Background: Evidence that ER can signal in both ligand-dependent and independent manner in endocrine resistant breast cancer (BC) provides rationale for therapies that are not only functional antagonists of ER but also reduce ER levels, thus targeting both modes of signaling. Furthermore, mutations in ESR1 affecting the ligand-binding domain (LBD) that drive ER-dependent transcription and proliferation in the absence of estrogen suggest that LBD-mutant forms are involved in mediating clinical resistance and next generation ER modulators with robust activity in both wild type and mutant ER tumors are needed. ARN-810 is a novel, orally bioavailable, ER antagonist that induces proteasomal ER degradation in BC cell lines at picomolar concentrations and tumor regression in tamoxifen-sensitive and resistant BC xenograft models.

Methods: ARN-810 was tested using standard 3+3 dose escalation to assess safety, PK, and Recommended Phase 2 Dose (RP2D). Key eligibility criteria included ER+ (HER2-) metastatic BC progressing ≥ 6 months (m) on endocrine therapy and ≤ 2 prior chemotherapies. Pre- and on-study tumor biopsies were obtained when feasible. Pharmacodynamics was assessed by functional imaging with [18F]-fluoroestradiol (FES)-PET, tumor-based ER/PR/Ki67 IHC, and ER target gene expression. Plasma PK was assessed following a single dose and at steady-state. Anti-tumor activity was assessed by clinical benefit rate (CBR) [complete response, partial response, or stable disease ≥ 6m] and progression-free survival (PFS).

Results: From April 2013 to June 2014, 32 patients (pts) (median age 61 (range 43 – 75); median number of prior therapies = 3 (range 1 – 7); visceral metastases 54%) were enrolled at 5 doses (100, 200, 400, 600, 800 mg) and 2 different regimens (once [QD] and twice daily) given orally with and without fasting. Increases in ARN-810 exposure were dose-dependent with no apparent food effect. At 4 weeks of treatment, complete reduction in FES uptake consistent with full receptor saturation and/or degradation was seen in 95% pts (21/22 scanned to date), including 2 pts with ESR1 mutations, suggesting ARN-810 exhibits greater ER occupancy than that recently reported for fulvestrant 500 mg (van Krutchen et al, ASCO 2014). Evidence of reduced ER levels and Ki67 staining was observed on treatment. To date, 19 pts (59.4%) remain on study with a preliminary CBR of 41%. RP2D, PFS and gene expression results will be provided at time of meeting. The most common adverse events were grades 1/2 nausea, diarrhea, fatigue, and abdominal pain. There was 1 dose limiting toxicity (grade 3 diarrhea) at 800 mg QD which led to expansion of that cohort, while in parallel, evaluation of the other dose regimens continues. No patients have discontinued the study due to toxicity.

Conclusions: ARN-810 appears to be safe and tolerable, with predictable PK, promising anti-tumor activity, and pharmacodynamic evidence of target engagement, ER degradation and reduced tumor proliferation in heavily pre-treated metastatic ER+ BC. In Phase II, ARN-810 will be studied in patients previously treated with aromatase inhibitors and fulvestrant, including those with ESR1 mutations.

Citation Format: Aditya Bardia, Maura N Dickler, Ingrid A Mayer, Eric P Winer, Umar Mahmood, Gary Ulaner, H Charles Manning, Peter Rix, Jeffrey H Hager, Debasish Roychowdhury, Edna Chow Maneval, Carlos L Arteaga, Jose Baselga. Phase I study of ARN-810, a novel and potent oral selective estrogen receptor degrader, in postmenopausal women with metastatic estrogen receptor positive (ER+), HER2- breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-13-01.