In a phase I trial reported in the Journal of Clinical Oncology, Aditya Bardia, MD, MPH, and colleagues identified activity of the oral selective estrogen receptor (ER) degrader (SERD) elacestrant in postmenopausal women with heavily pretreated ER-positive, HER2-negative breast cancer, including those with the ER alpha gene (ESR1) mutation.

Elacestrant is a nonsteroidal SERD that that has been shown to degrade the ER in a dose-dependent manner, as well as inhibit estradiol-dependent functions of ER target gene transcription induction and cell proliferation in ER-positive breast cancer cell lines.

Aditya Bardia, MD, MPH

Study Details

A total of 57 patients were enrolled. During the dose-escalation phase, patients received elacestrant at 200 mg to 1,000 mg once daily, with no dose-limiting toxicities being observed. The dose selected for phase II evaluation was 400 mg once daily. A total of 50 patients received 400 mg once daily (24 as one 400-mg tablet, and 26 as four 100-mg capsules) until disease progression or unacceptable toxicity. Among these patients, the median number of prior therapies for advanced disease was three (range = 1–7), including cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in 52% and SERDs in 52%. The ESR1 mutation was present in 50% of patients.

Toxicity

For all patients receiving 400 mg, the most common adverse events of any grade were nausea (50.0%; 33.3% with tablet vs 65.4% with capsules), dyspepsia (32.0%; 20.8% vs 42.3%), vomiting (30.0%; 16.7% vs 42.3%), and fatigue (28.0%; 20.8% vs 34.6%). Grade 3–4 adverse events occurred in 10 patients (41.7%) receiving the tablet and 12 patients (46.2%) receiving capsules. The most common in those receiving the tablet were syncope and decreased phosphorus in two patients (8%) each; the most common in those receiving capsules were increased aspartate transaminase in four patients (15.4%) and increased alanine transaminase in two (7.7%).

Responses

Among 31 patients in the response-evaluable population, responses (all partial) were observed in 6 patients (19.4%), including responses in 3 (15.0%) of 20 patients with prior SERD treatment, 3 (16.7%) of 18 with prior CDK4/6 inhibitor treatment, and 5 (33.3%) of 15 with an ESR1 mutation.

Among 47 patients in the clinical benefit–evaluable population, rates of clinical benefit (partial response or stable disease for ≥ 24 weeks) were 42.6% overall (20 of 47 patients), 33.3% in patients with prior SERD treatment (8 of 24), 30.4% in those with prior CDK4/6 inhibitor treatment (7 of 23), and 56.5% in patients with an ESR1 mutation (13 of 23).

Patients who experienced a partial response tended to exhibit a decline in ESR1 mutant allele frequency during treatment, with an increase at time of disease progression.

The investigators concluded, “Elacestrant [at] 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 [an] ESR1 mutation as well as those with prior CDK4/6 inhibitor and prior SERD [treatment]. A phase III trial investigating elacestrant vs standard endocrine therapy is ongoing [EMERALD; ClinicalTrials.gov identifier NCT03778931].”

As noted by the investigators, elacestrant is the first oral SERD to be studied in a phase III clinical trial. The trial is comparing elacestrant vs fulvestrant or an aromatase inhibitor, with the primary endpoints of progression-free survival in both the overall population and the population of patients with an ESR1 mutation.

Dr. Bardia, of Massachusetts General Hospital Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Radius Health, Inc. For full disclosures of the study authors, visit ascopubs.org.