SAN FRANCISCO – Entinostat, a novel oral histone deacetylase inhibitor taken once weekly, may overcome resistance to hormonal therapy in breast cancer, the results of a randomized phase-II trial suggest.
Investigators studied 130 women with estrogen receptor–positive advanced breast cancer progressing on aromatase inhibitor (AI) therapy. Results showed that, compared with exemestane (Aromasin) plus placebo, exemestane plus entinostat reduced the risk of progression-free survival events by 27% and the risk of death by 44%. It also was well tolerated.
Dr. Denise A. Yardley
"The combination ... is delaying the time to disease progression, allowing patients to maintain hormonal therapy longer, and delaying the need for change of therapy and subsequent considerations of chemotherapy," principal investigator Dr. Denise A. Yardley reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology.
"These results support our plans for a global, pivotal phase-III study due to begin enrollment in 2012," added Dr. Yardley, an oncologist with the Sarah Cannon Research Institute and Tennessee Oncology PLLC, both in Nashville.
In an additional finding, median progression-free survival was greatest, 8.5 months, in patients treated with the combination who had hyperacetylation of proteins in blood cells during the first cycle of treatment, suggesting that this could be a biomarker for efficacy. These data reveal "for the first time in a matched controlled trial, evidence of hyperacetylation from an HDAC [histone deacetylase] inhibitor correlating with improved outcomes," she noted.
Session chair Dr. Joyce O’Shaughnessy, an oncologist with the Baylor Sammons Cancer Center in Dallas, Texas Oncology, and US Oncology, characterized the trial’s findings as "very, very promising," saying, "I agree that it’s time for a phase III" trial. To her knowledge, this is the first randomized trial of an HDAC inhibitor in breast cancer.
A particularly impressive finding was the long progression-free survival seen in hyperacetylators, according to Dr. O’Shaughnessy. It will be important to determine whether this correlates with toxicity, as lack of toxicity might then identify patients who could benefit from dose-escalation of entinostat. "They need to really carefully look at that because you really want to optimize it for all the people in the phase-III trial," she commented.
Giving some mechanistic background to the trial, Dr. Yardley noted that HDAC inhibitors interfere with the condensation of chromatin and the silencing of genes, such as tumor suppressor genes.
Resistance to AIs occurs from upregulation and activation of growth factor signaling pathways that are not estrogen dependent. "Entinostat targets these growth factor signaling pathways, ultimately inhibiting tumor cell growth," she explained. Preclinical data also suggest that the drug resensitizes tumors to AIs.
The randomized phase-II trial, called ENCORE 301 (Entinostat Combinations Overcoming Resistance), was conducted among women in North America, the European Union, and Russia who were postmenopausal and had locally advanced or metastatic estrogen receptor–positive breast cancer that was progressing on a nonsteroidal AI (anastrozole or letrozole). Those with metastatic disease could have received up to one prior chemotherapy for metastases.
The patients were randomized in balanced fashion to double-blind treatment with exemestane plus placebo or exemestane plus entinostat. By study design, P values less than .1 were considered statistically significant.
Demographically, the patients were 62 years old on average. Eighty-five percent had experienced progression on an AI in the metastatic setting.
With a median follow-up of 18 months, entinostat was associated with longer median progression-free survival (4.28 vs. 2.27 months; hazard ratio, 0.73; P = .06), with similar findings in subgroups stratified by locally advanced vs. metastatic disease, age, and site of metastasis, Dr. Yardley reported.
In 49 patients, blood samples collected before and during the first cycle of therapy were analyzed to determine the percent change of lysines in peripheral blood mononuclear cell proteins that were acetylated. Results showed that progression-free survival was greatest, at 8.54 months, among entinostat-treated patients who had hyperacetylation, defined as an above-median percent change in lysines that were acetylated during the first cycle of treatment.
These findings "suggest that entinostat-induced hyperacetylation appeared to track with improved outcomes in these patients and suggest quite provocatively within the very first cycle of treatment that this may be a potential marker to assess the benefit from this treatment," said Dr. Yardley.
Furthermore, the association raises the "question, if you can identify early on a group that is not acetylating, whether increasing the dose may get them to be hyperacetylators and derive more benefit from the HDAC inhibitor," she said. Additionally, ongoing analyses are looking at whether hyperacetylation correlated with toxicity and could then be used as a surrogate for efficacy.