Deciphering the Mechanistic and Pharmacokinetic Attributes of GDC-9545: A Promising ER Antagonist for Breast Cancer Therapy

Estrogen receptor (ER) positive breast cancers rely on ER signaling for progression and even after developing resistance to endocrine therapies, highlighting the need for improved ER-targeting treatments. Fulvestrant is a full antagonist of ER, which is believed to work by degrading the ERα protein, but its clinical use is hampered by its physicochemical properties and the need for intramuscular injection.

Researchers are developing orally bioavailable molecules that maintain fulvestrant's antagonistic properties with better drug-like characteristics. However, new therapeutic candidates such as GDC-0810 and GDC-0927, which have been optimized for ER degradation, show different mechanisms. These drugs, along with fulvestrant, have distinct effects on ER degradation, transcriptional profiles, and their ability to inhibit cell growth in various ER+ breast cancer cell lines. In patient-derived xenograft (PDX) models, GDC-0927 demonstrates more effective transcriptional suppression and greater efficacy than GDC-0810, despite having a less favorable pharmacokinetic profile due to rapid clearance and poor oral absorption, leading to a high pill burden.

The article introduces GDC-9545, a non-steroidal ER ligand that effectively competes with estradiol for binding and induces an antagonistic conformation within the ER ligand binding domain. GDC-9545 induces ER turnover and transcriptional suppression, leading to strong anti-proliferative effects in vitro. It also shows reduced metabolism and enhanced oral bioavailability compared to GDC-0927, resulting in improved oral exposure across species. Due to its pharmacological properties and oral exposure, GDC-9545 achieves comparable anti-tumor activity to GDC-0927 at significantly lower doses and demonstrates greater in vivo efficacy than both GDC-0810 and fulvestrant at clinically relevant exposures. The superior efficacy of GDC-9545 is attributed to its high binding potency, complete suppression of ER signaling, and an improved drug metabolism and pharmacokinetic (DMPK) profile. GDC-9545 is currently under evaluation in Phase 1 clinical trials (ClinicalTrials.gov Identifier: NCT03332797).

The research was presented by Metcalfe C et al. at the 2018 San Antonio Breast Cancer Symposium and published in Cancer Research 2019;79(4 Suppl):Abstract nr P5-04-07.