Elacestrant extends PFS among certain women with metastatic breast cancer
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Elacestrant improved outcomes compared with standard endocrine therapy for certain women with pretreated ER-positive, HER2-negative metastatic breast cancer, according to results presented at San Antonio Breast Cancer Symposium.
Results of the randomized phase 3 EMERALD trial showed a significant PFS benefit and a trend toward improved OS among postmenopausal women whose disease progressed on prior targeted and endocrine therapies.
“Elacestrant is the first oral [elective estrogen receptor degrader] 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, director of the breast cancer research program at Mass General Cancer Center and associate professor at Harvard Medical School, said in a press release. “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.”
Standard treatment for ER-positive, HER2-negative metastatic breast cancer consists of endocrine therapy plus a cyclin-dependent kinase (CDK) 4/6 inhibitor.
However, the majority of patients with ER-positive metastatic disease develop resistance to treatment, sometimes due to development of ESR1 mutations, according to study background.
Fulvestrant, administered via intramuscular injections, is the only selective estrogen receptor degrader approved for breast cancer treatment. An “urgent need” exists for alternatives that can effectively treat ER-positive metastatic breast cancer, including patients with ESR1 mutations, Bardia said.
Elacestrant (Radius Health) is an orally administered selective estrogen receptor degrader.
A prior phase 1 trial showed the agent induced responses among heavily pretreated postmenopausal patients with ER-positive, HER2-negative metastatic breast cancer. The agent also exhibited an acceptable safety profile.
The multicenter, open-label EMERALD trial included 477 postmenopausal patients with ER-positive, HER2-negative metastatic breast cancer who received one or two prior lines of endocrine therapy without chemotherapy in the metastatic setting. All patients had progressed on prior CDK 4/6 inhibitor treatment.
Researchers randomly assigned 239 patients to 400 mg elacestrant daily. The other 238 received standard of care, which consisted of investigator’s choice of fulvestrant or an aromatase inhibitor.
Investigators stratified by ESR1 mutation status (confirmed, n = 228; none detected, n = 249), prior fulvestrant treatment and presence of visceral disease.
The elacestrant and standard therapy groups were balanced with regard to median age (63 years vs. 63.5 years), ESR1 mutation-positive status (48.1% vs. 47.4%) and percentage of patients who had received two prior lines of therapy (46% vs. 40.8%).
PFS by blinded independent review committee assessment among patients with ESR1 mutations, as well as PFS among all patients regardless of ESR1 mutation status, served as primary endpoints. OS, safety, tolerability and quality of life served as secondary endpoints.
The study met both primary endpoints.
Results showed reduced risk for disease progression or death with elacestrant among all patients (HR = 0.69; 95% CI, 0.55-0.88) and among those with ESR1 mutations (HR = 0.54; 95% CI, 0.38-0.76).
The benefit with elacestrant persisted across key prespecified subgroups based on number of prior lines of therapy, visceral metastases, prior fulvestrant treatment and geographic region.
Researchers reported higher 12-month PFS rates with elacestrant among all patients (22.3% vs. 9.4%) and among those with ESR1 mutations (26.7% vs. 8.1%).
A prespecified interim OS analysis revealed a trend in favor of elacestrant among all patients (HR = 0.75; 95% CI, 0.54-1) and in the ESR1 mutation-positive group (HR = 0.59; 95% CI, 0.36-0.95). Final OS results are anticipated in 2022.
Treatment-related adverse events that occurred more frequently in the elacestrant group than standard care group included nausea (25.3% vs. 8.7%), vomiting (11% vs 2.6%) and fatigue (11% vs 7.9%). Most of these events were grade 1 or grade 2, according to researchers.
Approximately twice as many patients assigned elacestrant experienced grade 3 or higher treatment-related adverse events (7.2% vs. 3.1%), a result primarily driven by nausea (2.1% vs. 0.9%).
Treatment-emergent adverse events led to treatment discontinuation for 6.3% of patients assigned elacestrant and 4.4% of those assigned standard care. No treatment-related deaths occurred in either group.
Researchers acknowledged a study limitation in that all patients enrolled received prior CDK 4/6 inhibitor treatment, so the clinical benefit of elacestrant for patients who have not received CDK 4/6 inhibitor therapy remains unclear.
Future studies will evaluate the efficacy of elacestrant during earlier lines of therapy, as well as in combination with other treatments, Bardia said.
A phase 2 trial will assess elacestrant in combination with abemaciclib (Verzenio, Eli Lilly), a CDK 4/6 inhibitor, for patients with brain metastases.
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Carlos L. Arteaga, MD, FAACR
This is an important study about the first selective estrogen receptor degrader other than fulvestrant in patients that progressed after a CDK 4/6 inhibitor. This is a major therapeutic priority for patients with ER-positive breast cancer. The results clearly suggest this new selective estrogen receptor degrader may become a new treatment option for patients with breast cancer, not only as a single therapy but in combination with other targeted therapies.
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Bardia A, et al. Abstract GS2-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 7-10, 2021; San Antonio.
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