A phase III trial presented by Jiang et al at the European Society for Medical Oncology (ESMO) 2018 Congress showed activity of histone deacetylase (HDAC) inhibitor therapy in advanced hormone receptor–positive breast cancer (Abstract 283O_PR).
Endocrine therapies are the foundation of treatment for patients with hormone receptor–positive breast cancer. However, resistance to endocrine therapy is common, which may lead to disease progression or recurrence. HDAC inhibitors are a type of epigenetic therapy, meaning they can switch genes on or off without changing the underlying DNA sequence. HDAC inhibitors have previously been shown to reverse resistance to hormone therapy (Munster et al, British Journal of Cancer), but no randomized trial so far has demonstrated superiority with an HDAC inhibitor over existing treatments in advanced breast cancer.
This phase III trial focused on chidamide, an HDAC inhibitor developed in China. The study enrolled 365 postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer from 22 centers in China. Patients had disease progression on previous endocrine therapy (tamoxifen and/or a nonsteroidal aromatase inhibitor). Patients were randomly allocated in a 2:1 ratio to receive chidamide at 30 mg twice a week plus endocrine therapy with exemestane at 25 mg daily or placebo plus exemestane.
The median progression-free survival was 7.4 months with chidamide plus exemestane and 3.8 months with placebo plus exemestane (hazard ratio = 0.755, 95% confidence interval = 0.582–0.978, P = .0336).
Zefei Jiang, MD, Director of the Department of Breast Cancer, 307th Hospital of PLA (AMMS China) in Beijing, said, “This is the first phase III trial to demonstrate that an HDAC inhibitor plus endocrine blockade improves progression-free survival compared to endocrine blockade alone in [patients with] hormone receptor–positive advanced breast cancer who have had disease progression after prior endocrine therapy.”
Serious adverse events occurred in 51 (20.9%) patients in the chidamide group and 7 patients (5.8%) in the placebo group. These events included reduced blood levels of neutrophils (50.8% vs 2.5%), platelets (27.5% vs 2.5%), and leukocytes (18.8% vs 2.5%) in the chidamide and placebo groups, respectively. There were no deaths due to chidamide.
Quality of life with the drug was not measured in the study, but Dr. Jiang commented, “The treatment regimen was generally well tolerated, and toxicities were similar to those previously observed with chidamide monotherapy. The most common adverse events were blood disorders, which were mostly asymptomatic and manageable.”
Commenting on the study, Suzette Delaloge, MD, MSc, Head of the Breast Cancer Group, Institut Gustave Roussy, said in a statement, “This is the first randomized phase III trial to reach a positive result with an HDAC inhibitor in advanced breast cancer. It suggests that there may be some hope for this type of drug in these patients, since until now the only positive results have been in earlier-stage breast cancer.”
Dr. Delaloge said the findings should prompt more research on HDAC inhibitors in patients with advanced breast cancer. She said, “Studies are needed in Western populations comparing an HDAC inhibitor to the standard of care, which is the combination of endocrine therapy plus an mTOR inhibitor (everolimus) or the combination of an endocrine therapy plus a [cyclin-dependent kinase] 4/6 inhibitor.”
In addition to this trial, two ongoing phase III studies are comparing exemestane plus the HDAC inhibitor entinostat vs exemestane plus placebo. One trial is being conducted in the United States (NCT02115282) and is planned to be completed in 2021, while the other trial is being run in China (NCT03538171) and is set to finish in 2020.
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