Elacestrant—an investigational oral selective estrogen receptor degrader (SERD)—achieved longer progression-free survival vs standard-of-care endocrine monotherapy as second- or third-line therapy in patients with estrogen receptor–positive, HER2-negative advanced or metastatic breast cancer in the phase III EMERALD study. Additional analyses of the EMERALD results showed a median progression-free survival of up to 8.6 months dependent on the duration of prior treatment with cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors (used as a surrogate for estrogen sensitivity). Safety was manageable and consistent with previous reports.

“Elacestrant should be given to people for whom clinicians feel endocrine monotherapy is the right choice. In my view, those patients have endocrine-sensitive tumors.”

— VIRGINIA KAKLAMANI, MD

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“These results show that when used as a single agent, elacestrant provided median progression-free survival of up to 8.6 months, based on the duration of previous CDK4/6 inhibitor therapy, with a manageable safety profile and the convenience of an oral tablet. This suggests elacestrant may have the potential to become a new standard of care as a monotherapy endocrine sequencing option in estrogen receptor–positive, HER2-negative advanced breast cancer after disease progression on CDK4/6 inhibitors, before moving to combination therapies,” said senior author Virginia Kaklamani, MD, a breast medical oncologist and Professor of Medicine at The University of Texas Health Sciences Center San Antonio. Dr. Kaklamani presented the results of an analysis of progression-free survival based on the duration of prior CDK4/6 therapy and an exploratory analysis of progression-free survival based on the presence of ESR1 mutations at the 2022 San Antonio Breast Cancer Symposium.¹

Background

Endocrine therapy plus a CDK4/6 inhibitor is used in the first-line setting for the management of estrogen receptor–positive, HER2-negative metastatic breast cancer. However, tumors eventually become resistant, mainly related to the development of ESR1 mutations.

Current practice is to use sequential endocrine monotherapy or combinations once patients experience disease progression on first-line therapy. However, low rates of progression-free survival have been observed with sequential endocrine monotherapy after CDK4/6 inhibitors are used. Combinations of endocrine therapy have been associated with significant toxicity, and about 25% of patients discontinue therapy.

“In this context, there is a significant need for potent oral SERDs for monotherapy and for enabling all-oral combinations,” Dr. Kaklamani explained.

Study Details

EMERALD is a phase III registrational trial that demonstrated statistically significant progression-free survival with elacestrant vs treatment with standard-of-case endocrine monotherapy (fulvestrant, letrozole, anastrozole, exemestane). EMERALD is unique among trials in the second- and third-line settings of metastatic breast cancer in that all enrolled patients had to have experienced disease progression on prior CDK4/6 inhibitors in the metastatic setting. Prior fulvestrant and prior chemotherapy were allowed.

A total of 478 patients were randomly assigned 1:1 to receive elacestrant at 400 mg/d vs investigator’s choice of fulvestrant, anastrozole, letrozole, or exemestane. Treatment was continued until disease progression or patient withdrawal.

Baseline characteristics were similar between the two treatment arms. Median age was around 63 years. About 70% had visceral metastasis. About 60% had one prior line of therapy, and approximately 40% had two prior lines. Between 80% and 87% had anastrozole as physician’s choice, and 23% to 30% used fulvestrant (given intramuscularly).

The co-primary endpoints were progression-free survival in all patients and in those with ESR1-mutated tumors. EMERALD met the primary co-endpoints in all patients (n = 239 in each arm) and in those patients harboring ESR1 mutations (115 given elacestrant and 113 given the standard of care).

Key Results and Safety

A post hoc analysis of progression-free survival based on the duration of prior CDK4/6 inhibitor therapy demonstrated that elacestrant monotherapy achieved clinically meaningful outcomes both in the total patient population as well as in patients with ESR1 mutations. A longer duration of prior CDK4/6 inhibitor therapy was positively associated with longer progression-free survival with elacestrant but not with the standard of care.

