vepdegestrant (ARV-471) / Arvinas, Pfizer - LARVOL DELTA

Arvinas Announces FDA Acceptance of the New Drug Application for Vepdegestrant for the Treatment of ESR1m, ER+/HER2- Advanced Breast Cancer (GlobeNewswire) - "Arvinas...with its partner Pfizer...announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for vepdegestrant for the treatment of patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), ESR1-mutated advanced or metastatic breast cancer who have previously received endocrine-based therapy. The FDA has assigned a Prescription Drug User Fee Act (PDUFA) action date of June 5, 2026....The NDA submission was based on data from VERITAC-2 (NCT05654623), a global, randomized Phase 3 clinical trial evaluating vepdegestrant versus fulvestrant."

FDA filing • PDUFA • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

TACTIVE-U Sub-Study B: TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer (Sub-Study B) (clinicaltrials.gov) - P1/2 | N=20 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=47 ➔ 20

Enrollment change • Enrollment closed • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • HER-2

Arvinas Reports Second Quarter 2025 Financial Results and Provides Corporate Update (GlobeNewswire) - "As part of Arvinas’ global collaboration with Pfizer, the companies plan to: Continue market preparations for vepdegestrant in advance of the PDUFA action date. Revise our vepdegestrant collaboration with Pfizer with the goal of maximizing the value of vepdegestrant. Present patient reported outcomes data from the VERITAC-2 clinical trial evaluating vepdegestrant versus fulvestrant for previously treated patients with ESR1 mutated- ER+/HER2- advanced or metastatic breast cancer at the European Society for Medical Oncology 2025 Congress (October 2025). Present results of the TACTIVE-N trial, a Phase 2 clinical trial of neoadjuvant vepdegestrant, in a mini oral session at European Society for Medical Oncology 2025 Congress (ClinicalTrials.gov Identifier: NCT05549505) (October 2025)."

Commercial • P2 data • P3 data • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Arvinas Reports Second Quarter 2025 Financial Results and Provides Corporate Update (GlobeNewswire) - "Added a combination cohort of vepdegestrant plus Pfizer’s KAT6 inhibitor (PF-07248144) to Pfizer’s ongoing Phase 1 clinical trial (ClinicalTrials.gov Identifier: NCT04606446)....ARV-393: Oral PROTAC BCL6 degrader: Continued recruiting patients in the first-in-human Phase 1 clinical trial in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) (ClinicalTrials.gov Identifier: NCT06393738)....ARV-806: Novel PROTAC KRAS G12D degrader: Initiated enrollment in the Phase 1 clinical trial evaluating ARV-806 in patients with solid tumors harboring KRAS G12D mutations (ClinicalTrials.gov Identifier: NCT07023731)."

Trial status • Castration-Resistant Prostate Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Solid Tumor

Patient-reported outcomes (PROs) with vepdegestrant (VEP) vs fulvestrant (FUL) in patients (pts) with estrogen receptor (ER) 1 gene mutated (ESR1m) ER+/human epidermal growth factor receptor 2 (HER2)− advanced breast cancer (aBC) in the phase 3 VERITAC-2 trial (ESMO 2025) - No abstract available

Clinical • Metastases • P3 data • Patient reported outcomes • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

TACTIVE-N: phase 2 study of neoadjuvant vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, or anastrozole in postmenopausal ER+/human epidermal growth factor receptor 2 (HER2)- localized breast cancer (BC) (ESMO 2025) - No abstract available

Clinical • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

PROTAC SERD vepdegestrant outperforms fulvestrant for advanced-stage ER+HER2- breast cancer harbouring acquired ESR1 mutations. (PubMed, Nat Rev Clin Oncol) - No abstract available

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ER • HER-2

NDA Submission of Vepdegestrant (ARV-471) to U.S. FDA: The Beginning of a New Era of PROTAC Degraders. (PubMed, J Med Chem) - No abstract available

Journal • NDA • Targeted Protein Degradation

Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomized, phase 3 VERITAC-2 study. (BASCO-MN 2025) - No abstract available

Clinical • Late-breaking abstract • Metastases • P3 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ER • HER-2

Advancing Predictions of Oral Drug Absorption, CYP3A4 Induction, and Transporter-Mediated Interactions Using a Human Primary Intestinal 3D Model (EpiIntestinal™). (PubMed, Clin Pharmacol Ther) - "However, PBPK modeling, using EpiIntestinal™ permeability data, accurately predicted the clinical maximum plasma concentration (Cmax) of the P-gp substrates digoxin and dabigatran etexilate, unlike the significant underpredictions from Caco-2 data...Combining induction parameters of rifampicin from EpiIntestinal™ with those from the TruVivo (human hepatic model) into PBPK modeling accurately captured DDI effects on midazolam, a sensitive CYP3A4/5 substrate. Additionally, the model accurately predicted clinical outcomes of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) mediated DDIs for ARV-471. These data underscore the potential of EpiIntestinal™ in predicting human Fa and Fg, and in quantitatively assessing CYP3A4 induction and transporter-based DDIs."

