Hormone receptor-positive (HR⁺) breast cancer accounts for approximately 70% of all breast cancer cases, representing a large population in need of effective treatment strategies. In recent years, first-line treatment with CDK4/6 inhibitors (CDK4/6i) has significantly improved patient outcomes. However, treatment options following CDK4/6i progression remain diverse, with no established standard of care and varying limitations among available therapies.The recent approval in China of the HDAC inhibitor entinostat introduces a novel, precision-targeted approach to breast cancer treatment. Unlike many targeted therapies, entinostat does not require biomarker testing before clinical use and has demonstrated clear survival benefits along with lower hematologic toxicity. It also offers the convenience of the first oral “weekly therapy” regimen for breast cancer.
As new therapeutic options become more accessible in clinical practice, how will the treatment landscape evolve for HR⁺/HER2⁻ advanced breast cancer in China? Oncology Frontier invited Dr. Jian Zhang from Fudan University Shanghai Cancer Center to share his insights.
Limitations of Post-CDK4/6i Strategies in the Era of Targeted Endocrine Therapy
The management of HR⁺/HER2⁻ advanced breast cancer has entered a new phase with the emergence of targeted endocrine therapy. Among these, CDK4/6 inhibitors—targeting the tumor cell cycle—have become the first-line standard, offering substantial survival benefits, with median progression-free survival (mPFS) exceeding 2 years and median overall survival (mOS) surpassing 5 years [¹].
However, treatment options after progression on CDK4/6i remain non-standardized, and current strategies have varying limitations. New agents with novel mechanisms of action are urgently needed to expand the therapeutic arsenal.
First, traditional chemotherapy remains an option for patients previously treated with CDK4/6i. Yet it typically achieves only 4–5 months of PFS [²][³], and its toxicity profile is considerable—posing challenges for many late-stage patients with compromised performance status.
Second, CDK4/6i continuation or switching to another agent in the same class has been explored. Trials such as PALMIRA and PACE, which examined continuation of the original CDK4/6i, failed to show meaningful benefit. The Phase II MAINTAIN study, in which most patients progressed on palbociclib and were then treated with ribociclib, showed a modest PFS benefit (5.33 vs. 2.76 months, HR 0.56) [⁴]. More recently, the postMONARCH trial—presented at this year’s ASCO Annual Meeting—was the first Phase III study to demonstrate a positive result for CDK4/6i reuse: abemaciclib offered a PFS advantage of 6.0 vs. 5.6 months (HR 0.73) [⁵].
While some clinical and real-world studies suggest a potential benefit from cross-line CDK4/6i use, the overall magnitude of benefit appears limited. For instance, in postMONARCH, the mPFS gain was only 0.4 months. Thus, further research is required to validate these findings.
Third, the PI3K-AKT-mTOR (PAM) pathway plays a pivotal role in resistance and progression in HR⁺/HER2⁻ advanced breast cancer. Several targeted therapies have emerged targeting this axis:
- mTOR inhibitors were among the first to be approved, but lack prospective data in CDK4/6i-pretreated populations.
- The CAPItello-291 trial confirmed that the AKT inhibitor capivasertib improved PFS in patients previously treated with CDK4/6i (7.2 vs. 3.6 months, HR 0.60). However, its current indication is mainly for patients with PIK3CA, AKT1 mutations, or PTEN loss [⁶].
- The SOLAR-1 study demonstrated the efficacy of the PI3K inhibitor alpelisib as a later-line therapy for endocrine-resistant patients, though only 5% had prior CDK4/6i exposure. Alpelisib is also primarily indicated for those with PIK3CA mutations [⁷].
Thus, while targeting the PAM pathway offers some benefit, these approaches are heavily dependent on biomarker presence. In addition, adverse events—such as hyperglycemia, mucositis, rash, and diarrhea—are common and may reduce treatment adherence.
Fourth, PARP inhibitors and novel selective estrogen receptor degraders (SERDs) have shown potential for patients who progress after CDK4/6i and endocrine therapies. Yet their use is similarly limited by the need for biomarkers such as BRCA mutations or ESR1 mutations, and overall clinical benefit remains modest.
A New Direction in HDACi Therapy: Entinostat Poised to Reshape the Treatment Paradigm
Histone deacetylases (HDACs) are key enzymes that regulate epigenetic modifications in cancer by removing acetyl groups from histone lysine residues. This deacetylation alters chromatin structure and gene expression, playing a critical role in tumor cell growth and transcriptional regulation. As a result, HDACs have become important therapeutic targets in the design of epigenetic anti-cancer agents [⁸][⁹]. In recent years, several novel HDAC inhibitors with promising therapeutic potential have emerged in the field of breast cancer.
Entinostat, a newly approved HDAC inhibitor in China, has shown significant potential to redefine treatment strategies for HR⁺/HER2⁻ breast cancer. In the Phase III clinical trial EOC103A3101 [¹⁰], 354 patients with locally advanced or metastatic HR⁺/HER2⁻ breast cancer—who had relapsed or progressed following endocrine therapy (either adjuvant or salvage)—were randomized to receive either entinostat or placebo in combination with exemestane.
The results were compelling: the median progression-free survival (PFS), as assessed by an independent review committee (IRC), nearly doubled in the entinostat group compared to the control group (6.32 vs. 3.72 months; HR 0.76, 95% CI: 0.58–0.98; P = 0.046). This survival benefit was consistent across all subgroups. Notably, in patients who had received prior CDK4/6 inhibitor therapy, entinostat reduced the risk of disease progression by 43% (HR 0.57).
