Breast cancer is the most common malignancy among women worldwide, with the HR+/HER2⁻ subtype being one of the most prevalent forms. With the rapid advancement of medical technology and the continuous emergence of new therapies, patient survival has significantly improved, bringing hope to many. Recently, the novel oral HDAC inhibitor entinostat received official approval from China’s National Medical Products Administration (NMPA) for use in combination with an aromatase inhibitor (AI) to treat patients with HR+/HER2⁻ locally advanced or metastatic breast cancer who have relapsed or progressed following endocrine therapy. On July 25, the first prescriptions were issued in Guangdong, Guangxi, Beijing, and other provinces in China, marking a major milestone. This significant breakthrough offers a new treatment option for patients with HR+/HER2⁻ advanced breast cancer and is expected to reshape the current therapeutic landscape.Large Patient Population and Unmet Clinical Needs Remain Following First-Line Therapy in HR+/HER2⁻ Breast Cancer
Breast cancer is now the most common malignant tumor affecting women globally, with HR+/HER2⁻ accounting for approximately 70% of all cases [¹]. In the past, patients with this subtype were primarily treated with chemotherapy and endocrine therapy. For those with advanced HR+/HER2⁻ breast cancer, the approval and clinical application of CDK4/6 inhibitors (CDK4/6i) have transformed treatment strategies and significantly extended survival. Currently, endocrine therapy (ET) in combination with CDK4/6i (such as palbociclib or ribociclib) has become the standard first-line regimen for these patients.
However, even with first-line CDK4/6i+ET therapy, disease progression remains a concern. Around 12.5% of patients experience rapid progression within 6 months of treatment initiation [²]. Moreover, once progression occurs, there is still no unified standard for subsequent lines of therapy [³–⁵].
The YOUNG BC-9 study analyzed physicians’ real-world treatment decisions and outcomes after progression on palbociclib. Results showed that the median progression-free survival (PFS) for patients receiving chemotherapy post-CDK4/6i progression was only 5.6 months [⁷]. Prior data also indicate that traditional chemotherapy offers limited efficacy and is associated with a high rate of adverse events [⁶–⁷]. Additionally, a real-world study showed that patients who received everolimus (an mTOR inhibitor) plus endocrine therapy after CDK4/6i progression had a median PFS of only 3.8 months [⁸].
At present, data supporting cross-line CDK4/6i treatment remain limited [⁹–¹²]. Guidelines from leading bodies such as ESMO, NCCN, and CACA similarly note that there is insufficient evidence supporting cross-line CDK4/6i use, and recommend careful clinical consideration in such cases [⁴,¹³,¹⁴].
HDAC Inhibitors Precisely Modulate Epigenetics, Offering Greater Benefits to Breast Cancer Patients
In breast cancer treatment, there is growing research interest in the role of epigenetic regulation. Among epigenetic therapies, histone deacetylase inhibitors (HDACis) are the most extensively studied agents in vitro, accounting for 45.45% of such compounds under investigation [¹⁵]. HDACis exert their effects by modulating histone acetylation levels, thereby influencing chromatin structure and gene transcription, ultimately inhibiting tumor cell growth and proliferation. In particular, these agents show great promise in overcoming various forms of endocrine resistance driven by epigenetic abnormalities, marking their significant therapeutic potential in the field of breast cancer treatment [¹⁶].
Epigenetic Pathways Dysregulated in Endocrine-Resistant ER+ Breast Cancer and Their Targeting by HDAC Inhibitors
As a novel histone deacetylase inhibitor (HDACi), entinostat demonstrates distinct therapeutic advantages in the treatment of breast cancer. Beyond correcting aberrant epigenetic states, entinostat exerts its effects through multiple mechanisms—such as activating p21 expression and upregulating PTEN levels—to inhibit the PI3K/AKT signaling pathway. This multimodal action helps overcome resistance to CDK4/6 inhibitors. In addition, entinostat has demonstrated immunomodulatory properties, contributing to a broader anti-tumor response against breast cancer cells.
