UGT1A4 Polymorphism is not Associated with a Clinically Relevant Change in Giredestrant Exposure

Abstract

Abstract Purpose Giredestrant is a potent, orally bioavailable, small-molecule selective estrogen receptor antagonist and degrader (SERD) that is being developed for the treatment of patients with estrogen receptor (ER)-positive breast cancer. In vitro, giredestrant was primarily metabolized by UGT1A4. The goal of this study was to investigate if UGT1A4 polymorphism had a clinically relevant impact on giredestrant exposure. Methods Genotyping and pharmacokinetic data were obtained from 118 and 61 patients in two clinical studies, GO39932 [NCT03332797] and acelERA Breast Cancer [NCT04576455], respectively. Results The overall allelic frequencies of UGT1A4*2 and UGT1A4*3 were 3.3% and 11%, respectively. Giredestrant exposure was consistent between patients with wild-type UGT1A4 and UGT1A4*2 and *3 polymorphisms, with no clinically relevant difference observed. In addition, haplotype analysis indicated that no other UGT1A4 variants were significantly associated with giredestrant exposure. Conclusion Therefore, this study indicates that UGT1A4 polymorphism status is unlikely a clinically relevant factor to impact giredestrant exposure and giredestrant can be administered at the same dose level regardless of patients’ UGT1A4 polymorphism status.