According to the first results of the EMERALD trial, elacestrant, the first oral selective estrogen receptor degrader, shows clinical benefit over standard endocrine therapy in patients with ER-positive/HER2-negative metastatic breast cancer who progress on CDK4/6 inhibitor plus endocrine therapy.
At the moment, endocrine therapy plus CDK4/6 inhibitor is the mainstay for the management of ER-positive/HER2-negative metastatic breast cancer. However, most patients eventually experience disease progression, including development of ESR1 mutations (mESR1). Elacestrant, an oral, selective estrogen receptor degrader, demonstrated preclinical and clinical activity in a phase 1 trial in ER-positive metastatic breast cancer, including responses in patients with prior fulvestrant, CDK4/6 inhibitor, and mESR1 tumors, thus forming the rationale for the phase 3 EMERALD trial (NCT03778931) [1]. EMERALD is a multicentre, international, open-label, randomized-controlled, phase 3 trial that enrolled post-menopausal patients with ER-positive/HER2-negative metastatic breast cancer who had received 1–2 prior lines of endocrine therapy and ≤1 line of chemotherapy in the metastatic setting, and who had prior progression on endocrine therapy plus a CDK4/6 inhibitor. A total of 477 patients (228 with mESR1) were randomized 1:1 to elacestrant (400 mg orally daily) or standard of care (investigator’s choice of fulvestrant or an aromatase inhibitor). The study had 2 primary endpoints: progression-free survival (PFS) in patients with tumors harboring mESR1, and PFS in all patients (mESR1 or mESR1 not detected). Secondary endpoints included overall survival (OS), safety, tolerability, and quality of life. Dr. Aditya Bardia (Massachusetts General Hospital, MA, USA) presented the results [2]. The study met both primary endpoints: there was a 30% reduction in the risk of progression in the elacestrant arm in all patients (HR 0.697; P=0.0018), and a 45% reduction in the risk of progression in patients with mESR1 (HR 0.546; P=0.0005). The PFS rate at 12 months was 22.3% with elacestrant versus 9.4% with standard of care in all patients, and 26.8% versus 8.2% in the mESR1 subgroup. For both endpoints, results in key prespecified subgroups, including visceral metastases, number of prior lines of therapy, pre-treatment with fulvestrant, were consistent with the overall outcome The prespecified interim OS analysis planned at the time of the final PFS analysis demonstrated a trend in favor of elacestrant in all patients and in patients with mERS1 (HR 0.751 and 0.592, respectively). The final OS analysis is expected next year. Common treatment-related adverse events with elacestrant included nausea (35%), vomiting (19%), and fatigue (19%), mostly grade 1/2. Treatment-emergent adverse events leading to discontinuation of elacestrant were infrequent (6.3%). “Elacestrant is the first oral, selective estrogen receptor degrader to demonstrate a statistically significant and clinically meaningful improvement of PFS 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. “This therapy has the potential to become the new standard of care for patients with this cancer. Future studies will aim to understand the efficacy of elacestrant during earlier lines of treatment and in combination with other therapies.”
- Bardia A, et al. J Clin Oncol. 2021;39:1360-1370.
- Bardia A, et al. 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 EMERALD phase 3 trial. SABCS 2021 Virtual Meeting, abstract GS2-02.
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