A comprehensive prospective clinical sequencing program analyzing 1,134 Chinese breast cancer cases—including 419 patients receiving neoadjuvant therapy, 606 undergoing surgery, and 109 with advanced disease—revealed significant genomic and clinical differences between Chinese and Western patients. Notably, the most pronounced differences were seen in the HR+/HER2⁻ subtype, which harbored more actionable targets [¹⁷]. HDAC inhibitors, including entinostat, exert anti-cancer effects by modulating common genetic alterations and signaling pathways involved in breast cancer. However, because gene mutations differ across ethnic groups, the efficacy of HDACis may vary by population. For Chinese patients, such agents may offer enhanced therapeutic benefits due to the higher frequency of relevant genetic alterations and pathway aberrations [¹⁸–¹⁹].
Phase III Trial of Entinostat in China Provides Robust Clinical Evidence of Benefit
To assess the efficacy and safety of entinostat in Chinese patients with breast cancer, domestic investigators conducted a Phase III randomized, double-blind, placebo-controlled clinical trial (EOC103A3101) [²⁰]. This study enrolled patients aged 18 to 75 with HR+/HER2⁻ locally advanced or metastatic breast cancer who had relapsed or progressed following prior endocrine therapy. Participants were randomly assigned in a 2:1 ratio to receive either entinostat or placebo, in combination with exemestane.
The results of the study demonstrated a significant improvement in progression-free survival (PFS) in the entinostat group compared with the placebo group, as assessed by the Independent Review Committee (IRC): 6.32 months versus 3.72 months, corresponding to a 24% reduction in the risk of disease progression or death (HR 0.76). Additionally, the median overall survival (OS) in the entinostat group reached 38.55 months—over 9 months longer than in the placebo group—translating to a 25% reduction in the risk of death (HR 0.75), indicating a favorable survival benefit.
Notably, entinostat also demonstrated clinical benefit in subgroups of patients who were resistant to CDK4/6 inhibitors or who had received prior salvage chemotherapy. The therapeutic advantage of entinostat was particularly evident in patients without visceral metastases, those with primary endocrine resistance, and those who had not previously received fulvestrant.
In terms of safety, the overall incidence of adverse events in the entinostat group was comparable to that in the placebo group, with most adverse events being mild to moderate in severity. The most common reasons for treatment discontinuation included neutropenia, elevated gamma-glutamyl transferase (GGT), and anemia. However, overall safety was manageable and within acceptable limits.
As an innovative HDAC inhibitor, entinostat has undergone rigorous clinical validation, demonstrating a significant extension in survival for patients with HR+/HER2⁻ advanced breast cancer. Notably, entinostat is currently the only HDACi to achieve a median overall survival (mOS) exceeding 38 months, offering tangible survival benefits for patients. Its favorable safety profile includes a marked reduction in the incidence of grade 3–4 hematologic adverse events, such as anemia and thrombocytopenia, thereby improving treatment tolerability and reducing the risk of therapy interruption.
Entinostat also stands out for its convenient administration. Its long half-life allows for a once-weekly dosing regimen—one tablet per week—minimizing the burden of frequent medication and significantly enhancing adherence. This simplified regimen enables patients to better integrate treatment into their daily lives, with less disruption and a positive impact on quality of life.
Conclusion and Outlook
Entinostat was recently approved by the National Medical Products Administration (NMPA) for use in combination with aromatase inhibitors for the treatment of HR+/HER2⁻ patients with locally advanced or metastatic breast cancer who have experienced disease progression following endocrine therapy. Compared to other HDAC inhibitors, entinostat offers clear differentiating advantages [²¹–²³]. First, it boasts a long elimination half-life of 61.9 hours, allowing for a once-weekly oral dosing regimen that greatly improves patient convenience and treatment adherence. Second, its efficacy is comparable to or better than other HDAC inhibitors, while its safety profile is significantly improved—with lower rates of grade ≥3 adverse events. In addition, entinostat demonstrates immunomodulatory effects that may enhance antitumor activity, providing additional therapeutic benefit to patients.
The approval of entinostat offers a promising new treatment option for patients with HR+/HER2⁻ advanced breast cancer. With its novel mechanism of action, strong clinical efficacy, and improved safety and convenience, entinostat is poised to play an increasingly important role in the post-CDK4/6i treatment landscape. As further clinical studies are conducted and clinical experience grows, entinostat is expected to bring new hope to more patients. At the same time, the continued development and integration of novel therapeutics will remain essential in expanding the arsenal of effective options for oncology care.
Reference
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