AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models

Abstract

Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERa, which is a potent and selective antagonist and downregulator of ERa in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity.Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERa protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER þ breast cells that could provide meaningful benefit to ER þ breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. Ó2016 AACR.

Novel Selective Estrogen Receptor Downregulators (SERDs) Developed against Treatment-Resistant Breast Cancer

“…24 Both 2 and 4 were reported to have physicochemical properties superior to 1 and are actively being studied in clinical trials. 20, 24, 25, 63 …”

“…15–17 The clinical efficacy of 1 , despite its poor physicochemical and pharmacokinetic characteristics, has inspired contemporary interest in orally bioavailable SERDs. The recent intensive interest in discovery and development of novel orally bioavailable SERDs is highlighted by the pursuit of SERDs on multiple scaffolds 18–21 , and the clinical development of GDC-0810 (ARN-810, 2 ) 22 , RAD-1901 23 , and AZD-9496 ( 4 ) 24, 25 by Genentech, Radius Health, and Astra Zeneca, respectively.…”

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

“…Interestingly, even in these patients who have seen multiple prior endocrine therapies, dependence on ER for tumor growth and sensitivity to other ER-targeting agents is often retained (5-7). On the basis of this continued dependence on ER, novel selective estrogen receptor degraders (SERD) have gained widespread attention as a means of delivering more durable responses and increasing progression-free survival in this setting (8)(9)(10)(11). Currently, fulvestrant (Faslodex, AstraZeneca) is the only approved SERD for the treatment of postmenopausal women with advanced ER þ breast cancer who have progressed on endocrine therapies (http://www.accessdata.fda.gov/drugsatfda_docs/ label/2011/021344s015lbl.pdf).…”

Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors

“…These include most prominently, the selective estrogen receptor modulator (SERM) and downregulator (SERD), Fulvestrant (Fulv, ICI 182,780), which is not orally active and must be administered as a large volume intramuscular injection (5). Although two new orally active SERDs have been reported recently (GDC-0810 (6) and AZD9496 (7)), they have some troubling side effects, including causing diarrhea in one-third of patients (8), which could limit their clinical implementation and suggests the need for developing other new antiestrogens.…”