Abstract P6-04-15: Oral selective estrogen receptor degrader AZD9496 demonstrated preclinical model specific differences to fulvestrant in estrogen receptor degradation, agonism and anti-tumour effects
Authors: Mandy Lawson, Natalie Cureton, Oona Delpuech, Pei Zhang, Azadeh Cheraghchi-Bashi-Astaneh, Sladjana Gagrica, Dawn Trueman, Gareth Maglennon, Daniel Sutton, Bairu Zhang, Jonathan Cairns, Teresa Klinowska, Christopher J Morrow
Journal: Cancer Research (2020)

Abstract Anti-hormonal therapy has been the mainstay for the treatment of estrogen receptor (ER) positive breast cancer for over 40 years. The selective ER degrader (SERD) fulvestrant (Faslodex) has been shown to provide clinical benefit over aromatase inhibitors and selective ER modulators. However, delivery of its maximum possible efficacy may be limited by the intra muscular route of administration. To overcome this, AstraZeneca developed the orally bioavailable SERD AZD9496. Here we report further preclinical characterisation of AZD9496 with regards to its ability to induce ERα degradation, antagonise and agonise ER in vitro and the impact on tumour xenografts. AZD9496 caused equivalent ERα degradation to fulvestrant in the MCF7 ER+ cell line. Interestingly, in other ER+ cell lines (e.g. CAMA1 and T47D), the maximal level of ERα degradation induced by AZD9496 was 54% of that induced by fulvestrant. RNAseq analysis of cell lines treated with AZD9496 or fulvestrant in the presence of estradiol did not reveal any differences in ER antagonism. Furthermore, no ER agonism was detected in ER+ breast cancer cell lines treated with AZD9496 in the absence of estradiol. However, unlike fulvestrant, AZD9496 was able to induce PR protein expression in the Ishikawa ER+ endometrial cancer cell line, demonstrating a potential to agonise ER. Also, in proliferation assays, while there was little difference in MCF7 cells between the maximal antiproliferative effect of fulvestrant and AZD9496, in CAMA1 and T47D cells the maximal antiproliferative effect of AZD9496 was 75% and 82% respectively of that caused by fulvestrant. In vivo, AZD9496 increased the uterine weight and induced PR expression in the uterus of juvenile rats, consistent with AZD9496 being a partial ER agonist albeit less than tamoxifen. AZD9496, at a maximally efficacious dose, did not induce the same degree of ER degradation or anti-tumour effect as a supraclinical dose of fulvestrant in CTC174, a patient derived xenograft that harbours a D538G ESR1 mutation and grows in the absence of supplemental estradiol. Taken together, these data suggest that, while AZD9496 is equivalent to fulvestrant in terms of ERα degradation and anti-proliferative/anti-tumour effects in some preclinical models, this is not the case in all models. However, it is not clear which, if any, model accurately reflects the clinical setting and how AZD9496 would compare to fulvestrant at exposures achievable in the clinic. Thus, testing AZD9496 vs fulvestrant in ER+ breast cancer patients is crucial to determine potential clinical benefit. Citation Format: Mandy Lawson, Natalie Cureton, Oona Delpuech, Pei Zhang, Azadeh Cheraghchi-Bashi-Astaneh, Sladjana Gagrica, Dawn Trueman, Gareth Maglennon, Daniel Sutton, Bairu Zhang, Jonathan Cairns, Teresa Klinowska, Christopher J Morrow. Oral selective estrogen receptor degrader AZD9496 demonstrated preclinical model specific differences to fulvestrant in estrogen receptor degradation, agonism and anti-tumour effects [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-04-15.