Elacestrant Shows Significant PFS Benefit in ESR1-Mutated Metastatic Breast Cancer

Elacestrant, a selective estrogen receptor degrader, demonstrated significant improvements in progression-free survival (PFS) compared with standard-of-care treatments for patients with ER-positive, HER2-negative, ESR1-mutated metastatic breast cancer. | Image Credit: sitthiphong - stock.adobe.com

Patients with ER-positive, HER2-negative metastatic breast cancer, particularly those with ESR1-mutated tumors, saw clinically meaningful improvements in progression-free survival (PFS) after using elacestrant compared with a standard-of-care drug, according to a study published in Clinical Cancer Research.¹

Endocrine therapy combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the first-line standard-of-care regimen for patients with ER-positive, HER2-negative metastatic breast cancers. The goal when treating this subtype of cancer following first-line treatment is to overcome endocrine resistance. An estimated 50% of patients develop ESR1 mutations, typically emerging during the first-line endocrine therapy in the metastatic setting with aromatase inhibitors.

The MONARCH 2 trial was a randomized, double-blind, placebo-controlled, phase 3 study of abemaciclib combined with fulvestrant or a placebo with fulvestrant in women with disease-progressed breast cancer.² The study revealed improvements in PFS and overall survival, regardless of PIK3CA or ESR1 mutation status.

Elacestrant, the first selective estrogen receptor degrader, received approval in January 2023 for postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following 1 line or more of endocrine therapy in the US.³ The medication is dispensed orally and displays increased efficacy compared with standard-of-care endocrine monotherapy.¹

Researchers conducted the EMERALD trial, an international, multicenter, randomized, open-label phase 3 clinical trial that compared single-agent elacestrant with standard-of-care treatment. Patients were randomized and received either 345 mg once daily of elacestrant or the investigator’s choice of standard-of-care endocrine monotherapy (fulvestrant, letrozole, anastrozole, or exemestane).

There were 478 patients in total that were enrolled in the EMERALD study, with 239 patients who took elacestrant and 239 patients who received standard-of-care. The median ages for both groups were in the early-to-mid sixties. Both cohorts also had majority of White women as participants.

Out of the 478 patients, there were 222 patients that had ESR1-mutated tumors and received endocrine therapy combined with CDK4/6i treatment in advanced or metastatic settings (elacestrant, n = 112; standard-of-care, n = 110). About 71.6% of this population received prior endocrine therapy combined with CDK4/6i for 12 months or greater.

Patients who had previously received endocrine therapy with CDK4/6i inhibitors for a longer duration experienced significant improvement in PFS when treated with elacestrant compared with standard-of-care treatments. This was particularly evident in patients who had been on prior treatment for at least 12 months. In this group, the median PFS was 8.6 months with elacestrant, compared with 1.9 months for standard-of-care.

All evaluated subgroups with ESR1-mutated tumors, previously treated with endocrine therapy and CDK4/6i for at least 12 months, showed clinically meaningful improvements in PFS with elacestrant compared with standard-of-care. Median PFS was 9.1 months with elacestrant vs 1.9 months with standard-of-care for patients with bone metastases, 7.3 months vs 1.9 months for those with liver and/or lung metastases, and 9 months vs 1.9 months for patients with fewer than 3 metastatic sites.

Further improvements were seen in patients with 3 or fewer metastatic sites (10.8 vs 1.8 months), those with PIK3CA mutations (5.5 vs 1.9 months), those with TP53 mutations (8.6 months vs 1.9), those with HER2-low expression (9 vs 1.9 months), and those with specific ESR1 mutations (ESR1-D538G and ESR1-Y537S, both 9 vs 1.9 months).

The majority of patients experienced mild adverse events (AEs), such as nausea, that were classified as grade 1 or 2 severity. Treatment-related discontinuation occurred in 8 patients (3.4%) who received elacestrant and 2 patients (0.9%) who received standard-of-care treatments. The most common all-grade gastrointestinal AEs were nausea (elacestrant, 35%; standard-of-care, 9%) and vomiting (elacestrant, 19%; standard-of-care, 9%). Overall safety data was consistent with the profile in the overall population.

The current study supports recommendations for routine testing for the emergence of ESR1 mutations in circulating tumor DNA throughout each disease progression.

“These results suggest that elacestrant may enable [endocrine therapy] sequencing in the second line before other targeted therapies and drug combinations and may delay chemotherapy-based regimens, including antibody-drug conjugates,” concluded study authors.

References

1. Bardia A, Cortés J, Bidard FC, et al. Elacestrant in ER+, HER2- metastatic breast cancer with ESR1-mutated tumors: subgroup analyses from the phase III EMERALD trial by prior duration of endocrine therapy plus CDK4/6 inhibitor and in clinical subgroups. Clin Cancer Res. 2024;30(19):4299-4309. doi:10.1158/1078-0432.CCR-24-1073
2. Tolaney SM, Toi M, Neven P, et al. Clinical significance of PIK3CA and ESR1 mutations in circulating tumor DNA: analysis from the MONARCH 2 study of abemaciclib plus fulvestrant [published correction appears in Clin Cancer Res. 2022 Oct 14;28(20):4587. doi: 10.1158/1078-0432.CCR-22-2874]. Clin Cancer Res. 2022;28(8):1500-1506. doi:10.1158/1078-0432.CCR-21-3276
3. Hoy SM. Elacestrant: first approval [published correction appears in Drugs. 2023 Dec;83(18):1735. doi: 10.1007/s40265-023-01978-2]. Drugs. 2023;83(6):555-561. doi:10.1007/s40265-023-01861-0