Abstract P3-04-10: Utility of the orally bioavailable selective estrogen receptor degrader AZD9496 in ESR1 mutant preclinical models of estrogen receptor positive breast cancer

Abstract

Abstract Approximately 70% of breast cancers express estrogen receptor alpha (ERα) and anti-hormonal therapies which either block the production of estrogen (e.g. anastrozole) or directly block ERα function (e.g. tamoxifen) remain the mainstay of treatment for these patients. While these therapies are highly effective resistance can occur. A common resistance mechanism to anti-hormonal agents is the mutation of ESR1, the gene that encodes ERα, which leads to ligand independent activity. Evidence is emerging that the selective estrogen receptor degrader (SERD) fulvestrant is effective in patients with ESR1 mutations. However, given the low bioavailability of fulvestrant and the still detectable levels of ER in clinical samples after treatment with fulvestrant it is hypothesised that SERDs with improved pharmacokinetic properties which are able to drive greater degradation of ERα may provide additional clinical benefit. We have previously described the discovery and characterisation of the orally bioavailable SERD AZD9496, which is currently in phase I clinical trials in ER+ breast cancer patients. Here we report the preclinical activity of AZD9496 in cell line and patient derived xenograft models expressing clinically relevant ESR1 mutations. We have engineered MCF-7 cells to express Y537S ESR1 which confers the ability to proliferate in the absence of estradiol, consistent with ligand independent activation of ER signalling. AZD9496 is able to inhibit proliferation of these cells and downregulate progesterone receptor protein expression at low nanomolar concentrations. Furthermore, when MCF-7 Y537S ESR1 cells are implanted as xenografts they grow in the absence of exogenous estradiol, are as sensitive to AZD9496 as parental MCF7 xenografts and demonstrate downregulation of ER dependent biomarkers. AZD9496 also has anti-tumour and pharmacodynamic efficacy in patient derived xenograft models expressing D538G ESR1. Taken together, these data strengthen the body of data suggesting that SERDs may be active in patients with tumours containing ESR1 mutations and supports the inclusion of this patient population in AZD9496 clinical trials. Citation Format: Morrow CJ, Lawson M, Ladd B, de Almeida C, James N, Curwen JO, Hanson L, Bell K, Goeppert A, Fisher D, Gangl E, De Savi C, Scott JS, D'Cruz C, Klinowska T, Weir HM. Utility of the orally bioavailable selective estrogen receptor degrader AZD9496 in ESR1 mutant preclinical models of estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-10.