Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models

  • Clin Cancer Res. 2024 Aug 15;30(16):3549-3563. doi: 10.1158/1078-0432.CCR-23-3465.
Sheryl M Gough  1 ,  John J Flanagan  1 ,  Jessica Teh  1 ,  Monica Andreoli  1 ,  Emma Rousseau  1 ,  Melissa Pannone  1 ,  Mark Bookbinder  1 ,  Ryan Willard  1 ,  Kim Davenport  1 ,  Elizabeth Bortolon  1 ,  Gregory Cadelina  1 ,  Debbie Gordon  1 ,  Jennifer Pizzano  1 ,  Jennifer Macaluso  1 ,  Leofal Soto  1 ,  John Corradi  1 ,  Katherine Digianantonio  1 ,  Ieva Drulyte  2 ,  Alicia Morgan  1 ,  Connor Quinn  1 ,  Miklós Békés  1 ,  Caterina Ferraro  1 ,  Xin Chen  1 ,  Gan Wang  1 ,  Hanqing Dong  1 ,  Jing Wang  1 ,  David R Langley  1 ,  John Houston  1 ,  Richard Gedrich  1 ,  Ian C Taylor  1
Affiliations
  • 1. Arvinas Operations, Inc., New Haven, Connecticut.
  • 2. Thermo Fisher Scientific, Materials and Structural Analysis, Eindhoven, Netherlands.
PMID: 38819400 DOI: 10.1158/1078-0432.CCR-23-3465
Abstract

Purpose: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast Cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast Cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed.

Experimental design: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast Cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI).

Results: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast Cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast Cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR Inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib.

Conclusions: Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast Cancer.

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