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

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 .

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

Conflict of interest statement

A.B. held consulting/advisory board positions at Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly, Foundation Medicine, and received contracted research/grant to institution from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca, and Eli Lilly. I.M. received consulting fees/ research support from Genentech and is an employee of AstraZeneca. E.W. and H.M.L. received consulting fees and research support from Genentech. C.X.M. held consulting/advisory board positions at Gilead, AstraZeneca, Sanofi-Genzyme, Jacobio, Natera, Novartis, Inivata, Biovica, Athenex, Bayer, Esai, and OncoSignal and received funding from Pfizer and Puma. B.A.P. received contracted research support to the institution from Pfizer, Novartis, Glaxo Smith Kline, Genentech/Roche, and Oncternal Therapeutics Inc., consulting fees from Dare Bioscience, Bioatla Inc. (spouse), EMD Serona (spouse), and Samumed LLC (spouse), and has stock ownership in Merck. M.B. held advisory board positions at Pfizer, Novartis, and Lilly and received speakers bureau fees from Pfizer, Novartis, and Lilly and travel expenses from Pfizer and Roche. C.L.A. held advisory board positions at Novartis, Lilly, Merck, TAIHO Oncology, Immunomedics, Daiichi Sankyo, AstraZeneca, Sanofi, OrigiMed, and Susan G. Komen Foundation, received research grant support from Pfizer, Lilly, and Takeda, and has stock ownership in Provista. S.C., M.G., C.-W.C., J.F., H.M.M., J.G., and I.C. are employees and stockholders of Roche/Genentech. J.M.S. and L.S.F. are former employees and stockholders of Roche/Genentech. E.C.M. is a former employee of Seragon. K.J. received consulting fees from AbbVie, AstraZeneca, Blueprint Medicines, Biotheranostics, BMS, Genentech, Jounce Therapeutics, Lilly Pharmaceuticals, Novartis, Pfizer, Seattle Genetics, SunPharma Pvt Ltd, and Taiho Oncology and contracted research grants to institution from ADC Therapeutics, AstraZeneca, Clovis Oncology, Debio Pharmaceuticals, Genentech, Immunomedics, Novartis, Lilly Pharmaceuticals, Merck/VelosBio, Novartis, Novita Pharmaceuticals, Pfizer, Puma Biotechnology, and Zymeworks.

© 2022. The Author(s).

Figures

Fig. 1

Pharmacodynamics of GDC-0810. A Functional imaging with 18F-FES-PET for patient on GDC-0810 600-mg QD (fasting regimen) at baseline and cycle 2 day 3 with best response of stable disease. B ER protein levels and tumor cell proliferation (Ki-67) at baseline and treatment-related reductions after 3 cycles of treatment for patient on GDC-0810 600-mg QD (non-fasting regimen) with best response of stable disease. C Waterfall 18F-FES-PET response for patients in six dose cohorts in phase Ia and cohort A1 in phase IIa

Fig. 2

Patient time on study. Two cohorts in phase Ia, and all cohorts in phase Ib and IIa were dosed under non-fasting conditions

Fig. 3

Kaplan–Meier plot of progression-free survival for patients in phase Ia (top) and phases 1b/IIa (bottom)