Entinostat Doesn't Overcome Endocrine Resistance in Breast Cancer

Sara Freeman

January 13, 2021

The histone deacetylase (HDAC) inhibitor entinostat failed to overcome resistance to endocrine therapy in hormone receptor–positive, HER2-negative, advanced breast cancer in a phase 3 trial.

The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.

These results were reported at the 2020 San Antonio Breast Cancer Symposium.

"Clearly, we were very disappointed with these results after so many years of work," said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.

"I think we've realized again the importance of phase 3 confirmation of promising phase 2 data," she said, referring to results of the phase 2 ENCORE 301 trial.

"I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses," Connolly said.

Why HDAC Inhibitors in Advanced Breast Cancer?

"Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem," Connolly said.

One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.

Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.

Phase 3 Trial Details and Results

The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.

The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.

A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.

"I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112," Connolly said, observing that the study started in 2014 before the use of these drugs was really established.

Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).

The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).

The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.

Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).

There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.

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.

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, 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," 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. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Burstein had no relevant disclosures.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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