Furthermore, the median overall survival (OS) in the entinostat arm reached 38.39 months—the longest OS reported to date in Phase III trials of HDAC inhibitors for this patient population—representing a 17% reduction in the risk of death compared to the control group (HR 0.83).
In terms of safety, the most common grade ≥3 hematologic adverse events associated with entinostat were neutropenia, thrombocytopenia, and leukopenia. Importantly, the incidence of these adverse events was numerically lower than what has been previously reported for other HDAC inhibitors [¹¹].
Based on the positive results of this study, in April 2024, China’s National Medical Products Administration (NMPA) approved entinostat in combination with an aromatase inhibitor (AI) for the treatment of patients with locally advanced or metastatic HR⁺/HER2⁻ breast cancer who have relapsed or progressed following prior endocrine therapy.
Optimized PK/PD Profile: The First Weekly Oral Therapy for Breast Cancer
Entinostat is a benzamide-class HDAC inhibitor that targets the commonly involved HDAC isoforms HDAC1, HDAC2, and HDAC3. It exhibits strong biological activity or potency, with an in vitro human serum protein binding rate of 89% to 92% [¹²].
Notably, entinostat has an average elimination half-life of 61.9 hours and a time to peak concentration of just 1 hour [¹³]. Compared to other HDAC inhibitors, it shows several-fold improvements in drug absorption efficiency and duration of effect, allowing it to exert anti-tumor activity both more rapidly and more durably.
The approved formulation of entinostat is administered once weekly by mouth. It is currently the first weekly oral anti-tumor therapy for breast cancer available in clinical practice. The extended dosing interval can significantly improve patient adherence.
Conclusion
HR⁺/HER2⁻ advanced breast cancer has entered the era of targeted endocrine therapy. However, after failure of CDK4/6 inhibitors combined with endocrine therapy, there remains no established standard of care. The survival benefit of chemotherapy is limited, and its toxicity is considerable. Cross-line CDK4/6 inhibitor therapy, PI3K-AKT-mTOR pathway–targeted therapy, PARP inhibitors, and novel SERDs are all restricted by biomarker requirements, limited PFS improvement, or insufficient clinical evidence, presenting clear limitations in treatment.
In recent years, precision modulation of epigenetics has become a new focus in the development of anti-cancer therapies for breast cancer. The Phase III clinical trial of entinostat has confirmed that it can bring significant PFS benefit and overall survival exceeding 38 months, with a favorable safety profile.
Furthermore, entinostat does not require biomarker testing, which can reduce diagnostic and treatment costs. As the first weekly oral targeted therapy for breast cancer, it also offers convenience in administration. These advantages suggest that entinostat has the potential to bring both survival and quality-of-life benefits to patients with HR⁺/HER2⁻ advanced breast cancer, and may further transform the treatment landscape for this population in China.
Dr. Jian Zhang
Chief Physician, Department of Medical Oncology / Phase I Clinical Trial Ward Fudan University Shanghai Cancer Center Doctoral Supervisor
Director, Clinical Research Center Fujian Hospital, Fudan University Shanghai Cancer Center Executive Deputy Director, Department of Medical Oncology
- Chief Physician, Department of Medical Oncology
- Recipient of the “Shanghai Medical Rising Star” Outstanding Young Talent Award
- Chair, Committee on Clinical Research of Antitumor Drugs, Chinese Medical Education Association
- Chair, Committee on Cancer Prevention and Clinical Research, Chinese Association of Geriatric Health Care
- Chair, Yangtze River Academic Belt Breast Cancer Alliance (YBCSG)
- Chair-Elect, Committee on Clinical Research of Antitumor Drugs, Shanghai Anti-Cancer Association
- Standing Committee Member, Breast Cancer Committee, Chinese Anti-Cancer Association
- Deputy Convener, Youth Committee, Breast Cancer Committee, Chinese Anti-Cancer Association
- Vice Chair, Youth Committee, Breast Cancer Committee, Chinese Research Hospital Association
- Vice Chair, Committee on Breast Cancer Prevention and Research, Chinese Maternal and Child Health Association
- Vice Chair, Youth Committee, National Committee for Clinical Application Monitoring of Antitumor Drugs
- Vice Chair, Cardio-Oncology Committee, Shanghai Anti-Cancer Association
- Standing Committee Member, CSCO Expert Committee on Supportive and Rehabilitative Oncology
- Standing Committee Member, Cancer Rehabilitation Committee, Chinese Association of Rehabilitation Medicine
- Member, CSCO Breast Cancer Expert Committee
- Member, Committee on Oncology Clinical Research Management, Chinese Anti-Cancer Association
- First group of part-time clinical drug reviewers, Center for Drug Evaluation (CDE), National Medical Products Administration (NMPA)
Honors and Editorial Roles
- Named one of the “Top 10 Medical Pioneer Experts” in 2023
- Recipient of the 2023 “People’s Good Doctor” Outstanding Contribution Award
- Associate Editor, Diseases & Research
- Associate Editor, Electronic Journal of Comprehensive Oncology, People’s Medical Publishing House
Academic Achievements
- First author, co-first author, or corresponding author of over 80 SCI-indexed publications, including in: Lancet Oncology, Annals of Oncology, Nature Communications, Clinical Cancer Research, Journal of Hematology & Oncology, Signal Transduction and Targeted Therapy, ACS Nano, and others.
