Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women

Abstract

Background and objectives: Advanced estrogen receptor-positive (ER+) breast cancer is currently treated with endocrine therapy. Elacestrant is a novel, nonsteroidal, selective estrogen receptor degrader with complex dose-related ER agonist/antagonist activity that is being developed as a treatment option for ER+ breast cancer.

Methods: Two first-in-human phase 1 studies of elacestrant in healthy postmenopausal women (Study 001/Study 004) were conducted to determine its pharmacokinetic and pharmacodynamic profile as well as its safety and maximum tolerated dose.

Results: In total, 140 postmenopausal subjects received at least one dose of study drug (114 received elacestrant and 26 received placebo). Single-ascending dose and multiple-ascending dose assessments showed that doses up to 1000 mg daily were safe and well tolerated, and the maximum tolerated dose was not reached. Oral administration of elacestrant had an absolute bioavailability of 10% and a mean half-life ranging from 27 to 47 h, reaching steady state after 5-6 days. Mean occupancy of the ER in the uterus after seven daily doses was 83% for 200 mg and 92% for 500 mg daily. The median ratio of elacestrant concentrations in the cerebral spinal fluid vs. plasma was 0.126% (500 mg dose) and 0.205% (200 mg dose). Most adverse events were related to the upper gastrointestinal tract.

Conclusions: These data demonstrate that elacestrant has good bioavailability when administered orally with a half-life that supports once-daily administration. Engagement of the ER and some ability to cross the blood-brain barrier was demonstrated in addition to an acceptable safety profile.

Fig. 1

Subject disposition in Study 001. ^aSubject withdrew informed consent after period 1; IV intravenous, MAD multiple ascending dose, PBO placebo, po orally, qd once daily, SAD single ascending dose

Fig. 2

Subject disposition in Study 004. PBO placebo, po orally, qd once daily. ^aIn Cohort 4, only nine of the ten planned subjects enrolled because of logistical considerations. All withdrawals from the study were due to adverse events

Fig. 3

Geometric mean elacestrant plasma concentration values plotted on a logarithmic scale against time since last dose. Individual plots were derived from subjects in: a Study 001, SAD part, following a single dose of elacestrant. b Study 001, MAD part, following the last dose (day 7) of elacestrant. c Study 004, following the last dose (day 7) of elacestrant. ^aThe elacestrant plasma concentrations for this group were below LLOQ (< 0.05 ng/ml) and therefore these data could not be presented. SAD single ascending dose, MAD multiple ascending dose

Fig. 4

Representative ERα occupancy based on FES-PET imaging of the uterus at baseline and after 6 days of oral elacestrant administration at: a 200 mg and b 500 mg. ¹⁸F-FES-PET scans 4 h post-dose on day 6 in Cohort 6 of Study 004 in a subject 3 from subgroup 1 (elacestrant 200 mg daily) and b subject 7 from subgroup 2 (elacestrant 500 mg daily)