Journal • Breast Cancer • Oncology • Solid Tumor • CYP3A4

A Study to Learn How a Tablet Compared With an IV Infusion of the Study Medicine Called Vepdegestrant is Taken up Into the Blood in Healthy Adults (clinicaltrials.gov) - P1 | N=10 | Completed | Sponsor: Pfizer | Recruiting ➔ Completed

Trial completion

Molecular Design of Novel Protein-Degrading Therapeutics Agents Currently in Clinical Trial. (PubMed, Pharmaceutics) - "For instance, drugs like ARV-471 and ARV-110 are in advanced phases for treating metastatic breast cancer and prostate cancer, respectively, by targeting estrogen and androgen receptors. The conducted trials not only emphasize the therapeutic potential of protein degradation but also highlight the challenges associated with bioavailability, stability, and delivery mechanisms. As these clinical trials advance, they possess the potential to transform treatment paradigms, providing renewed hope for patients facing complex and refractory conditions."

Journal • Review • Breast Cancer • CNS Disorders • Genito-urinary Cancer • Hematological Malignancies • Immunology • Multiple Myeloma • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • AR • IKZF1 • IRAK4

Vepdegestrant: "VERITAC-2 trial in 2L+ ER+ HER2- breast cancer met primary endpoint in ESR1m patients but not in ITT population"; Breast cancer (Pfizer) - A Spotlight on Pfizer's Breast Cancer Portfolio

P3 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Oncology

Targeting the Undruggable: Recent Progress in PROTAC-Induced Transcription Factor Degradation. (PubMed, Cancers (Basel)) - "Several clinically advanced PROTACs, including ARV-110 and ARV-471, demonstrate the therapeutic potential of this technology. Despite challenges in pharmacokinetics and E3 ligase selection, emerging data suggest that PROTACs can successfully target TFs, paving the way for new treatment strategies across oncology and other disease areas."

Journal • Review • Oncology • Targeted Protein Degradation • AR • BRD4 • CRBN • ER • MYC

Characterization of preclinical radio ADME properties of ARV-471 for predicting human PK using PBPK modeling. (PubMed, J Pharm Anal) - "Furthermore, no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans. This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer. (PubMed, N Engl J Med) - P3 | "Among patients with ER-positive, HER2-negative advanced breast cancer, vepdegestrant was associated with significantly longer progression-free survival than fulvestrant in the subgroup with ESR1 mutations but not in the full patient population. (Funded by Pfizer and Arvinas Estrogen Receptor; VERITAC-2 ClinicalTrials.gov number, NCT05654623.)."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CDK4 • ER • HER-2

Arvinas and Pfizer's Vepdegestrant Significantly Improves Progression-Free Survival for Patients with ESR1-Mutant, ER+/HER2- Advanced Breast Cancer (GlobeNewswire) - P3 | N=624 | VERITAC-2 (NCT05654623) | Sponosr: Pfizer | "Arvinas, Inc...and Pfizer Inc...announced detailed results from the Phase 3 VERITAC-2 clinical trial (NCT05654623)...These data, which were highlighted in the American Society of Clinical Oncology (ASCO)...will be presented today in a late-breaking oral presentation (Abstract LBA1000)...In the trial, vepdegestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) among patients with an estrogen receptor 1 (ESR1) mutation, reducing the risk of disease progression or death by 43% compared to fulvestrant [Hazard Ratio (HR)=0.57 (95% CI 0.42–0.77); 2-sided P<0.001]....The trial did not reach statistical significance in improvement in PFS in the intent-to-treat (ITT) population, with a median PFS of 3.7 months for vepdegestrant versus 3.6 for fulvestrant [HR=0.83 (95% CI 0.68–1.02); 2-sided P=0.07]."

