Roisin M. Connolly, MB BCh
A dual approach to overcoming resistance to endocrine therapy in patients with advanced hormone receptor (HR)–positive breast cancer is under investigation in a phase III trial that adds the novel drug entinostat to standard exemestane therapy after disease progression.
The combination has generated excitement in the oncology drug development field after demonstrating an 8-month overall survival (OS) benefit over exemestane alone in the phase II ENCORE 301 study.1
Those positive results prompted the FDA to grant a breakthrough therapy designation to entinostat in this setting.
The regimen is now being tested in the E2112 trial, which seeks to randomize 600 patients to exemestane plus entinostat versus exemestane plus placebo (NCT02115282).
“This overall survival benefit is something that we don’t see very frequently and, in fact, has not been seen to date with any other combinations that are currently approved in this space,” said Roisin M. Connolly, MB BCh, principal investigator for the E2112 trial, in an interview with OncologyLive
“Recent combinations of agents have indicated a progression-free survival [PFS] advantage— some very significant—and have led to FDA approval, but none of them have yet shown an overall survival advantage, so we’re very excited about running this phase III study and we hope that it will confirm the results,” said Connolly, who is an assistant professor of Oncology at Johns Hopkins Medicine in Baltimore.
The 2 oral medications are administered on a 28-day cycle. All patients receive 25-mg exemestane daily. Participants in the experimental arm receive 5-mg entinostat on days 1, 8, 15, and 22, while patients in the control arm receive a placebo.
The trial is open to patients with HR-positive, HER2-negative advanced or metastatic breast cancer whose disease has progressed after taking a nonsteroidal aromatase inhibitor (AI). Patients who have been treated with a CDK inhibitor, fulvestrant, everolimus, or even a limited amount of prior exemestane are eligible to participate, said Connolly. Additionally, women of any menopausal status and men with advanced breast cancer would be considered for the study.
Researchers are casting a wide net for potential participants. Oncologists at nearly 600 locations throughout the United States have signed on to recruit patients, according to the ClinicalTrials.gov website.
Notably, patients do not have to undergo a biopsy to participate, said Connolly. She said the all-oral treatment regimen also is “straightforward” and that entinostat has proved to be well tolerated by patients. Side effects seen in the prior trial with entinostat include gastrointestinal upset, fatigue, and laboratory abnormalities such as neutropenia and electrolyte imbalances.
The primary endpoints of the study are OS and PFS, while secondary endpoints include toxicity, objective response rates, and time to treatment deterioration.
Potential Impact of Combination
If successful, the combination may provide clinicians with another option for patients who have developed resistance to anti-hormonal therapies. Connolly and colleagues have noted that endocrine therapies have been effective in treating patients with HR-positive breast cancer, but that de novo or acquired resistance remains a significant clinical problem.2
Entinostat is a histone deacetylase (HDAC) inhibitor, a class of drugs that modifies epigenetic processes including areas near the promoter regions of genes, Connolly said.
“This may alter, for example, how the estrogen receptor is expressed in patients with breast cancer, and it has been shown to affect growth factor pathways that can lead to resistance,” said Connolly. “If we are impacting these processes with this pill, maybe we can overcome treatment resistance.”
"Researchers will be measuring lysine acetylation through blood tests every 2 weeks to determine whether changes in these protein levels can be used as a biomarker to evaluate response to entinostat," said Connolly. "If we can identify a biomarker of response to this therapy, we can further personalize treatment options for patients." By pairing entinostat with exemestane, a steroidal AI, investigators are attacking 2 pathways simultaneously. The combination proved effective in shrinking tumors in mice that had become resistant to letrozole, a nonsteroidal AI, thus paving the way for clinical studies in humans, said Connolly. In the ENCORE 301 trial, the combination of entinostat plus exemestane resulted in an improvement in PFS over exemestane alone (4.3 months vs 2.3 months; HR, 0.73),1 which met a prespecified primary endpoint for significance.
However, the combination demonstrated a more noteworthy impact on OS, an exploratory endpoint in the study. The median OS was 28.1 months with the exemestane plus entinostat regimen versus 19.8 months with exemestane and placebo (HR, 0.59; 95% CI, 0.36-0.97; P
Connolly said the “very large benefit” in OS was unexpected but may indicate that entinostat has an impact on the patient’s immune system. She noted that a similar pattern has been seen with immunotherapy agents that have aleady reached the clinic.
The E2112 study is being conducted by the ECOG-ACRIN Cancer Research Group with sponsorship from the National Cancer Institute and additional support from Syndax Pharmaceuticals, the company developing the drug.
- Yardley DA, Ismail-Khan RR, Melichar B, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol. 2013;31(17):2128-2135. doi: 10.1200/JCO.2012.43.7251.
- Connolly RM, Zhao F, Miller K, et al. E2112: randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. J Clin Oncol. 2015;33(suppl; abstr TPS636).