In the group of patients with prior exposure to CDK4/6 inhibitors of 12 months or longer, among all patients in the trial, elacestrant achieved a median progression-free survival of 3.8 months vs 1.9 months with the standard of care, representing a 39% reduction in the risk for disease progression or death. In all patients exposed to CDK4/6 inhibitors for 18 months or longer, median progression-free survival was 5.5 months with elacestrant vs 3.3 months with the standard of care, for a 30% reduction in the risk for disease progression or death. Among all patients exposed to CDK4/6 inhibitors for at least 6 months, median progression-free survival was 2.8 months vs 1.9 months, respectively.

“In patients exposed to a CDK4/6 inhibitor for up to 6 months, neither arm did very well,” commented Dr. Kaklamani.

Among the ESR1-mutated population, progression-free survival was also improved with longer prior exposure to CDK4/6 inhibitors. In ESR1-mutated tumors and with at least 18 months of prior exposure to CDK4/6 inhibitors, median progression-free survival was 8.6 months with elacestrant vs 2.1 months with the standard of care, a 53% reduction in the risk for disease progression or death. Results were similar in those with ESR1-mutated tumors and at least 12 months of treatment on CDK4/6 inhibitors. For those with ESR1-mutated tumors and at least 6 months of prior treatment with CDK4/6 inhibitors, median progression-free survival was 4.1 months vs 1.9 months, respectively.

Updated safety was consistent with previous reports. Most of the adverse events, including nausea, were grade 1 or 2, and no grade 4 treatment-related adverse events were reported. Rates of discontinuation of therapy due to an adverse event were low: 3.4% and 0.9%, respectively. No treatment-related deaths were reported in either arm. No hematologic safety signals emerged, and no patient enrolled in the trial had sinus bradycardia. Antiemetic therapy for nausea and/or prophylaxis was given to 8% of those given elacestrant, 3.7% of those given fulvestrant, and 10.3% of those given anastrozole.

Which Endocrine Therapy to Choose?

In a separate interview with The ASCO Post, Dr. Kaklamani explained that elacestrant has a good safety profile and is a relatively low-risk therapy. “It’s not the right therapy for everyone,” she said. “We must identify patients who are ‘endocrine-sensitive,’ and right now, we do that using the duration of therapy on prior CDK4/6 inhibitors as a clinical measure.”

“When we start to get to longer than 12 months of CDK4/6 exposure, that’s when you see the benefit of elacestrant, suggesting these tumors are more endocrine-sensitive. This is a crude way of looking at endocrine sensitivity. Unfortunately, we don’t have a more sensitive biologic tool, so we rely on clinical characteristics, one of which is the prior duration of CDK4/6 therapy,” she explained.

Which patients should receive elacestrant once it is approved? “Elacestrant should be given to people for whom clinicians feel endocrine monotherapy is the right choice,” Dr. Kaklamani said. “In my view, those patients have endocrine-sensitive tumors. I would define that as exposure to CDK4/6 inhibitors for more than 6 months and preferably longer.”

Dr. Kaklamani commented on the use of elacestrant in relation to ESR1 mutations. “The benefit seen with elacestrant was more striking in ESR1-mutated tumors. It performed as well as other endocrine therapies in those with ESR1 wild-type tumors. The choice between these therapies will depend on the side-effect profile and whether you want to give an intramuscular therapy or an oral medication. Compliance could turn out to be an issue with elacestrant. Patients were compliant on a clinical trial, but real-world experience could be different,” she explained. “If the drug gets approved, we will figure this out.” 

DISCLOSURE: Dr. Kaklamani has served as a consultant or advisor to Pfizer, Gilead Sciences, Genentech, Genomic Health, AstraZeneca, Daiichi Sankyo, and Puma Biotechnology.

REFERENCE

1. Kaklamani V, Bidard FC, Neven P, et al: EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2– metastatic breast cancer: Updated results by duration of prior CDK4/6 inhibitor in metastatic setting. 2022 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 8, 2022.