Late-breaking abstract • P3 data • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomized, phase 3 VERITAC-2 study. (ASCO 2025) - P3 | "Vepdegestrant demonstrated statistically significant and clinically meaningful improvement in PFS vs fulvestrant in the ESR1m population. No statistically significant improvement in PFS was observed in the all-pt population. Vepdegestrant was generally well tolerated with low discontinuation rates due to TEAEs."

Clinical • Late-breaking abstract • Metastases • P3 data • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Fatigue • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ER • HER-2

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 (GlobeNewswire) - "Arvinas, Inc...announced the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) with its partner Pfizer Inc...for vepdegestrant for the treatment of patients with ER-positive (ER+)/human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) ESR1-mutated advanced or metastatic breast cancer previously treated with endocrine-based therapy. This submission is based on results from VERITAC-2 (NCT05654623), a global, randomized Phase 3 trial evaluating vepdegestrant versus fulvestrant."

FDA filing • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

C4551001: Study of PF-07248144 in Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1 | N=320 | Recruiting | Sponsor: Pfizer | N=186 ➔ 320 | Trial completion date: Mar 2027 ➔ Jan 2028 | Trial primary completion date: Aug 2025 ➔ Jan 2028

Enrollment change • Trial completion date • Trial primary completion date • Breast Cancer • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Solid Tumor • CDKN2A • ER • HER-2

Sarah Cannon Research Institute to Showcase Cancer Insights at 2025 ASCO Annual Meeting (Businesswire) - "Today, Sarah Cannon Research Institute (SCRI), one of the world’s leading oncology research organizations conducting community-based clinical trials, announced that it will showcase its latest research highlights through more than 155 accepted abstracts and presentations at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago from May 30-June 3, 2025. Over 75 investigators from more than 20 research sites in SCRI’s network are first authors and co-authors on the clinical trial updates featured at the Annual Meeting, including findings from 55 early-phase clinical trials."

Clinical data • Platinum resistant • Biliary Tract Cancer • Colorectal Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Non Small Cell Lung Cancer • Ovarian Cancer • Solid Tumor

Circulating tumor DNA (ctDNA) in patients with stage 2/3 HR+HER2-negative breast cancer (BC) treated with neoadjuvant endocrine therapy (NET) in the I-SPY2 endocrine optimization pilot (EOP) trial. (ASCO 2025) - P2 | "Pts were randomized to one of 7 neoadjuvant-based treatment arms including arms containing AI, Z-endoxifen, Lasofoxifene, vepdegestrant (ARV-471), and Abemaciclib. In this study of pts with Stage 2/3 HR+ HER2- BC with largely MammaPrint low risk signatures, over one-third of pts had detectable ctDNA at baseline. Detectable ctDNA at baseline was associated with cN+ disease, larger FTV, and high baseline Ki67. The majority of pts with positive ctDNA at baseline cleared the ctDNA on NET."

Circulating tumor DNA • Clinical • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

PROTAC Technology as a New Tool for Modern Pharmacotherapy. (PubMed, Molecules) - "Promising results from clinical studies on the compound ARV-471 confirm the effectiveness of this approach. New types of PROTACs, like TF-PROTAC and PhosphoTAC, are designed to enhance the effectiveness, stability, and absorption of treatment drugs. The conclusions of the review highlight the broad therapeutic potential of PROTACs in various diseases and their relevance for the future of therapies, particularly in oncology."

Journal • Review • Alzheimer's Disease • Atherosclerosis • Atopic Dermatitis • Cardiovascular • CNS Disorders • Dermatitis • Dermatology • Human Immunodeficiency Virus • Huntington's Disease • Immunology • Infectious Disease • Movement Disorders • Novel Coronavirus Disease • Oncology • Targeted Protein Degradation

C4891038: A Study to Learn How Different Tablets of the Study Medicine Vepdegestrant Are Taken up Into the Blood in Healthy Adults (clinicaltrials.gov) - P1 | N=12 | Completed | Sponsor: Pfizer | Recruiting ➔ Completed

Trial completion

VERITAC: A Phase 1/2 Trial of ARV-471 Alone and in Combination With Palbociclib (IBRANCE®) in Patients With ER+/HER2- Locally Advanced or Metastatic Breast Cancer (clinicaltrials.gov) - P1/2 | N=217 | Active, not recruiting | Sponsor: Arvinas Estrogen Receptor, Inc. | Trial completion date: Mar 2025 ➔ Aug 2025

Trial completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2