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Vepdegestrant

Topic: Chemistry

 From HandWiki - Reading time: 5 min

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.; Mori, Y.; Yoshimitsu, J. 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. 
  2. ↑ Iwata, H.; Hamilton, E.P.; Ma, C.X.; De Laurentiis, M.; Hurvitz, S.A.; Wander, S.A.; Danso, M.A.; Lu, D.R. 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. 
  3. ↑ "Arvinas, Pfizer reworking partnership on 'Protac' cancer drug | BioPharma Dive" (in en-US). https://www.biopharmadive.com/news/arvinas-pfizer-vepdegestrant-partnership-rework-breast-cancer/757043/. 
  4. ↑ "Estrogen Receptor". https://www.arvinas.com/research-and-development/estrogen-receptor/. 
  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. PMID 35046570. 
  6. ↑ "Vepdegestrant (ARV-471) PROTAC ER Degrader". https://www.medchemexpress.com/vepdegestrant.html. 
  7. ↑ Hamilton, Erika P.; Ma, Cynthia; De Laurentiis, Michelino; Iwata, Hiroji; Hurvitz, Sara A.; Wander, Seth A.; Danso, Michael; Lu, Dongrui R. 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. 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). 30 June 2025. https://clinicaltrials.gov/study/NCT05654623. Retrieved 17 September 2025. 
  9. ↑ 9.0 9.1 "Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial". https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizer-announce-positive-topline-results-phase-3/. 
  10. ↑ "VERITAC-2 Trial Shows Vepdegestrant Significantly Improves Survival in ESR1-Mutant Breast Cancer". 24 March 2025. https://www.appliedclinicaltrialsonline.com/view/veritac-trial-vepdegestrant-survival-esr1-mutant-breast-cancer. 
  11. ↑ "Arvinas Announces Results from the VERITAC-2 Trial Selected as Late-Breaking Oral Presentation at the 2025 ASCO Annual Meeting". 23 April 2025. https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-results-veritac-2-trial-selected-late-breaking. 
  12. ↑ 12.0 12.1 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. PMID 38819400. 
  13. ↑ "FDA Grants Fast Track Status to Vepdegestrant for ER+/HER2– Metastatic Breast Cancer". 6 February 2024. https://www.onclive.com/view/fda-grants-fast-track-status-to-vepdegestrant-for-er-her2-metastatic-breast-cancer. 
  14. ↑ "Vepdegestrant Gains FDA Fast Track Designation in ER+/HER2- Breast Cancer". 6 February 2024. https://www.targetedonc.com/view/vepdegestrant-gains-fda-fast-track-designation-in-er-her2--breast-cancer. 
  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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