The Selective Estrogen Receptor Degrader ZN-c5 Has Broad Antitumor Activity in Wild-Type and Mutant ER-Positive...

Endocrine therapy has proven to be beneficial for patients with estrogen receptor (ER)-positive, HER2-negative (ER+/HER2-) breast cancer; however, de novo or acquired resistance remains a major clinical challenge. Upon progression, many of the cancers continue to be ER dependent, highlighting the opportunities for novel ER-targeting therapies. Fulvestrant, a selective ER degrader (SERD) that antagonizes and degrades ER simultaneously, has demonstrated activity in ER+/HER2- breast cancers the ability to overcome endocrine resistance. Fulvestrant has limitations, including challenging administration by intramuscular injection and poor bioavailability, resulting in suboptimal drug exposure; hence, several next-generation oral SERDs with improved drug properties have been developed and are currently being evaluated in the clinic for their therapeutic benefit. In this study, we describe the discovery of ZN-c5, an orally bioavailable SERD with favorable pharmacokinetic properties and potent activities against both wild-type and mutant ER. In vivo studies showed that ZN-c5 treatment resulted in significant tumor growth inhibition in a variety of breast cancer models and patient-derived xenograft models that harbor ESR1 mutations. Combination with CDK4/6 inhibitors or PI3K pathway inhibition enhanced antitumor effects compared with single-agent alone. ZN-c5 also demonstrated bone-protective effect as observed in a mouse osteoporosis model. These data support the clinical utility of ZN-c5 as monotherapy and as a combination therapy for patients with ER+/HER2- breast cancers. Although encouraging plasma exposure and tolerability have been observed for ZN-c5 in patients, further studies are needed to optimize its therapeutic efficacy.