SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay for the management of ER+/HER2- metastatic breast cancer as first-line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including development of ESR1 (Estrogen Receptor gene alpha) mutations.
ESR1 is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER+ breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI, in advanced breast cancer. In a recently published study (JAMA Oncol.2016;2:1310-1315), ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% versus 11%).
Fulvestrant is a parenteral, Selective Estrogen Receptor Degrader (SERD) and is the only SERD approved for the treatment of postmenopausal women with HR-positive metastatic breast cancer. However, acquired ESR1 mutations can also occur following Fulvestrant treatment, possibly because of poor bioavailability and incomplete ER blockade when administered intramuscularly. There is therefore an urgent unmet need for an alternate SERD that has activity in tumors harboring ESR1 mutations, and has improved bioavailability allowing oral administration.
Elacestrant is an oral, nonsteroidal, Selective Estrogen Receptor Degrader (SERD) that degrades the Estrogen Receptor (ER) in a dose-dependent manner and inhibits estradiol-dependent functions of ER target gene transcription induction and breast cancer cell proliferation. Estradiol-stimulated tumor growth was diminished by Elacestrant in the ER+ xenograft models derived from heavily pretreated patients, including models resistant to CDK 4/6 inhibitors, Fulvestrant and those harboring ESR1 mutations Y537S and D538G. In an early Phase I trial, Elacestrant was noted to have an acceptable safety profile, and demonstrated single-agent activity with confirmed Partial Responses in heavily pretreated patients with ER+ metastatic breast cancer.
EMERALD trial is a multicenter, International, randomized, open-label, Phase III study designed to evaluate the benefit of Elacestrant in patients with ER+ HER2- advanced or metastatic breast cancer. In this study, 477 postmenopausal women with ER+/HER2- metastatic breast cancer were randomly assigned 1:1 to receive either Elacestrant 400 mg orally daily (N=239) or the Standard of Care which included investigator’s choice of Fulvestrant or an Aromatase Inhibitor including Anastrozole, Letrozole, or Exemestane (N=238). Treatment was given until disease progression. Both treatment groups were well balanced. The median patient age was 63 years, and patients must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor, had 1 or fewer lines of chemotherapy for advanced disease, and had an ECOG performance status of 0 or 1. In the study, 48% had tumors with mutated ESR1 and these patients were evenly distributed in both treatment groups. Patients were stratified by ESR1-mutation status, prior treatment with Fulvestrant, and visceral metastases. The co-Primary end points were Progression Free Survival (PFS) in the overall population, and in those with ESR1 mutations. Overall Survival (OS) was a Secondary end point.
Treatment with Elacestrant resulted in a statistically significant and clinically meaningful improvement in PFS, compared with Standard of Care. There was a 31% reduction in the risk of progression or death in the Elacestrant group for all patients (HR=0.69; P=0.0018) and a 45% reduction in the risk of progression or death among those with ESR1 mutations (HR=0.55; P=0.0005).
The PFS at 12 months with Elacestrant was 22.3% in all patients compared with 9.4% for those receiving the Standard of Care treatment. Among the ESR1 mutation group, the 12 month PFS rate was more pronounced and was 26.8% with Elacestrant, compared to 8.2% with Standard of Care. The benefits with Elacestrant compared with Standard of Care, was consistent across multiple prespecified subgroups including patients who had received prior Fulvestrant. There also was a trend toward improved Overall Survival in patients who received Elacestrant, compared with Standard of Care. The final OS results however are not expected until late 2022. Elacestrant was well tolerated and treatment discontinuation rate was not significantly different between the two treatment groups.
It was concluded that Elacestrant is the first oral Selective Estrogen Receptor Degrader that demonstrated significant and clinically meaningful improvement in PFS compared with Standard of Care endocrine therapy in patients with ER+/ HER2- metastatic breast cancer in the second/third line after treatment with a CDK4/6 inhibitor, and has the potential to become the new standard of care in the study population.
Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of the EMERALD phase 3 trial. Bardia A, Neven P, Streich G, et al. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-02.