Implications and next steps
“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.
“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.
Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”
When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”
Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.
“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”
The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.