Treatment of hormone sensitive breast tumors with endocrine therapy such as antiestrogens or aromatase inhibitors has improved their clinical outcomes. However, not all tumors respond and the ones that do respond may eventually acquire resistance. One of the proposed mechanisms of resistance to endocrine therapy is overexpression of ERα and cross-talk of ERα with growth factor receptors. Studies including our own have shown that downregulation of ER with pure antiestrogen fulvestrant in combination with AIs may prolong responsiveness of the tumors to endocrine agents. Fulvestrant has been employed as either first or second line treatment for ER positive breast cancers alone or in combination with AIs. Studies have suggested that further escalation of dose may provide further benefit. However, dose escalation of fulvestrant which is administered via intramuscular injection is difficult due to its poor solubility. To overcome this shortcoming of an injectable drug, a novel orally active SERD (selective estrogen receptor downregulator), AZD9496 was developed. In addition to being orally active, AZD9496 is selective for mammary ERα. In the current study, we compared the effect of AZD9496 and fulvestrant on the growth of MCF-7Ca (human estrogen receptor positive MCF-7 cells stably transfected with human placental aromatase gene) xenografts grown in ovariectomized athymic nude mice. Tumors were allowed to form with androstenedione (aromatizable source of estrogen) supplement. When the tumors reached ~250 mm3, mice were grouped such that the mean tumor volumes were not significantly different (p>0.99). Mice bearing xenografts of MCF-7Ca were then treated with fulvestrant (1 mg/d-sc) or AZD9496 (5 mg/kg/d-po), alone or in combination with anastrozole (200μg/d-sc) for 23 weeks. Tumors were measured weekly and growth rate was calculated. AZD9496 was significantly better at inhibiting the growth of tumors compared to control (p<0.001) and anastrozole (p=0.04). AZD9496 was equally effective in inhibiting the growth of MCF-7Ca xenografts as fulvestrant (growth rate, p>0.99 and tumor volume on week 23, p=0.99). In the second study, efficacy of AZD9496 was evaluated on against anastrozole resistant MCF-7Ca xenografts. Tumors were treated with anastrozole (200μg/d) for 13 weeks. During this time, the tumors initially regressed but eventually began to grow and had doubled in volume. At this time-point, they were regrouped to receive second line treatment. Single agent AZD9496 was marginally significant compared to continued anastrozole treatment (p=0.07). Nevertheless, second line treatment with AZD9496 was equally effective as fulvestrant (p=0.36). The combination of anastrozole with AZD9496/fulvestrant was more effective in reducing tumor growth compared to continued anastrozole treatment. Next, we measured the effect of AZD9496 on the mouse uterus. Uterine weight of mice treated with AZD9496 was not significantly different from mice that were treated with androstenedione (p=0.99). These results suggest that AZD9496 was selective for tumor ERα and had no effect on the uterine ERα. These results suggest that AZD9496 may be a better alternative to fulvestrant due to its selectivity for mammary ER and same efficacy as fulvestrant obtained upon oral administration. Citation Format: Sabnis GJ, Kazi A, Schech A, Yu S, Golubeva O, Weir H, Brodie A. A new oral SERD AZD9496 for treatment of hormone dependent postmenopausal 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 P2-09-10.