Member, Breast Cancer Committee, CACA
  • Standing Committee Member, Breast Cancer Expert Committee, Chinese Society of Clinical Oncology (CSCO)
  • Standing Committee Member, Oncology Physicians Branch, Chinese Medical Doctor Association
  • Chair, Breast Cancer Group, Oncology Physicians Branch, Chinese Medical Doctor Association
  • Vice Chair, Breast Cancer Committee, Chinese Research Hospital Association
  • President, Beijing Cancer Prevention and Treatment Society
  • Recipient of the 5th “People’s Good Doctor” Award
  • National March 8th Red-Banner Pacesetter
Post Views: 1,304
Last updated on 2025.03.26