The investigational oral selective estrogen receptor degrader (SERD) elacestrant significantly decreased the risk of death or disease progression and increased progression-free survival compared with standard-of-care endocrine monotherapy in the second- or third-line setting  for postmenopausal patients with estrogen receptor (ER)-positive/HER2-negative metastatic breast cancers that progressed after endocrine and CDK4/6 inhibitor therapies, according to results from the phase III EMERALD trial presented by Aditya Bardia, MD, MPH, and colleagues at the 2021 San Antonio Breast Cancer Symposium (Abstract GS2-02).

Patients with metastatic ER-positive breast cancer are typically treated with endocrine therapy, such as aromatase inhibitors or fulvestrant; however, resistance to these treatments commonly develops, in some cases due to mutation of the ESR1 gene. Fulvestrant, which is delivered through intramuscular injections, is currently the only SERD approved for patients with breast cancer.

Elacestrant is the first oral SERD to demonstrate a statistically significant and clinically meaningful improvement of progression-free survival in patients with ER-positive/HER2-negative metastatic breast cancer in the second- and third-line settings, including for patients whose tumors harbor ESR1 mutations....

— Aditya Bardia, MD, MPH

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“There is an urgent unmet need for alternative SERDs that are effective against ER-positive metastatic breast cancer, including those with ESR1 mutations,” said Dr. Bardia, who is Director of the Breast Cancer Research Program at Massachusetts General Cancer Center and Associate Professor at Harvard Medical School.

More on Elacestrant

Elacestrant is an investigational SERD that, unlike fulvestrant, is administered orally. Dr. Bardia explained that elacestrant has greater absorption, improved pharmacokinetics, and enhanced inhibition of ER compared with fulvestrant. In addition, elacestrant has demonstrated greater antitumor activity in mouse xenograft models of ER-positive breast cancer. A phase I clinical trial found that elacestrant treatment had an acceptable safety profile and led to responses in heavily pretreated postmenopausal patients with ER-positive/HER2-negative metastatic breast cancer.

To understand how elacestrant compares to the current standard of care, Dr. Bardia and colleagues initiated the phase III EMERALD trial. Elacestrant is the first oral SERD to be studied in a randomized phase III clinical trial.

EMERALD Details

The trial enrolled 477 postmenopausal patients with ER-positive/HER2-negative metastatic breast cancer who had received one or two prior lines of endocrine therapy without chemotherapy in the metastatic setting, and who had disease progression on prior treatment with a CDK4/6 inhibitor. Patients were randomly assigned to receive either elacestrant or standard of care (investigator’s choice of fulvestrant or an aromatase inhibitor). Among the enrolled patients, 228 had tumors with mutated ESR1: 115 in the elacestrant arm and 113 in the standard-of-care arm.

Dr. Bardia and colleagues found that patients in the elacestrant arm had a 30% lower risk of death or disease progression compared with those in the standard-of-care arm; among patients whose tumors had ESR1 mutations, those in the elacestrant arm had a 45% reduced risk of death or disease progression. Subgroup analyses showed that elacestrant improved outcomes regardless of the presence of visceral metastases, the number of prior lines of therapy, pretreatment with fulvestrant, or geographic region.  

At 12 months, patients in the elacestrant arm had a significantly higher rate of progression-free survival than those who received the standard of care (22.32% vs. 9.42%). Among patients with ESR1-mutated tumors, 12-month progression-free survival rates were 26.76% in those treated with elacestrant compared to 8.19% in patients treated with the standard of care. An interim analysis of overall survival showed a trend in favor of elacestrant, including in patients with ESR1-mutated tumors, according to Dr. Bardia.

Certain grade 1 or 2 treatment-related adverse events were more common among patients treated with elacestrant compared with standard of care, including nausea (25.3% vs 8.7%), vomiting (11% vs 2.6 %), and fatigue (11% vs 7.9%). Grade 3 or higher treatment-related adverse events were observed among 7.2% of patients in the elacestrant arm and 3.1% of those in the standard-of-care arm. There were no treatment-related deaths in either arm.

“Elacestrant is the first oral SERD to demonstrate a statistically significant and clinically meaningful improvement of progression-free survival in patients with ER-positive/HER2-negative metastatic breast cancer in the second- and third-line settings, including for patients whose tumors harbor ESR1 mutations,” said Dr. Bardia. “Elacestrant was well tolerated with manageable and reversible side effects. This therapy has the potential to become the new standard of care for patients with this cancer.”

Dr. Bardia noted that future studies will aim to understand the efficacy of elacestrant during earlier lines of treatment and in combination with other therapies. A planned phase II trial will examine the impact of elacestrant in combination with abemaciclib specifically for patients with brain metastases.

A limitation of this study was that all enrolled patients had received prior treatment with a CDK4/6 inhibitor; thus, the efficacy of elacestrant in patients without prior CDK4/6 inhibitor treatment remains unknown.

Disclosure: The study was supported by Radius Health. Dr. Bardia has served as a consultant or on an advisory board for Radius Health, Pfizer, Novartis, Genentech, Merck, Immunomedics/Gilead Sciences, Sanofi, Daiichi Sankyo/AstraZeneca, Phillips, Eli Lilly and Company, and Foundation Medicine; he has conducted contracted research or received grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Sankyo/Astra Zeneca, Natera Inc, and Eli Lilly and Company.