Breakthrough Designation Granted to Entinostat for Advanced Breast Cancer

Arlene M. Morris

The novel HDAC inhibitor entinostat in combination with exemestane has received a Breakthrough Therapy designation from the FDA for its potential to reverse resistance to hormonal therapies used to treat patients with advanced estrogen receptor (ER)-positive breast cancer.

The new designation was based on results from the phase II ENCORE 301 study in which entinostat was administered in combination with exemestane. Initial results from this trial were presented in 2011, though enrollment in the phase III trial has yet to begin. The FDA’s Breakthrough Therapy designation will likely speed up the initiation of this trial, with patient enrollment expected in early 2014.

As part of the Breakthrough Designation, the FDA will work closely with Syndax Pharmaceuticals, the company developing entinostat, to create an efficient phase III trial design, which typically results in fewer patients enrolled to clinical trials. Communication between Syndax and the FDA will also be increased.

"The FDA's decision to designate entinostat a Breakthrough Therapy is important validation of the drug's therapeutic potential in women with advanced breast cancer," said Arlene M. Morris, Syndax's chief executive officer, in a statement. "This breakthrough designation will allow us to more rapidly bring this new treatment option to patients who may benefit from its availability."

The mechanism of action for entinostat is believed to help reduce resistance to aromatase inhibitors (AIs). Preclinical data suggest that entinostat inhibits growth factor signaling pathways to normalize ER-alpha expression, which are common pathways for resistance. As such, through this mechanism of action, treatment with entinostat may help to reverse resistance.

In the ENCORE 301 study, 130 postmenopausal women with locally recurrent or metastatic ER-positive breast cancer were randomized in a 1:1 ratio to receive exemestane with or without entinostat following progression on a nonsteroidal AI (NSAI). The primary endpoint of the trial was progression-free survival (PFS) by RECIST criteria.

In a March 2012 follow-up analysis published in the Journal of Clinical Oncology, the median PFS was 4.3 months versus 2.3 months, for entinostat and placebo, respectively (HR = 0.73; P = 0.06). In patients resistant to NSAIs (n = 45), the median PFS was 3.72 months compared to 1.78 months, in favor of the combination (HR = 0.47).

The median overall survival in the combination arm was 28.1 months compared to 19.8 months in the exemestane arm (HR = 0.59; P = 0.036). In a subset of patients (n = 49) with increased protein acetylation, the median PFS with the combination was 8.5 months compared with 2.8 months for patients without acetylation (HR = 0.32).

Overall, the combination of entinostat and exemestane was well tolerated; the most common all grade adverse events were fatigue (46%), nausea (40%), uncomplicated neutropenia (25%), and vomiting (21%). However, the rate of grade 3/4 adverse events was comparable between arms.

"Currently, women with ER-positive breast cancer who have progressed on hormonal therapy have limited therapeutic options," said Morris. "Entinostat’s epigenetic mechanism may reverse resistance to hormonal therapy, delaying the need for toxic chemotherapeutic agents and improving survival when given in combination with aromatase inhibitors."

On September 4, 2013, Syndax announced a licensing, development, and commercialization agreement with a specialty pharmaceutical company in China, Eddingpharm. As part of this agreement, Eddingpharm was granted permission to participate in the first 3 global phase III registration trials for entinostat, which is being examined in a variety of other tumor types in addition to breast cancer.

"We look forward to working closely with Syndax to develop entinostat in breast and lung cancer as well as other indications,” said Xin Ni, chairman and chief executive officer of Eddingpharm said in a statement at the time of the agreement. “We are focused on bringing new and effective treatments to patients in our Asian communities and we believe this partnership with Syndax has the potential to help a large number of cancer patients across our Asian markets."

The phase III E2112 trial investigating entinostat will be conducted in collaboration with the ECOG-ACRIN Cancer Research Group. The trial will combine endocrine therapy with entinostat for patients with hormone receptor-positive metastatic breast cancer.