A phase I trial evaluated the selective estrogen receptor degrader elacestrant in breast cancer.

  • Major Finding: A phase I trial evaluated the selective estrogen receptor degrader elacestrant in breast cancer.

  • Concept: This drug could fulfill a need for patients for whom tumors resist conventional endocrine therapy.

  • Impact: The results of this trial have spurred a phase III trial of elacestrant versus standard of care.


Mutation of estrogen receptor gene alpha (ESR1) is a common mode of endocrine resistance for ER+, HER2 breast cancers treated with aromatase inhibitors, as it confers ligand-independent activation of ER. Although targeting ER directly with selective estrogen receptor degraders (SERD), such as fulvestrant, can have activity in ESR1-mutant tumors, fulvestrant suffers from poor oral bioavailability, necessitating intramuscular injection, and the response rate is only approximately 10%. To help address this clinical need, Bardia and colleagues initiated a multicenter, open-label phase I clinical trial of the oral SERD elacestrant (RAD1901) in 57 female patients with pretreated (median lines of therapy = 3; 52% had received prior SERD treatment) ER+, HER2 advanced or metastatic breast cancer. Of the 50 patients who received the recommended phase II dose, 31 were in the response-evaluation cohort; among these 31, the objective response rate was 19.4%, with all observed responses being partial responses, and the median duration of response was 5.8 months. Notably, an exploratory analysis provided early evidence of benefit even for patients whose tumors harbored confirmed ESR1 mutations, including mutations typically associated with endocrine therapy resistance; among these 15 patients, the objective response rate was 33.3%. Interestingly, among the 16 patients with ESR1 mutations at baseline for whom paired baseline and post-baseline tumor samples were available for sequencing, the ESR1 mutant allele fraction most often decreased during treatment, and patients whose disease exhibited partial responses tended to have an initial decrease followed by an increase in mutant allele fraction at the time of disease progression. This finding is in line with preclinical data and suggests that, if validated as a biomarker in larger cohorts, ESR1 mutant allele frequency may be a useful biomarker of response. Importantly, elacestrant demonstrated a favorable safety profile, with most adverse events being grade 1 or 2. In summary, this work demonstrates the promise of ER+, HER2 metastatic breast cancer with elacestrant, which is currently being evaluated in comparison with standard-of-care endocrine therapy in a phase III trial.

Bardia A, Kaklamani V, Wilks S, Weise A, Richards D, Harb W, et al. Phase I study of elacestrant (RAD1901), a novel selective estrogen receptor degrader, in ER-positive, HER2-negative advanced breast cancer. J Clin Oncol 2021 Jan 29 [Epub ahead of print].

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