Vepdegestrant

Vepdegestrant
Clinical data
Pronunciation/ˌvɛpdəˈdʒɛstrənt/
VEP-də-JES-trənt
Trade namesVeppanu
Other namesARV-471
AHFS/Drugs.comMonograph
MedlinePlusa626067
License data
Routes of
administration		By mouth
Drug classEstrogen receptor antagonist
ATC code
  • None
Legal status
Legal status
Identifiers
  • (3S)-3-[6-[4-[[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
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC45H49N5O4
Molar mass723.918 g·mol−1
3D model (JSmol)
  • 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=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, sold under the brand name Veppanu, is an anti-cancer medication used for the treatment of breast cancer.[1][3] It is a heterobifunctional protein degrader.[1][3] It was developed by Arvinas and Pfizer.[4] It is taken by mouth.[1][3]

Vepdegestrant was approved for medical use in the United States in May 2026.[3]

Medical uses

Veppanu is indicated for the treatment of adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 (ESR1)-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy.[1][3][5]

Adverse effects

The US prescribing information includes warnings and precautions for QTc interval prolongation and embryo-fetal toxicity.[1][3]

Mechanism of action

Vepdegestrant is designed as a PROTAC that recruits the ubiquitin-proteasome system to target the estrogen receptor for degradation.[6] 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.[7] In laboratory studies, vepdegestrant demonstrated ER degradation in ER-positive breast cancer cell lines with reported DC50 values of approximately 1-2 nM.[8]

History

Efficacy was evaluated in VERITAC-2 (NCT05654623), a randomized, open-label, active-controlled, multi-center trial in 624 adults with ER-positive, HER2-negative, advanced or metastatic breast cancer, of whom 270 had tumors carrying ESR1 mutations.[3] Participants were required to have disease progression on one to two lines of endocrine therapy, including one line with a CDK4/6 inhibitor.[3] Participants were randomized (1:1) to receive vepdegestrant orally once daily, or fulvestrant intramuscularly on days 1 and 15 of cycle 1 and then once monthly thereafter.[3] Randomization was stratified by ESR1 mutation status and visceral metastasis.[3] ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid (ctDNA) using central or local testing.[3]

Phase I/II trials

Vepdegestrant has been evaluated in early-phase clinical trials as both monotherapy and in combination with other agents in participants 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 participants.[9]

Phase III VERITAC-2 trial

The Phase III VERITAC-2 trial (NCT05654623) is a randomized, open-label study comparing vepdegestrant to fulvestrant in participants with ER+/HER2- advanced breast cancer.[10] The trial enrolled 624 participants at sites in 26 countries who had previously received treatment with a CDK4/6 inhibitor plus endocrine therapy.[11]

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.[11] However, the trial did not achieve statistical significance in the overall intent-to-treat population.[12] Detailed results were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.[13]

In the Phase III VERITAC-2 trial, vepdegestrant demonstrated a 43% reduction in the risk of disease progression or death versus fulvestrant in the ESR1-mutant subgroup. It extended median progression-free survival to 5.0 months from 2.1 months.[14]

Preclinical studies

In preclinical studies, vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved tumor growth inhibition (TGI).[15] 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.[15]

Society and culture

The US 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.[16][17]

Vepdegestrant was approved for medical use in the United States in May 2026.[3][18]

Names

Vepdegestrant is the international nonproprietary name.[19]

Vepdegestrant is sold under the brand name Veppanu.[3]

References

  1. 1 2 3 4 5 6 "Veppanu- vepdegestrant tablet". DailyMed. 1 May 2025. Retrieved 1 August 2026.
  2. ↑ "Veppanu- vepdegestrant tablet, film coated". DailyMed. 12 June 2026. Retrieved 1 August 2026.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 "FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer". U.S. Food and Drug Administration (FDA). 1 May 2026. Retrieved 5 May 2026. Public Domain This article incorporates text from this source, which is in the public domain.
  4. ↑ "Arvinas, Pfizer reworking partnership on 'Protac' cancer drug". BioPharma Dive. Retrieved 17 September 2025.
  5. ↑ "Novel Drug Approvals for 2026". U.S. Food and Drug Administration (FDA). 1 May 2026. Retrieved 5 May 2026. Public Domain This article incorporates text from this source, which is in the public domain.
  6. ↑ "Estrogen Receptor". Arvinas. Retrieved 17 September 2025.
  7. ↑ 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.
  8. ↑ "Vepdegestrant (ARV-471) PROTAC ER Degrader". MedChemExpress. Retrieved 17 September 2025.
  9. ↑ 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.
  10. ↑ "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.
  11. 1 2 "Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial". Arvinas. Retrieved 17 September 2025.
  12. ↑ "VERITAC-2 Trial Shows Vepdegestrant Significantly Improves Survival in ESR1-Mutant Breast Cancer". Applied Clinical Trials Online. 24 March 2025. Retrieved 17 September 2025.
  13. ↑ "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.
  14. ↑ Campone M, De Laurentiis M, Jhaveri K, Hu X, Ladoire S, Patsouris A, et al. (7 August 2025). "Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer". New England Journal of Medicine. 393 (6): 556–568. doi:10.1056/NEJMoa2505725. PMID 40454645.
  15. 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.
  16. ↑ "FDA Grants Fast Track Status to Vepdegestrant for ER+/HER2– Metastatic Breast Cancer". Oncology Live. 6 February 2024. Retrieved 17 September 2025.
  17. ↑ "Vepdegestrant Gains FDA Fast Track Designation in ER+/HER2- Breast Cancer". Targeted Oncology. 6 February 2024. Retrieved 17 September 2025.
  18. ↑ "Arvinas Announces FDA Approval of Veppanu (vepdegestrant) for the Treatment of ESR1m, ER+/HER2- Advanced Breast Cancer". Arvinas (Press release). Retrieved 5 May 2026.
  19. ↑ World Health Organization (2023). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 89". WHO Drug Information. 37 (1). hdl:10665/366661.

Further reading

  • Clinical trial number NCT05654623 for "A Study to Learn About a New Medicine Called Vepdegestrant (ARV-471, PF-07850327) in People Who Have Advanced Metastatic Breast Cancer (VERITAC-2)" at ClinicalTrials.gov
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