A New Era in ER+ Breast Cancer: Best-in-Class Oral Selective Estrogen Receptor Degrader (SERD) Designed as an Endocrine Backbone Treatment

Abstract

There has been intense interest in developing orally bioavailable SERDs, energized by the recent discovery of treatment-resistant ESR1 mutations. Overcoming the two decades long challenge of combining all the desirable activities and properties into one molecule, GDC-9545 (giredestrant) was identified with an exceptional preclinical profile. This Viewpoint seeks to place this molecule in the historical context of previously reported oral SERDs and highlights the exciting clinical potential for a best-in-class oral SERD.

Activators of the Anticipatory Unfolded Protein Response with Enhanced Selectivity for Estrogen Receptor Positive Breast Cancer

“…While endocrine therapy has substantially improved the 5 year survival rates for patients with ERα+ breast cancer, there remains an acute need for new treatments for drug-resistant, advanced ERα+ breast cancers. , Several new therapies seek to address this need with promising clinical trial data, including novel next-generation SERDs, ,,− selective estrogen receptor covalent antagonists (SERCA), , and ERα-targeting proteolysis targeting chimeras (PROTACs). − However, these endocrine therapies utilize known inhibitory mechanisms that induce cancer cell cytostasis and lead to only limited tumor regression in preclinical models . This challenge is exemplified by the recently reported next-generation oral SERD, GDC-9545 (giredestrant), which has potent antiproliferative activity in cell culture but fails to quantitatively regress highly estrogen-dependent MCF-7 tumors as a single agent (orally administered).…”

Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer In Vitro and In Vivo

“…Fulvestrant (Figure ) is the first SERD approved by the FDA for the treatment of metastatic ER + BC but is limited by poor drug-like properties and an inconvenient administration method. This gave impetus to research efforts into a new generation of orally bioavailable SERDs with greater potency, and a number of new oral SERDs have progressed into clinical trials over the past few years. − In 2023, elacestrant was approved by the FDA as the first oral SERD for the treatment of patients with advanced or metastatic ER + BC . The clinical success of SERDs suggests that the strategy of degrading ERα protein can provide an effective way for the treatment of ER + BC including endocrine-resistant ones.…”

Selenium Analogue of LSZ102 as a Highly Potent ER‐α Binder

“…Therefore, the development of new orally available SERD or SERM/SERD hybrid (SSH) drugs is actively pursued [13] . Giredestrant or GDC‐9545 ( 7 ) [14] is probably the best oral SERD to date, but numerous other compounds have shown high potency and have entered clinical trials, including benzo[ b ]thiophene based rintodestrant or G1T48 ( 8 ) and LSZ102 ( 10 ) [14b] …”