Breast cancer (BRCA) remains a significant global health challenge, characterized by high malignancy and mortality rates among women. While conventional treatments like surgery, chemotherapy, and hormone therapy exist, the need for novel therapeutic approaches is pressing, especially for patients with poor responses to standard care. Epigenetic modifications, particularly histone deacetylation (HDAC), have emerged as key players in BRCA progression and drug resistance.
Clinical Trial Landscape
A recent analysis of the Trialtrove database revealed 97 clinical trials evaluating HDAC inhibitors in BRCA. These trials span 24 regions, with the United States and China leading in the number of studies. The majority of trials are in early phases (Phase I and II: 87.6%), with a smaller proportion in Phase III (4.1%) and Phase IV (8.2%). Half of the registered Phase IV trials are focused on long-term safety, efficacy, and expanding approved indications.
Key HDAC Inhibitors in BRCA Trials
Chidamide (Epidaza), an oral selective HDAC inhibitor, is the most investigated in BRCA, with over half of its trials in Phase II and 20% reaching Phase IV. Vorinostat (Zolinza), already FDA-approved for cutaneous T-cell lymphoma (CTCL), is the second most studied HDAC inhibitor. Entinostat is also being evaluated, although trials involving this drug have largely been completed or terminated in BRCA. Other HDAC inhibitors are being explored, predominantly in Phase I or II trials.
Combination Therapy Strategies
Given the complexity of BRCA and its molecular subtypes, combination therapies are gaining traction. Clinical trials are exploring HDAC inhibitors in conjunction with chemotherapy, hormone therapy, targeted therapy, and immunotherapy. A significant number of trials (35) are evaluating HDAC inhibitors with hormone therapies, including selective ER modulators (e.g., Tamoxifen), aromatase inhibitors (e.g., Exemestane, Letrozole, and Anastrozole), and selective ER down-regulators (e.g., Fulvestrant).
Immunotherapy and Targeted Therapy Combinations
While immunotherapy is revolutionizing cancer treatment, trials combining HDAC inhibitors with immunotherapy in BRCA are still relatively limited. Most of these trials are in the planning or ongoing stages, indicating that this combination approach is in its early phases. Targeted therapies, combined with HDAC inhibitors, are also being investigated, with 21 trials exploring their effectiveness. These targeted strategies involve HER2 inhibitors (e.g., Trastuzumab), CDK4/6 inhibitors (e.g., Dalpiciclib, BEBT-209 and Ibrance), PARP inhibitors (e.g., Olaparib, Fluzoparib), tyrosine kinase inhibitors (e.g., Lapatinib), VEGFA inhibitor (e.g., Bevacizumab) or mTOR inhibitors (e.g., Everolimus).
Future Directions
Despite the progress, the mechanisms underlying the efficacy of HDAC inhibitors in BRCA remain largely unknown. Further research is needed to elucidate how these inhibitors modulate the tumor microenvironment, particularly in the context of immunotherapy. Insights from studies, such as the Phase II trial combining Entinostat with Nivolumab in metastatic pancreatic cancer, which utilized RNA sequencing and CyTOF to explore immune profile changes, are expected to guide future research and treatment strategies.
In summary, clinical studies of HDAC inhibitors in BRCA are being conducted globally, with a focus on early-phase trials. Chidamide, Vorinostat, and Entinostat are among the most studied drugs. Combination therapies, tailored to the molecular subtypes of BRCA, are a key focus. Future research into the mechanisms of HDAC inhibitor treatments will be crucial for optimizing their integration into BRCA treatment regimens.
