Indications
Elacestrant is approved for use in the treatment of specific breast cancer conditions. It is indicated for postmenopausal women or adult men who have ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, particularly when the disease has progressed after at least one line of endocrine therapy. In the European Union, an additional stipulation is that patients must have previously undergone treatment with a CDK 4/6 inhibitor before using elacestrant.
Pharmacodynamics
The pharmacodynamics of elacestrant reveal a need for further characterization regarding its exposure-response relationships and time course. At the approved dosage, elacestrant does not increase the QTc interval beyond 20 milliseconds. There are, however, possible side effects such as hypercholesterolemia and hypertriglyceridemia in patients. Additionally, caution is advised when considering the drug for pregnant women due to potential fetal harm. Notably, elacestrant is distinguished from other selective estrogen receptor modulators and degraders by its ability to cross the blood-brain barrier.
Absorption
When administered at the recommended dose of 345 mg once daily, elacestrant achieves a steady-state maximum concentration (Cmax) of 119 ng/mL and an area under the curve (AUC0-24h) of 2440 ng·h/mL. Between doses of 43 mg and 862 mg, the Cmax and AUC increment more than dose-proportionally. The drug reaches steady-state by the sixth day of administration with a mean accumulation ratio of 2-fold as measured by AUC0-24h. Elacestrant has a time to maximum concentration (tmax) ranging from 1 to 4 hours, with an oral bioavailability of approximately 10%. The presence of a high-fat meal increases both the Cmax and AUC of elacestrant by 42% and 22%, respectively, compared to fasting conditions.
Metabolism
Elacestrant undergoes hepatic metabolism primarily via the enzyme CYP3A4, with CYP2A6 and CYP2C9 playing minor roles in its metabolic process.
Mechanism of Action
Elacestrant is an oral selective estrogen receptor degrader (SERD) designed to target estrogen receptor-alpha (ERα). Breast tumors that express ERα often rely on estrogen to drive their growth, making endocrine therapies that inhibit the estrogen receptor (ER) a common strategy in the management of these cancers. SERDs, such as Elacestrant, function by antagonizing the transcriptional activity of the ER and facilitating its degradation. In ER-positive (ER+) and HER2-negative (HER2-) breast cancer cells, Elacestrant effectively inhibits 17β-estradiol-driven cell proliferation and promotes the degradation of ERα via the proteasomal pathway. Additionally, Elacestrant impedes ER nuclear translocation and enhances ER turnover, thereby disrupting downstream signaling pathways. This compound demonstrates both in vitro and in vivo anti-tumor efficacy, especially in ER+ HER2- breast cancer models that have shown resistance to fulvestrant and cyclin-dependent kinase 4/6 inhibitors, as well as in models with mutations in the estrogen receptor 1 gene (ESR1).
