Giredestrant immobilizes the estrogen receptor to exert potent antitumor efficacy against ER-active breast cancers.

Estrogen receptor α (ER) is one of the most successfully prosecuted therapeutic targets in oncology. Selective ER degraders (SERDs) are being pursued as next-generation therapies. Giredestrant is a potent orally bioavailable SERD and full ER antagonist, which has demonstrated clinical superiority over standard-of-care therapy. Here, we describe its key pharmacological attributes, and account for its benefit across the ER+ breast cancer spectrum. The antiproliferative potential of giredestrant is dictated by ER activity; it outperforms approved agents in ER activity-high contexts. ER immobilization likely underlies giredestrant's profound inhibitory potential. ER immobilization is not observed for heterobifunctional chimera degraders, which fail to match the antiproliferative potential of giredestrant despite superior ER degradation. Giredestrant redistributes enhancers, decreasing the expression of estrogen-induced genes and inducing the expression of putative tumor suppressors. These molecular data, together with results from recent trials, rationalize giredestrant's potential to serve as an optimized endocrine backbone for ER+ breast cancer.