EMERALD: A randomized, open label, phase III trial to evaluate the efficacy and safety of elacestrant (RAD1901) versus investigator’s choice (IC) of endocrine therapy (ET) for ER+/HER2- advanced breast cancer (BC) following CDK4/6 inhibitor (CDK4/6i) therapy.

Abstract

TPS1104 Background: Estrogen receptor-positive (ER+) BC comprises ~70% of all BC and advanced/metastatic ER+ disease (mBC) remains a major clinical challenge. The addition of CDK4/6i to ET has improved progression-free survival (PFS); however, novel treatments are needed after progression. Putative mechanisms of endocrine resistance, such as ESR1 mutations (mESR1), also indicate the need for additional therapies. Elacestrant, an oral selective estrogen receptor degrader (SERD), demonstrated anti-tumor activity in preclinical models of ER+ BC, including models resistant to CDK4/6i and models with mESR1. An interim evaluation of a phase 1 trial ( NCT02338349 ) of elacestrant in heavily pretreated patients (pts) with mBC, demonstrated an overall response rate (ORR) of 27% with a PFS of 5.4 mo (Bardia, SABCS, 2017). Responses were seen in pts with prior CDK4/6i and with wild-type (WT) or mESR1. Methods: This is a multicenter, international, randomized, open-label, active-controlled phase 3 trial for post-menopausal women or men with mBC. Pts must have received 1-2 prior lines of ET, ≤1 line of chemotherapy for mBC, and have documented progression on a CDK4/6i. Pts with measurable disease (RECIST v1.1) or bone-only disease are eligible. Pts are randomized 1:1 to elacestrant (400 mg orally daily) or IC of fulvestrant or an aromatase inhibitor. Stratification factors include ESR1 mutation status (detected by ctDNA), prior fulvestrant treatment and presence of visceral disease. The primary endpoints are PFS by blinded independent review committee (IRC) in pts with mESR1 and in all pts (WT or mESR1). Secondary endpoints include: overall survival; PFS by IRC in WT, PFS by investigator review; ORR, duration of response, and clinical benefit rate; safety; pharmacokinetics; and quality of life. Approximately 466 pts will be enrolled to detect 340 PFS events in all pts (power ≥90%, hazard ratio (HR) = 0.667) and 160 PFS events in the mESR1 subset (power ≥80%, HR = 0.610), overall α level at 2-sided 5% using the Hochberg procedure. The EMERALD study is open for enrollment. Clinical trial information: NCT03778931.