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Elacestrant monotherapy improved progression-free survival over standard-of-care (SOC) treatment in patients with estrogen receptor–positive, HER2-negative breast cancer, including those whose tumors harbored ESR1 mutations, meeting the primary end points of the phase 3 EMERALD trial.
Elacestrant (RAD1901) monotherapy improved progression-free survival over standard-of-care (SOC) treatment in patients with estrogen receptor (ER)–positive, HER2-negative breast cancer, including those whose tumors harbored ESR1 mutations, meeting the primary end points of the phase 3 EMERALD trial (NCT03778931).1
Topline results from the trial also showed that the toxicity profile of the selective estrogen receptor degrader (SERD) was comparable to what had previously been observed with the agent in a prior trial.
The Menarini Group and Radius Health, Inc. announced plans to proceed with regulatory submissions for the agent in this indication in both the United States and the European Union in 2022. Moreover, data from the trial are expected to be presented at the 2021 San Antonio Breast Cancer Symposium.
“We are extremely excited as elacestrant is the first oral SERD to show positive topline results in a pivotal trial as a monotherapy vs SOC for the treatment of ER-positive, HER2-negative advanced or metastatic breast cancer,” Elcin Barker Ergun, chief executive officer of the Menarini Group, stated in a press release. “The results pave the way toward our working with the regulators to bring elacestrant to patients with ER-positive, HER2-negative advanced or metastatic breast cancer, which remains a huge unmet medical need. Notably, the topline results were also positive for the ESR1 mutation subsegment, an important driver of resistance to endocrine therapy in [these] patients.”
In preclinical models of ER-positive breast cancer and several patient-derived xenograft models derived from heavily pretreated patients, elacestrant has been shown to have antitumor activity.2 The SERD has also been found to have activity in models that were resistant to both CDK4/6 inhibitors and fulvestrant (Faslodex), including those that harbored ESR1 mutations.
Results from a phase 1 trial (NCT02338349) evaluating the agent at a dose of 400 mg in a total of 40 patients with ER-positive, HER2-negative advanced breast cancer showed that the agent had favorable tolerability and single-agent activity, even in those with ESR1 mutations.3 Notably, these patients also had received a median of 3 prior therapies.
Specifically, the SERD elicited an overall response rate (ORR) of 19% in this population, and a PFS of 4.5 months. In the subset of patients whose tumors harbored an ESR1 mutation, the ORR achieved with the agent was 33%. Patients who previously received a CDK4/6 inhibitor and fulvestrant were still found to respond to the treatment.
For the international, multicenter, open-label, active-controlled EMERALD trial, investigators set out to compare the safety and effectiveness of elacestrant with SOC options such as fulvestrant or an aromatase inhibitor in postmenopausal women and men with ER-positive, HER2-negative metastatic breast cancer in all patients irrespective of ESR1 mutational status, and specifically in those with any ESR1 mutation identified via circulating tumor DNA.
To be eligible for enrollment, patients needed to be at least 18 years of age or older and have progressed or relapsed on, or after, 1 or 2 lines of endocrine therapy, 1 of which must have been given with a CDK4/6 inhibitor for ER-positive, HER2-negative metastatic disease. They also needed to have received at least 1 chemotherapeutic regimen in the advanced/metastatic setting, measurable disease per RECIST v1.1 criteria, and an ECOG performance status of 0 or 1.
If patients previously received an investigational SERD or ER antagonist, had symptomatic visceral disease, a history of endometrial intraepithelial neoplasia, or another malignancy within 5 years before enrollment, except for adequately treated basal or squamous cell skin cancer or carcinoma in situ of the cervix, they were excluded.
Patients also could not meet any of the following criteria 6 months before enrollment: myocardial infarction or severe/unstable angina, ongoing grade 2 or higher cardiac dysrhythmias, grade 2 or higher QTcF, uncontrolled atrial fibrillation of any grade, coronary/peripheral artery bypass graft or heart failure of New York Heart Association Class II or greater, cerebrovascular accident including transient ischemic attack, or abnormal coagulation profiles or any history of coagulopathy except for stable anticoagulation for an event prior to 6 months.
The trial planned to enroll a total of 466 patients. Study participants were randomized 1:1 to receive either elacestrant at a daily dose of 400 mg or investigator’s choice of fulvestrant, anastrozole, letrozole, and exemestane. Patients were stratified based on ESR1 mutational status (yes vs no), prior fulvestrant (yes vs no), and the presence of visceral metastases (yes vs no).
The primary end point of the trial was PFS per independent review committee (IRC) assessment in all patients and the subgroup of those with ESR1 mutations. A key secondary end point is overall survival in both groups of patients. Other end points, irrespective of subset, include IRC-assessed ORR; duration of response (DOR); clinical benefit rate (CBR); investigator-assessed PFS, ORR, DOR, CBR; safety and tolerability; pharmacokinetics; and patient-reported outcomes.
Other exploratory end points include time to chemotherapy, alterations in ctDNA relevant to ER-positive disease and the CDK4/6 pathway and correlation with response, and alterations in tumor-specific genes, proteins, and RNAs associated with oncogenic pathways and proliferation in tissue biopsies.
A full evaluation of the data is ongoing and the company announced plans to publish these findings in a peer-reviewed journal.
“The trial results being statistically significant demonstrate a clinically meaningful improvement of PFS in the elacestrant group vs endocrine SOC in patients previously treated with endocrine therapies and CDK4/6 inhibitors,” Aditya Bardia, MD, MPH, of Massachusetts General Hospital, associate professor of the Medicine Department at Harvard Medical School, and principal investigator for EMERALD, stated in a press release. “The results provide a significant advancement for patients suffering from this devastating disease. It is also important to see the positive data for those patients with ESR1 mutations, known to confer additional resistance to standard endocrine therapy.”