Background: Resistance to current endocrine therapies remains a clinical challenge. Fulvestrant has established estrogen receptor (ER) degradation as a critical therapeutic strategy characterized by approximately 50% ER degradation, a clinical benefit rate (CBR) of < 20% in the post CDK 4/6 setting, and a suboptimal intramuscular route of administration. ARV-471 is a selective, orally bioavailable PROteolysis-TArgeting Chimera (PROTAC®) small molecule that induces degradation of wildtype and mutant ER. ARV-471 demonstrates superior ER degradation and antitumor activity compared to fulvestrant in endocrine sensitive and resistant xenograft models. Methods: This is a multi-center, first-in-human, open label study to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ARV-471 administered orally in patients with ER+/HER2- advanced/metastatic breast cancer. The phase 1 monotherapy dose escalation used a 3+3 design with backfill to assess ARV-471 in pre-/post-menopausal women. Premenopausal women had to be on ovarian suppression. Patients were required to have received at least one prior CDK 4/6 inhibitor and at least 2 prior endocrine therapies. Up to 3 prior lines of chemotherapy were allowed. Results: As of June 6th, 2021, 50 patients were treated in the monotherapy escalation at total daily doses of 30mg (n=3), 60mg (n=3), 120mg (n=7), 180/200mg (n=11), 360mg (n=15), 500mg (n=8), and maximum administered dose of 700mg (n=3). A maximum tolerated dose was not reached and no dose limiting toxicities (DLTs) were observed. The most common (≥ 10%) treatment related adverse events (TRAEs) were nausea (24%), fatigue (12%), and vomiting (10%) that were predominantly grade 1 in severity. Two patients experienced grade 3 adverse events (AEs) that were potentially related to ARV-471: 1 patient treated at 180mg had a transient headache lasting 1 day, and 1 patient treated at 360mg had a venous thromboembolism (VTE) a few days after a minor procedure. There were no AEs > grade 3 potentially related to ARV-471. All AEs were manageable with only one patient discontinuing ARV-471 due to a TRAE (grade 3 VTE). ARV-471 demonstrated a dose-related increase in plasma exposure up to 500mg, with doses of 60mg daily and above resulting in steady-state Cmax and AUC24 that exceeded the exposure associated with tumor regression in preclinical models. Analysis of 12 paired biopsies from patients treated at 30 to 360mg daily demonstrated up to 90% ER degradation in tumors expressing WT or mutant ER. Of 34 patients who were evaluable for clinical benefit (confirmed complete response, partial response, or stable disease ≥ 24 weeks) the CBR was 41%. As of the data cutoff date, 6 of the 34 patients were continuing to receive study treatment, including 2 patients who had been on treatment for over 16 months. Two confirmed partial responses were observed among the 28 patients with baseline measurable disease and at least 1 on-treatment tumor assessment. Conclusion: ARV-471 was well tolerated with no DLTs at total daily doses up to 700mg. ARV-471 demonstrated robust ER degradation in paired biopsy samples and encouraging clinical activity (41% CBR) in patients who received prior CDK 4/6 inhibitors. ARV-471 is now being evaluated in the VERITAC Phase 2 monotherapy expansion at 200 mg and 500 mg once daily.

Citation Format: Erika Hamilton, Linda Vahdat, Hyo S Han, Jennifer Ranciato, Richard Gedrich, Chi F Keung, Deborah Chirnomas, Sara Hurvitz. First-in-human safety and activity of ARV-471, a novel PROTAC® estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-08.