ARV-471 is an oral PROTAC ER degrader that binds to and degrades wild-type ER and clinically relevant mutants. ARV-471 directly recruits the ubiquitin-proteasome system to degrade ER, whereas selective ER degraders (SERDs) indirectly cause ER degradation. In a first-in-human phase I/II study, ARV-471 monotherapy was well tolerated and showed clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. The phase III monotherapy dose (200 mg once daily [QD]) was chosen due to comparable efficacy and favorable tolerability relative to 500 mg QD and robust ER degradation in paired tumor biopsies. The randomized phase III VERITAC-2 study (NCT05654623) will compare efficacy and safety of ARV-471 vs the SERD fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy and endocrine therapy (ET).
Eligible patients (aged ≥18 years) have a confirmed diagnosis of ER+/HER2- locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation; 1 prior line of combination CDK4/6 inhibitor therapy and ET; ≤1 additional line of ET; most recent ET given for ≥6 months before disease progression; and radiological disease progression during or after the last line of therapy. Prior chemotherapy in the locally advanced or metastatic setting and prior fulvestrant are not permitted. Patients (N∼560) are randomized 1:1 to receive 200 mg ARV-471 orally QD continuously or fulvestrant intramuscularly on days 1 and 15 in the first 28-day cycle and on day 1 in subsequent cycles; patients are stratified by
NCT05654623.
Medical writing support: Justine Lempart, PhD, of Apollo Medical Communications, and funded by Arvinas Operations, Inc.
Arvinas Estrogen Receptor, Inc.
Arvinas Estrogen Receptor, Inc.
E. Hamilton: Financial Interests, Institutional, Other, Consulting/Advisory Role: Genentech/Roche, Novartis, Lilly, Pfizer, Mersana, iTeos, Janssen, Loxo, Relay Therapeutics, Olema Pharmaceuticals, Orum Therapeutics, Stemline Therapeutics, Arcus, AstraZeneca, Daiichi Sankyo, Seagen, Ellipses Pharma, Greenwich LifeSciences, Tubulis, Verascity Science; Financial Interests, Institutional, Research Grant: Oncomed, Genentech/Roche, Zymeworks, Millennium, Rgenix, Arqule, Clovis, Acerta Pharma, Sermonix Pharmaceuticals, Black Diamond, Karyopharm, Curis, Syndax, FujiFilm, Novartis, Boehringer Ingelheim, Immunomedics, Taiho, Deciphera, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson MediPharma, MedImmune, Seagen, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Merus, Regeneron, Arvinas, StemCentRx, InventisBio, Verastem, eFFECTOR Therapeutics, CytomX, Lycera, Mersana, Radius Health, AbbVie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, G1 Therapeutics, PharmaMar, Olema, Immunogen, Plexxicon, Amgen, Akesobio Australia, Shattuck Labs, ADC Therapeutics, Aravive, Jacobio, Atlas MedX, Ellipses, Incyte, Mabspace Biosciences, ORIC Pharmaceuticals, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Repertoire Immune Medicine, Treadwell Therapeutics, Accutar Biotechnology, Artios, BeiGene, Bliss BioPharmaceuticals, Cascadian Therapeutics, Context Therapeutics, Cullinan-Florentine, Dantari, Duality Biologics, Elucida Oncology, Infinity Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Loxo Oncology, Oncothyreon, Relay Therapeutics, Orum Therapeutics, Prelude Therapeutics, Profound Bio, Tolmar, Torque Therapeutics. C.X. Ma: Financial Interests, Personal, Other, Consulting Fees: Olaris, Novartis, Gilead, AstraZeneca, Sanofi-Genzyme, Biovica, Jacobio, Natera, Inivata, Athenex, Bayor, OncoSignal; Financial Interests, Personal, Other, Research Funding: Pfizer, Puma; Financial Interests, Personal, Research Grant: Arvinas. M. De Laurentiis: Financial Interests, Personal, Other, Consulting: Roche, Novartis, Pfizer, Lilly, Amgen, AstraZeneca, MSD, Pierre Fabre, Seattle Genetics, Gilead Sciences, Ispen, Takeda, Genzyme; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Royalties: Roche, Novartis, Pfizer, Lilly, Amgen, Pierre Fabre, AstraZeneca, MSD, Seattle Genetics, Gilead Science, Takeda, Ispen; Financial Interests, Personal, Research Grant: Novartis, Roche, Puma Biotechnology, Lilly, Pfizer, Daiichi Sankyo, MSD, Macrogenics, Bristol Myers Squibb, Genzyme, AstraZeneca, Eisai. H. Iwata: Financial Interests, Personal, Advisory Board: Chugai, Daiichi Sankyo, AstraZeneca, Lilly, Sanofi; Financial Interests, Personal, Invited Speaker: Chugai, Daiichi Sankyo, AstraZeneca, Lilly, Pfizer, Sanofi, Taiho; Financial Interests, Personal and Institutional, Invited Speaker: Chugai, Daiichi Sankyo, AstraZeneca, MSD, Amgen, Sanofi, Lilly, Novartis, Bayer, Pfizer, Kyowa Hakko Kirin, Behringer, Nihon Kayaku. S.A. Hurvitz: Financial Interests, Personal, Research Grant: Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, OBI Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, Zymeworks; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, AstraZeneca. S.A. Wander: Financial Interests, Personal, Advisory Board, Consulting: Foundation Medicine, Veracyte, Hologic, Biovica, Eli Lilly, Pfizer, Puma Biotechnology; Financial Interests, Personal, Invited Speaker: 2ndMD, Elli Lilly, Guardant Health; Financial Interests, Personal, Research Grant: Genentech, Eli Lilly, Pfizer, Nuvation Bio, Regor Therapeutics. M.A. Danso: Financial Interests, Personal, Advisory Role: Novartis, Pfizer, Immunomedics, Seattle Genetics; Financial Interests, Personal, Royalties: Amgen. D.R. Lu, Y. Liu, L. Tran: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. J. Perkins: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Royalties: Pfizer. S. Anderson: Financial Interests, Personal, Full or part-time Employment: Arvinas Operations, Inc.; Financial Interests, Personal, Stocks/Shares: Arvinas Operations, Inc. M. Campone: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, Sanofi, Lilly, Pfizer, Seagen, Gilead, Daiichi Sankyo; Financial Interests, Personal, Other, Consultant: Sanofi, Novartis, Daiichi Sankyo, PET-Therapy, Menarini, Diaccurate; Financial Interests, Personal, Speaker’s Bureau: Novartis, Lilly; Financial Interests, Personal, Other, Travel: Pfizer, Novartis, Roche, AstraZeneca, Lilly.