Novel HDAC Inhibitor Improves Outcomes in Patients with Estrogen-Sensitive Breast Cancer

October 2011, Vol 2, No 6

San Francisco, CA—A novel histone deacetylase (HDAC) inhibitor, when added to the aromatase inhibitor exemestane (Aromasin), appears to restore sensitivity to the endocrine agent by significantly delaying recurrences and creating an increased survival trend.

The findings come from the Entinostat Combinations Overcoming Resistance (ENCORE 301) study presented at the 2011 Breast Cancer Symposium by Denise Yardley, MD, Sarah Cannon Research Institute and Tennessee Oncology, Nashville.

“This combination may allow patients to remain on hormonal therapy longer, delaying the need for chemotherapy,” Dr Yardley suggested. ENCORE 301 was a phase 2 trial of exemestane with and without entinostat in postmenopausal women with estrogen receptor–positive advanced breast cancer that had progressed during previous nonsteroidal aromatase inhibitor therapy. A total of 114 patients were randomized to exemestane plus placebo or weekly entinostat.

The median progression-free survival (PFS) was 4.28 months with entinostat/ exemestane versus 2.27 months with exemestane alone, a significant, 27% reduction in risk.

At a median follow-up of 18 months, the median overall survival (OS) was 26.9 months with the combination versus 20.3 months with exemestane alone—a 54% reduction in risk for mortality. “We saw a trend for an OS benefit. This is an exploratory end point with data that are still maturing,” Dr Yardley said. The regimen was well tolerated.

Pharmacodynamic Analysis Shows Strong Benefit in Subgroup

In a biomarker analysis of a subgroup of 49 patients, those who demonstrated hyperacetylation (a chemical process) in blood samples derived the greatest benefit from the combination therapy. The mechanism of action of HDAC inhibitors involves inducing hyperacetylation of lysines on histones and a number of other proteins.

The risk of disease progression was reduced by 77% in this subgroup of patients: the median PFS was 8.54 months with the combination therapy versus 1.92 months with exemestane alone.

“This suggests that entinostatinduced hyperacetylation tracked with improved outcomes and may be a potential marker of benefit,” Dr Yardley said.

Joyce O’Shaughnessy, MD, Baylor Sammons Cancer Center, Dallas, TX, who moderated the symposium where these results were presented, called the use of entinostat in advanced hormonally sensitive breast cancer “very, very promising.” A phase 3 global study will begin enrolling patients in early 2012.

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