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

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

VERITAC-3: A Study of Vepdegestrant (ARV-471, PF-07850327) Plus Palbociclib Versus Letrozole Plus Palbociclib in Participants With Estrogen Receptor Positive, Human Epidermal Growth Factor Negative Advanced Breast Cancer (clinicaltrials.gov) - P3 | N=59 | Active, not recruiting | Sponsor: Pfizer | N=1180 ➔ 59 | Trial completion date: Jul 2030 ➔ Dec 2026 | Trial primary completion date: Aug 2028 ➔ Dec 2026

Enrollment change • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Neutropenia • Oncology • Solid Tumor • ER • HER-2

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 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open

PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor Degraders for Treatment of Estrogen Receptor-Positive Advanced Breast Cancer. (PubMed, Target Oncol) - "Preclinical data demonstrate increased tumor growth inhibition with vepdegestrant alone or in combination with CDK4/6 inhibitors compared with the selective ER degrader fulvestrant. In a first-in-human phase 1/2 clinical study, vepdegestrant administered orally as monotherapy or in combination with palbociclib showed promising clinical activity and a favorable safety profile in patients with heavily pretreated ER+/HER2- advanced breast cancer. Several other PROTAC ER degraders (AC699, ERD-3111, ERD-4001, and HP568) are in early development and have demonstrated activity in preclinical breast cancer models, with some recently entering clinical trials. The data highlight the potential for PROTAC ER degraders to be a new backbone therapy in breast cancer."

Journal • Review • Breast Cancer • Estrogen Receptor Positive 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 • Targeted Protein Degradation • ER • HER-2

TACTIVE-K: A Study to Learn About Vepdegestrant When Given With PF-07220060 to People With Advanced or Metastatic Breast Cancer. (clinicaltrials.gov) - P1/2 | N=65 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting

Enrollment closed • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Anticipated Upcoming Milestones and Expectations (GlobeNewswire) - "Share data with global regulatory authorities to potentially support regulatory filings (2Q 2025) and submit new drug application to the U.S. Food and Drug Administration for potential approval (2H 2025); Add a combination cohort of vepdegestrant plus Pfizer’s KAT6 inhibitor (PF-07248144) to Pfizer’s ongoing Phase 1 trial (NCT04606446)....ARV-806: Novel PROTAC KRAS G12D degrader: Initiate a first-in-human Phase 1 trial in patients with solid tumors harboring KRAS G12D mutations (2H 2025)."

FDA filing • Filing • New P1 trial • Trial status • Solid Tumor

HP568, a highly potent and orally bioavailable ER PROTAC for breast cancer treatment, currently undergoing phase 1/2 clinical studies (AACR 2025) - P1/2 | "In direct efficacy comparisons with ARV-471, HP568 shows superior, dose-dependent tumor growth inhibition (TGI) of 90%-123%, well correlated with drug exposure and pharmacodynamic biomarkers. Importantly, in models resistant to fulvestrant, including MCF-7 ERα D538G and Y537S cell-derived CDX mice, it demonstrates significant dose-dependent TGI (29%-115%) while maintaining favorable safety profiles...The Phase 1 dose escalation part of the study is assessing safety, pharmacokinetics, pharmacodynamics, preliminary antitumor activity, and potential efficacy biomarkers. The Phase 2 expansion will evaluate HP568 both as a monotherapy and in combination with a CDK4/6 inhibitor.HP568 structure will not be disclosed."

Clinical • Late-breaking abstract • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Discovery of a highly potent and orally bioavailable ER PROTAC degrader for the treatment of breast cancer (AACR 2025) - "A promising therapeutic strategy to overcome endocrine resistance in ER+ breast cancer is the development of ER degraders using the proteolysis targeting chimera (PROTAC) technology.Facilitated by our new cereblon ligand library, we have discovered a potent and orally bioavailable ER PROTAC degrader GLR203801, with its binding affinity to cereblon increased by 20-fold than that of ARV-471. GLR203801 also effectively inhibited the viability of breast-cancer patient derived ER+ organoids. The good tolerance of GLR203801 in toxicity study both in SD rats and beagle dogs supports it as a promising preclinical candidate for further clinical development."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CRBN • ER

Arvinas Announces Results from the VERITAC-2 Trial Selected as Late-Breaking Oral Presentation at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting (GlobeNewswire) - "Arvinas, Inc...today announced that data from the global Phase 3 VERITAC-2 clinical trial...evaluating vepdegestrant versus fulvestrant in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer will be presented as a late-breaking oral presentation at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 30 – June 3 in Chicago, IL. The presentation includes the first pivotal data for vepdegestrant, a potential first-in-class investigational oral PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader."

