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Selective Estrogen Receptor Degrader Elacestrant in ER-Positive, HER2-Negative Advanced Breast Cancer
TAKE-HOME MESSAGE
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In this phase I clinical trial, the authors evaluated elacestrant, a nonsteroidal oral selective estrogen receptor degrader, in heavily pretreated, postmenopausal patients with estrogen receptor–positive, HER2 negative metastatic breast cancer. The most common treatment-related adverse events were nausea, dyspepsia, vomiting, and fatigue; grade 3/4 treatment-related adverse events included syncope and decreased blood phosphorus levels. The overall response rate was 19.4%, with a median progression-free survival of 4.5 months. The overall response rate in patients with ESR 1 mutation was 33.3%. The median progression-free survival in the overall population was 4.5 months, and was 7.4 months in patients with ESR 1 mutation.
- Elacestrant was found to have an acceptable safety profile and interesting antitumor activity in heavily pretreated populations. Phase III trials are ongoing.
abstract
This abstract is available on the publisher's site.
Access this abstract nowPURPOSE
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.
Additional Info
Disclosure statements are available on the authors' profiles:
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], A Bardia, V Kaklamani, S Wilks, A Weise, D Richards, W Harb, C Osborne, R Wesolowski, M Karuturi, P Conkling, RG Bagley, Y Wang, MG Conlan, P KabosFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Metastatic Breast Cancer
For patients with hormone receptor–positive, HER2-negative metastatic breast cancer, the general treatment paradigm is to exhaust hormonal therapy options prior to moving on to chemotherapy. The goal of therapy is palliation, and we try to maximize treatments that are associated with a better quality of life. The development of resistance to endocrine therapy is almost universal, which has led to research into the pathways that mediate this resistance, and ultimately the approval of several targeted therapies. Estrogen receptor gene alpha (ESR1) mutations are known to confer resistance to endocrine therapy and have been recognized as a prognostic and predictive biomarker, as well as a potential therapeutic target. In the current study, elacestrant, an oral investigational SERD, was evaluated in a group of heavily pretreated women with metastatic breast cancer, including those with ESR1 mutations. The primary objective of this phase I dose-finding study was to identify the maximum tolerated dose and/or recommended phase II dose. The objective response rate of 19.4% and clinical benefit rate of 42.6% in a group of patients who had a median of three prior therapies is quite encouraging, especially in light of the fact that responses were seen even in those with prior fulvestrant and/or prior CDK4/6i therapy, as well as those with ESR1 mutations. Most importantly, most adverse events were grade 1/2 in severity. Patients with metastatic disease tend to be more tolerant of hormonal therapy side effects than those with early-stage disease, as they recognize the goals of treatment are different and the alternative of chemotherapy is far less appealing. However, many patients still suffer with side effects and are particularly bothered by the intramuscular mode of administration of fulvestrant. The development of oral SERDs that are better-tolerated and efficacious even in patients with ESR1 mutations will be an important new therapeutic option for patients with metastatic disease.