The oral selective estrogen receptor degrader GDC-0810 (ARN-810) in postmenopausal women with hormone receptor-positive HER2-negative (HR + /HER2 −) advanced/metastatic breast cancer

Aditya Bardia, Ingrid Mayer, Eric Winer, Hannah M. Linden, Cynthia X. Ma, Barbara A. Parker, Meritxell Bellet, Carlos L. Arteaga, Sravanthi Cheeti, Mary Gates, Ching Wei Chang, Jill Fredrickson, Jill M. Spoerke, Heather M. Moore, Jennifer Giltnane, Lori S. Friedman, Edna Chow Maneval, Iris Chan, Komal Jhaveri

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Purpose: GDC-0810 (ARN-810) is a novel, non-steroidal, orally bioavailable, selective estrogen receptor degrader (SERD) that potentially inhibits ligand-dependent and ligand-independent estrogen receptor (ER)-mediated signaling. Methods: A phase Ia/Ib/IIa dose escalation, combination treatment with palbociclib or a luteinizing hormone-releasing hormone, and expansion study determined the safety, pharmacokinetics, and recommended phase 2 dose (RP2D) of GDC-0810 in postmenopausal women with ER + (HER2 −) locally advanced or metastatic breast cancer (MBC). Baseline plasma ctDNA samples were analyzed to determine the ESR1 mutation status. Results: Patients (N = 152) received GDC-0810 100–800 mg once daily (QD) or 300–400 mg twice daily, in dose escalation, expansion, as single agent or combination treatment. Common adverse events regardless of attribution to study drug were diarrhea, nausea, fatigue, vomiting, and constipation. There was one dose-limiting toxicity during dose escalation. The maximum tolerated dose was not reached. GDC-0810 600 mg QD taken with food was the RP2D. Pharmacokinetics were predictable. FES reduction (> 90%) highlighting pharmacodynamic engagement of ER was observed. Outcomes for the overall population and for patients with tumors harboring ESR1 mutations included partial responses (4% overall; 4% ESR1), stable disease (39% overall; 42% ESR1), non-complete response/non-progressive disease (13% overall; 12% ESR1), progressive disease (40% overall; 38% ESR1), and missing/unevaluable (5% overall; 5% ESR1). Clinical benefit (responses or SD, lasting ≥ 24 weeks) was observed in patients in dose escalation (n = 16, 39%) and expansion (n = 24, 22%). Conclusion: GDC-0810 was safe and tolerable with preliminary anti-tumor activity in heavily pretreated patients with ER + advanced/MBC, with/without ESR1 mutations, highlighting the potential for oral SERDs. Clinical Trial and registration date April 4, 2013. NCT01823835.

Original languageEnglish
Pages (from-to)319-331
Number of pages13
JournalBreast Cancer Research and Treatment
Volume197
Issue number2
DOIs
StatePublished - Jan 2023

Keywords

  • GDC-0810; HR +
  • HER2 −
  • Metastatic breast cancer
  • Phase 1
  • Postmenopausal
  • Selective estrogen receptor degrader

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