Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer

Abstract

PURPOSE This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer, including those with estrogen receptor gene alpha ( ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D). METHODS The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability. RESULTS Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction. CONCLUSION Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor–positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.

ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

“…In addition, some of these SERDs are effective preclinically against ESR1-MUT in cell lines and in PDX models that have complete fulvestrant resistance, through unknown mechanisms [ 38 , 39 , 53 ]. Elacestrant (RAD1901) has been effective against cells and PDX models with fulvestrant and CDK4/6i resistance [ 51 ], and Phase 1 data show efficacy in ESR1-MUT patients and patients pretreated with fulvestrant and CDK4/6i [ 54 ]. Elacestrant is in a Phase 3 trial for patients after progression on ET and CDK4/6i (EMERALD: NCT03778931).…”

Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective

“…The clinical benefit was associated with a decline in ESR1 mutant allele fraction. This study concluded that elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with ER+ MBC, in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD [73] (Table 2).…”

Endocrine Treatment for Breast Cancer Patients Revisited—History, Standard of Care, and Possibilities of Improvement

“…As mentioned above, fulvestrant is the only approved SERD for the therapy of postmenopausal aBC patients to date. However, since there is a lack of oral bioavailability of fulvestrant, therefore requiring intramuscular injection of it [ 83 , 84 ], other novel SERDs with the potential of oral bioavailability are being investigated [ 85 , 86 , 87 , 88 , 89 ] ( Table 2 ). A first-in-human study on the SERD AZD9496, for instance, showed an acceptable safety profile and a prolongation of disease stabilization in women with hormone-receptor-positive aBC [ 90 ], but its preoperative influence on estrogen receptor expression was not superior to fulvestrant within a recent window of an opportunity trial in eBC [ 91 ].…”