Vepdegestrant

Vepdegestrant
Clinical data
Other namesARV-471
Legal status
Legal status
  • Investigational
Identifiers
IUPAC name
  • (3S)-3-[6-[4-{{#parsoidfragment:3}}1-[4-[(1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC45H49N5O4
Molar mass723.918 g·mol−1
3D model (JSmol)
SMILES
  • C1CC2=C(C=CC(=C2)O)[C@H]([C@H]1C3=CC=CC=C3)C4=CC=C(C=C4)N5CCC(CC5)CN6CCN(CC6)C7=CC8=C(C=C7)C(=O)N(C8)[C@H]9CCC(=O)NC9=O
InChI
  • InChI=1S/C45H49N5O4/c51-37-12-15-39-33(27-37)8-13-38(31-4-2-1-3-5-31)43(39)32-6-9-35(10-7-32)48-20-18-30(19-21-48)28-47-22-24-49(25-23-47)36-11-14-40-34(26-36)29-50(45(40)54)41-16-17-42(52)46-44(41)53/h1-7,9-12,14-15,26-27,30,38,41,43,51H,8,13,16-25,28-29H2,(H,46,52,53)/t38-,41+,43+/m1/s1
  • Key:TZZDVPMABRWKIZ-XMOGEVODSA-N

Vepdegestrant (developmental code name ARV-471) is an investigational oral proteolysis-targeting chimera (PROTAC) compound that targets the estrogen receptor for protein degradation. It is being developed for the treatment of estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer by Arvinas and Pfizer.[1][2][3]

Mechanism of action

Vepdegestrant is designed as a PROTAC that recruits the ubiquitin-proteasome system to target the estrogen receptor for degradation.[4] The compound contains both an E3 ubiquitin ligase-binding moiety and an estrogen receptor-binding domain, intended to bring these proteins into proximity to trigger ubiquitination and subsequent proteasomal degradation of the ER protein.[5] In laboratory studies, vepdegestrant demonstrated ER degradation in ER-positive breast cancer cell lines with reported DC50 values of approximately 1-2 nM.[6]

Clinical development

Phase I/II trials

Vepdegestrant has been evaluated in early-phase clinical trials as both monotherapy and in combination with other agents in patients with ER+/HER2- breast cancer. In a first-in-human Phase I/II study, vepdegestrant monotherapy was well tolerated and showed clinical activity in pretreated patients.[7]

Phase III VERITAC-2 trial

The Phase III VERITAC-2 trial (NCT05654623) is a randomized, open-label study comparing vepdegestrant to fulvestrant in patients with ER+/HER2- advanced breast cancer.[8] The trial enrolled 624 patients at sites in 26 countries who had previously received treatment with a CDK4/6 inhibitor plus endocrine therapy.[9]

In March 2025, results were announced from the VERITAC-2 trial. According to company statements, the study met its primary endpoint in the ESR1-mutant patient population, showing improvement in progression-free survival compared to fulvestrant.[9] However, the trial did not achieve statistical significance in the overall intent-to-treat population.[10] Detailed results were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.[11]

Preclinical studies

In preclinical studies, vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved tumor growth inhibition (TGI).[12] The compound showed high efficacy as monotherapy and demonstrated synergistic effects when combined with CDK4/6 inhibitors or PI3K/mTOR pathway inhibitors in preclinical ER+ breast cancer models.[12]

Regulatory status

The U.S. Food and Drug Administration (FDA) granted Fast Track designation to vepdegestrant in February 2024 as a monotherapy for the treatment of adults with ER+/HER2- metastatic breast cancer.[13][14]

Following company-reported results from the VERITAC-2 trial, Arvinas stated it submitted a New Drug Application (NDA) to the FDA in June 2025 for vepdegestrant in patients with ESR1-mutant ER+/HER2- advanced or metastatic breast cancer whose disease progressed following previous treatment.[15]

