Abstract OT1-04-04: EMERALD: A randomized, open-label, phase 3 trial to evaluate the efficacy and safety of elacestrant (RAD1901), a novel oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine therapy for ER+/HER2- advanced breast cancer following CDK4/6 inhibitor therapy

Background: Estrogen receptor-positive (ER+) breast cancer (BC) comprises ~70% of all BC and advanced/metastatic ER+ disease (mBC) remains a major clinical challenge. The addition of CDK4/6i to endocrine therapy (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 SERD, demonstrated anti-tumor activity in preclinical models of ER+ BC, including models resistant to CDK4/6 inhibitors (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 investigator’s choice of fulvestrant or an aromatase inhibitor. Stratification factors include ESR1 mutation status (detected by ctDNA), prior fulvestrant treatment and presence of visceral disease. The co-primary endpoints are PFS by blinded independent review committee (IRC) in pts with mESR1 and in all pts (mESR1 or mESR1 not detected). Secondary endpoints include: overall survival; 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. NCT03778931 Citation Format: Philippe Aftimos, Aditya Bardia, Virginia G Kaklamani, Janice Lu, Teeru Bihani, JungAh Jung, Alfred T Anderson-Villaluz, Maureen G Conlan, Javier Cortes. EMERALD: A randomized, open-label, phase 3 trial to evaluate the efficacy and safety of elacestrant (RAD1901), a novel oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine therapy for ER+/HER2- advanced breast cancer following CDK4/6 inhibitor therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-04-04.