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

A comprehensive mechanistic investigation of factors affecting intestinal absorption and bioavailability of two PROTACs in rats. (PubMed, Eur J Pharm Biopharm) - "In the rat, ARV-110 and ARV-471 were enzymatically degraded in the intestinal lumen and in plasma, and their intestinal permeability and systemic exposure seem to be reduced due to P-gp efflux."

Journal • Preclinical • Gastrointestinal Disorder • Targeted Protein Degradation

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 | Not yet recruiting | Sponsor: Pfizer

New P1 trial

Vepdegestrant for the treatment of HR+/HER2- breast cancer. (PubMed, Expert Opin Pharmacother) - "The results of the phase III VERITAC-2 study, comparing vepdegestrant with fulvestrant, are expected to be available in 2025, and will provide the first data on the true clinical significance of vepdegestrant. Several phase III studies of combinations with vepdegestrant including + atirimociclib (a cyclin-dependent kinase 4 inhibitor) have been or are planned to be conducted. The results of these may not only transform the treatment landscape for advanced HR+/HER2- breast cancer but may pave the way for PROTAC as a new class of anti-cancer drugs that may make previously undruggable targets druggable."

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

Analysis of the Main Directions in the Development of Mono and Combination Pharmacotherapy Acting on Hormonal Signaling Pathways of Breast Cancer According to the FDA Databases and Clinicaltrials.gov. (PubMed, Curr Med Chem) - "It is evident that traditional endocrine treatments play a pivotal role in the management of HR+ BC. However, the emergence of resistance necessitates the development of novel therapeutic strategies. These strategies should be based on pharmacokinetics, further investigation of the molecular signaling pathways of BC, such as new SERMs, SERDs, PROTACs, as well as new drug groups, like SERCAs, CERANs, SHERPAs. Combination therapy represents the most promising avenue for BC treatment. While PROTAC combination with new monotherapeutic agents for BC treatment has yet to be investigated, we believe that such combinations have the potential to make the treatment more selective, effective, and personalised in the future."

Journal • Breast Cancer • Endocrine Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CDK4

Conquering PROTAC molecular design and drugability. (PubMed, Bioanalysis) - "Clinical successes, including ARV-110 for castration-resistant prostate cancer and ARV-471 for breast cancer, exemplify their ability to overcome resistance and provide durable effects. By addressing challenges in pharmacokinetics, safety, and scalability, PROTACs are poised to revolutionize precision medicine. This article presents a forward-looking perspective on conquering the molecular design and drugability of PROTACs, paving the path for transformative therapies."

Journal • Breast Cancer • Castration-Resistant Prostate Cancer • CNS Disorders • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation

Arvinas and Pfizer Announce Positive Topline Results from Phase 3 VERITAC-2 Clinical Trial (GlobeNewswire) - P3 | N=624 | VERITAC-2 (NCT05654623) | Sponsor: Pfizer | "The trial met its primary endpoint in the estrogen receptor 1-mutant (ESR1m) population, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to fulvestrant. The results exceeded the pre-specified target hazard ratio of 0.60 in the ESR1m population. The trial did not reach statistical significance in improvement in PFS in the intent-to-treat (ITT) population....Overall survival was not mature at the time of the analysis, with less than a quarter of the required number of events having occurred. The trial will continue to assess overall survival as a key secondary endpoint....Detailed results from VERITAC-2 will be submitted for presentation at a medical meeting later this year, and these data will be shared with global regulatory authorities to potentially support regulatory filings."

P3 data: top line • Breast Cancer