See also

References

  1. ↑ Iwata, H.; Naito, Y.; Hattori, M.; Yoshimura, A.; Yonemori, K.; Aizawa, M.; et al. (November 2023). "58P Safety and pharmacokinetics (PK) of vepdegestrant in Japanese patients with estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: Results from a Japanese phase I study". Annals of Oncology. 34: S1488 – S1489. doi:10.1016/j.annonc.2023.10.193. S2CID 265657144.
  2. ↑ Iwata, H.; Hamilton, E.P.; Ma, C.X.; De Laurentiis, M.; Hurvitz, S.A.; Wander, S.A.; et al. (November 2023). "73TiP Global phase III studies evaluating vepdegestrant in estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: VERITAC-2 and VERITAC-3". Annals of Oncology. 34: S1493. doi:10.1016/j.annonc.2023.10.207. S2CID 265654990.
  3. ↑ "Arvinas, Pfizer reworking partnership on 'Protac' cancer drug | BioPharma Dive". www.biopharmadive.com. Retrieved 17 September 2025.
  4. ↑ "Estrogen Receptor". Arvinas. Retrieved 17 September 2025.
  5. ↑ Sakamoto, Kathryn M.; Kim, Kwon B.; Kumagai, Ayumu; Mercurio, Frank; Crews, Craig M.; Deshaies, Raymond J. (18 January 2022). "PROTAC targeted protein degraders: the past is prologue". Nature Reviews Drug Discovery. 21 (3): 181–200. doi:10.1038/s41573-021-00371-6. PMC 8765495. PMID 35046570.
  6. ↑ "Vepdegestrant (ARV-471) PROTAC ER Degrader". MedChemExpress. Retrieved 17 September 2025.
  7. ↑ Hamilton, Erika P.; Ma, Cynthia; De Laurentiis, Michelino; Iwata, Hiroji; Hurvitz, Sara A.; Wander, Seth A.; et al. (2024). "VERITAC-2: a Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer". Future Oncology (London, England). 20 (32): 2447–2455. doi:10.1080/14796694.2024.2377530. ISSN 1744-8301. PMC 11524203. PMID 39072356.
  8. ↑ "A Study to Compare the Efficacy and Safety of Vepdegestrant (ARV-471) Versus Fulvestrant in Participants With Estrogen Receptor-positive, HER2-negative Advanced Breast Cancer (VERITAC-2)". ClinicalTrials.gov. 30 June 2025. Retrieved 17 September 2025.
  9. 1 2 "Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial". Arvinas. Retrieved 17 September 2025.
  10. ↑ "VERITAC-2 Trial Shows Vepdegestrant Significantly Improves Survival in ESR1-Mutant Breast Cancer". Applied Clinical Trials Online. 24 March 2025. Retrieved 17 September 2025.
  11. ↑ "Arvinas Announces Results from the VERITAC-2 Trial Selected as Late-Breaking Oral Presentation at the 2025 ASCO Annual Meeting". Arvinas. 23 April 2025. Retrieved 17 September 2025.
  12. 1 2 Gough, Sheryl M.; Flanagan, John J.; Teh, Jimmy (15 August 2024). "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". Clinical Cancer Research. 30 (16): 3549–3562. doi:10.1158/1078-0432.CCR-23-3465. PMC 11325148. PMID 38819400.
  13. ↑ "FDA Grants Fast Track Status to Vepdegestrant for ER+/HER2– Metastatic Breast Cancer". Oncology Live. 6 February 2024. Retrieved 17 September 2025.
  14. ↑ "Vepdegestrant Gains FDA Fast Track Designation in ER+/HER2- Breast Cancer". Targeted Oncology. 6 February 2024. Retrieved 17 September 2025.
  15. ↑ "Arvinas Announces Submission of New Drug Application to U.S. FDA for Vepdegestrant for Patients with ESR1-Mutated ER+/HER2- Advanced or Metastatic Breast Cancer" (Press release). Arvinas. 24 June 2025. Retrieved 17 September 2025.
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