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Entinostat plus exemestane improved outcomes in advanced ER-positive breast cancer
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The addition of entinostat to exemestane improved clinical outcomes in postmenopausal women with ER-positive advanced breast cancer that progressed on nonsteroidal aromatase inhibitors, according to results of a phase 2 study.
“Entinostat differs from the other histone deacetylase inhibitors by its class I specificity,” Denise A. Yardley, MD, of the Sarah Cannon Research Institute and Tennessee Oncology in Nashville, told HemOnc Today. “In addition, for the first time, we identified a potential biomarker in a subset of patients with ER-positive tumors that was associated with a greater PFS. This may ultimately offer the potential for improved clinical outcomes with entinostat.”
Denise A. Yardley
The study included 130 postmenopausal women. Yardley and colleagues randomly assigned 64 patients to exemestane 25 mg daily plus entinostat (SNDX-275, Syndax) 5 mg once weekly. The other 66 patients received exemestane plus placebo.
PFS served as the primary outcome measure. OS was an exploratory endpoint. Researchers also collected blood samples from a subset of patients to assess for protein lysine acetylation as a biomarker of entinostat activity.
The researchers hypothesized that the addition of entinostat to exemestane would prevent hormone therapy resistance and exemestane would sensitize breast cancer cells to anti-estrogen therapy.
Patients assigned to exemestane plus entinostat experienced longer PFS (4.3 months vs. 2.3 months; HR=0.73; 95% CI, 0.50-1.07) and longer median OS (28.1 months vs. 19.8 months; HR=0.59; 95% CI, 0.36-0.97) compared with those assigned to exemestane plus placebo.
Prolonged PFS was associated with protein lysine hyperacetylation in the exemestane plus entinostat biomarker set. More women in the exemestane plus entinostat group discontinued treatment due to adverse events (11% vs. 2%).
“Delaying drug resistance and disease progression represents a significant unmet need, which — with entinostat — could prolong survival and decrease substantial health care costs associated with chemotherapy and hospitalization,” Yardley said. “Through epigenetic modulation, entinostat’s proven ability to target multiple mechanisms of resistance establishes it as a promising candidate for preventing and overcoming not only aromatase inhibitor-mediated resistance, but also tumor resistance with other agents.”
In collaboration with the NCI, additional research is under way to evaluate entinostat in triple-negative breast cancer and non–small cell lung cancer. A phase 3 confirmatory trial in breast cancer also is planned, Yardley said.
Denise A. Yardley, MD, can be reached at Sarah Cannon Cancer Center, 250 25th Ave. North, Suite 100, Nashville, TN 37203; email: dyardley@tnonc.com.
Disclosure: Yardley reports consultant fees from Syndax Pharmaceuticals.
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