Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of estrogen receptor (ER)+ breast cancer (BC). However, many patients (pts) relapse or develop resistance to available hormonal agents via estrogen-dependent and estrogen-independent mechanisms. Furthermore, mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen can mediate resistance. Therefore, next generation ER targeting agents with robust activity in both wild type and mutant ER tumors are needed. GDC-0810 is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader that induces tumor regression in tamoxifen-sensitive and resistant ER+ BC xenograft models. Methods: A phase I dose escalation study with 3+3 design was conducted in postmenopausal women with ER+ (HER2-) locally advanced or metastatic BC (progressing after ≥ 6 months on endocrine therapy; ≤ 2 prior chemotherapies) to determine the safety, pharmacokinetic (PK) and recommended phase II dose (RP2D) of GDC-0810. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples, CT scans, and when feasible, paired pre and on-study tumor biopsies were obtained. Results: Forty-one pts (median # of prior therapies: 4) were enrolled at 5 total daily dose levels (100-800 mg) and 2 regimens: once (QD) or twice (BID) daily given orally with and without fasting. Increases in GDC-0810 exposure were dose-dependent. The common treatment-related adverse events (AEs) were grade 1/2 diarrhea (63%), fatigue (46%), nausea (44%), flatulence (24%), vomiting (22%), and anemia (22%). Diarrhea was mostly Grade 1, intermittent in nature, and manageable with dose modifications, dietary adjustments, and treatment with PRN loperamide. There was one dose limiting toxicity of Grade 3 diarrhea at 800 mg QD (fasting). 600 mg QD given with food was determined to be single agent R2PD. Complete/near complete (>90%) suppression of FES uptake was observed in 90% of pts with FES-PET scans, including 5 pts with known ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-study biopsies. At a median follow-up of 8 months 13 of 31 (42%) pts on study achieved stable disease > 6 months while 10 pts remain active on study with followup Conclusions: GDC-0810 has a tolerable safety profile to date, with predictable PK, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated patients with advanced or metastatic ER+ BC. A phase IIa study of GDC-0810 is ongoing in postmenopausal women with ER+ (HER2-) advanced or metastatic BC who have been previously treated with an aromatase inhibitor, including tumors with ESR1 mutations (clinicaltrials.gov NCT01823835). Citation Format: Maura Dickler, Aditya Bardia, Ingrid Mayer, Eric Winer, Peter Rix, Jeff Hager, Meng Chen, Iris Chan, Edna Chow-Maneval, Carlos Arteaga, Jose Baselga. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with estrogen receptor+ HER2-, advanced/metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT231. doi:10.1158/1538-7445.AM2015-CT231