Elacestrant

Elacestrant, a tetrahydronaphthalene compound, is a potent, selective and orally active estrogen receptor-α (ERα) antagonist and degrader.

Elacestrant inhibits the estradiol-dependent and independent growth of ERα-positive breast cancer cells, including models harbouring estrogen receptor 1 (ESR1) gene mutations. Elacestrant displayed potent antitumor activity in patient derived xenograft models previously exposed to multiple endocrine therapies, harbouring wild type ESR1 or ESR1 gene mutations in the ligand binding domain.

In patients with ER+ advanced breast cancer with a median of 2.5 prior lines of endocrine therapy, dosed with elacestrant dihydrochloride 400 mg (345 mg of elacestrant) daily, median reduction in tumour 16α-18F-fluoro-17β-estradiol (FES) uptake from baseline to Day 14 was 88.7% demonstrating reduced ER availability and antitumor activity measured by FES-PET/CT in patients with prior endocrine therapies.

The elacestrant oral bioavailability is approximately 10%. Steady state is reached by Day 6 following once daily dosing. C_max and AUC increase slightly more than proportional to dose for doses ≥50 mg (salt form).

Absorption

Following oral administration, elacestrant was rapidly absorbed, reaching C_max within 1-4 hours. The geometric mean C_max was 52.86 ng/mL (35.2% coefficient of variation [CV%]) and AUC_inf was 1566 ng*h/mL (38.4% CV) after single dose administration of 345 mg of elacestrant in fed conditions. At steady state, the median [min, max] plasma concentration at 4h post-dose (C_4h) and AUC are predicted to be 108 ng/mL [27.5–351] and 2190 ng*h/mL [461–8470], respectively.

Effect of food

Administration of elacestrant 345 mg tablet with a high-fat high-calorie meal increased C_max and AUC by 40% and 20%, respectively, as compared to fasted administration. When the tablet was coadministered with a light meal, C_max and AUC increased in a similar fashion, i.e., by 30 and 20%, respectively. Ingestion with food may reduce gastrointestinal adverse effects.

Distribution

Plasma protein binding of elacestrant is >99% and independent of concentration and hepatic impairment status. Elacestrant penetrates the blood brain barrier in a dose-dependent manner. Following once daily administration of elacestrant for 7 consecutive days, median concentrations of elacestrant in the cerebrospinal fluid were 0.0966 ng/mL and 0.155 ng/mL at the doses of 200 and 500 mg, respectively.

Based on population pharmacokinetic analysis, elacestrant is extensively distributed in the tissues with an apparent peripheral volume of distribution of 5411 L. The apparent central volume of distribution of elacestrant at steady state is 422 L.

Biotransformation

Elacestrant was a minor (<10% of plasma radioactivity) component in human plasma. 4-[2-(Ethylamino)ethyl]benzoic acid (EAEBA) glucuronide was a major human plasma metabolite (about 41% of plasma radioactivity). Elacestrant is primarily metabolised by CYP3A4 with a potential small contribution by CYP2A6 and CYP2C9.

Elimination

The half-life of elacestrant is predicted to be approximately 30 hours. After a single dose, the mean (% CV) clearance of elacestrant was 220.3 L/hr (38.4%). At steady state, the mean (% CV) clearance of elacestrant is predicted to be 186 L/hr (43.5%).

Following a single oral dose of 345 mg radiolabeled elacestrant, 81.5% (majority as unchanged) was recovered in feces and 7.53% (trace as unchanged) was recovered in urine. Elacestrant renal clearance is very low (≤2.3 mL/min) and it was eliminated by oxidative metabolism and fecal excretion.

Special populations

Effect of age, weight and gender

From analyses of population pharmacokinetic data in cancer patients, no dose adjustment is warranted based on body weight, age, and gender.

Hepatic impairment

The C_max and AUC values were similar between subjects in the mild hepatic impairment group (ChildPugh A) and the normal hepatic function group upon single dose administration of elacestrant 176 mg. There were significant increases in AUC_0–t (76%) and AUC_0–∞ (83%) in the moderate hepatic impairment group (Child-Pugh B) compared to the normal hepatic function group. The C_max values were similar between the normal and moderate impairment groups.

The geometric mean elimination half-life (t_1/2) tended to increase with increasing severity of hepatic impairment. Elacestrant has not been studied in subjects with severe hepatic impairment (Child-Pugh C).

In PBPK modeling simulation of elacestrant at 345 mg, the steady state AUC and C_max were predicted to increase by 2.14- and 1.92-fold, respectively, in subjects with moderate hepatic impairment compared to patients with normal hepatic function.

Elacestrant displayed low acute toxicity. In repeated dose toxicity studies in rats and monkeys, the antiestrogenic activity of elacestrant was responsible for the effects seen, particularly in the female reproductive system, but also in other organs sensitive to hormones such as mammary gland, pituitary and testes. Sporadic emesis and diarrhoea were recorded in monkeys. In addition, in long-term studies (26 weeks in rats and 39 weeks in cynomolgus monkeys), increased vacuolation of the mucosal epithelium of the non-glandular stomach were observed in rats and vacuolated macrophage infiltrates in the small intestine were recorded in both rats and monkeys. In monkeys this effect occurred at a level of systemic exposure of about 70% of the human exposure.

Elacestrant showed no genotoxic potential in the Ames test, chromosomal aberrations in human lymphocytes and in the micronucleus assay in rats.

Fertility studies in animals have not been conducted. In repeated-dose toxicity studies effects related to fertility were observed in rat and monkey female reproductive tract; these effects occurred below human exposures at MRHD (maximum recommended dose). Decreased cellularity of Leydig cells in rat testes was also observed at exposure levels 2.7-fold higher than in humans.

In embryo-foetal development studies in rats, oral administration of elacestrant resulted in maternal toxicity (body weight loss, low food consumption, red vulvar discharge) and increased resorptions, increased post-implantation loss, and reduced number of live foetuses and foetal variations and malformations below human exposures at MHRD.