The first histone deacetylase (HDAC) inhibitor to be successfully tested in a randomized, placebo-controlled study of metastatic breast cancer has demonstrated that clinical outcome can be predicted shortly after administration of the drug, entinostat, according to researchers from the company that developed the agent.
“The ability to have a marker of benefit within the first several weeks of using this drug represents an exciting advance in personalized medicine,” commented lead researcher Peter Ordentlich, PhD, in a statement issued by the American Association for Cancer Research (AACR). The findings were presented at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, held November 12-16, 2011, in San Francisco, California.
“The goal of entinostat in breast cancer is to extend the benefit of hormone therapy and delay the time that patients will need to use chemotherapy,” explained Ordentlich, a founder of Syndax Pharmaceuticals, Inc., Waltham, Massachusetts, and the company’s executive director of translational science. Syndax developed entinostat, an oral small-molecule drug that inhibits HDAC enzymes, affecting gene expression.
Ordentlich and colleagues conducted ENCORE-301, a phase 2 study of 130 postmenopausal women with estrogen receptor (ER)-positive invasive breast cancer. The women were randomly assigned to receive the aromatase inhibitor exemestane with either entinostat or placebo. The combination therapy delayed cancer progression by 27% compared with exemestane treatment alone (4.3 months vs 2.3 months). Overall survival was also significantly longer in the combination group at a median follow-up of 18 months: 26.9 months vs 20.3 months.
Blood samples from 27 of the combination-therapy participants and 22 others showed that 1 day after treatment, levels of protein lysine acetylation, a biological marker of entinostat activity, were not linked to clinical benefit; however, levels measured 8 and 15 days after therapy were. Patients with elevated levels of protein lysine acetylation had a 68% reduced risk of disease progression compared with those who did not have sustained elevated levels.
Hyperacetylation was also associated with longer median progression-free survival across individual cell lines: in B cells, 8.5 months vs 1.9 months for persons without sustained elevated levels of acetylation; in T cells, 6.6 months vs 1.8 months; and in monocytes, 6.2 months vs 1.9 months.