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

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

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 | "Clinical Trial Registration Number: NCT05654623 The abstract will be released to the public on May 31, 2025 at 7:00 AM"

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

C4891024: 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 C) (clinicaltrials.gov) - P1/2 | N=11 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=67 ➔ 11 | Trial completion date: Jan 2027 ➔ Nov 2025 | Trial primary completion date: Jul 2026 ➔ Nov 2025

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Arvinas Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Corporate Update (GlobeNewswire) - "As part of Arvinas global collaboration with Pfizer, the companies plan to: Announce topline data for the VERITAC-2 Phase 3 monotherapy clinical trial evaluating vepdegestrant in patients with ER+/HER2- metastatic breast cancer (mBC) in a topline press release 1Q25 and present full results of the trial at a medical conference in 2025. Initiate two new Phase 3 combination trials in patients with ER+/HER2- mBC (pending emerging data and regulatory feedback) in 2025...With the prioritization of the vepdegestrant plus atirmociclib combination for the first-line setting, the VERITAC-3 Phase 3 clinical trial evaluating vepdegestrant plus palbociclib in the first-line will not proceed beyond the study lead-in."

New P3 trial • P3 data: top line • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Arvinas Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Corporate Update (GlobeNewswire) - "As part of Arvinas global collaboration with Pfizer, the companies plan to: Continue to collect safety and efficacy data from ongoing TACTIVE-U sub-studies evaluating combination of vepdegestrant with abemaciclib, ribociclib, or samuraciclib (ClinicalTrials.gov Identifiers: NCT05548127, NCT05573555, and NCT06125522) and submit key data for presentation at medical conference. Continue enrollment in the Phase 2 TACTIVE-K clinical trial (atirmociclib + vepdegestrant) and submit initial Phase 1b data for presentation at a medical conference."

P1 data • P1/2 data • Breast Cancer

A Study to Learn About the Study Medicine Called Vepdegestrant (ARV-471, PF-07850327) in People With ER+/HER2- Advanced Breast Cancer in China (clinicaltrials.gov) - P1 | N=9 | Completed | Sponsor: Pfizer | Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Unleashing the Power of Covalent Drugs for Protein Degradation. (PubMed, Med Res Rev) - "Two prominent PROTACs, ARV-471 and ARV-110, are currently undergoing phase III and II clinical trials, respectively. The concept of covalent degradation has also been utilized in various new forms of degraders, including covalent molecule glue (MG), in-cell click-formed proteolysis targeting chimera (CLIPTAC), HaloPROTAC, lysosome-targeting chimera (LYTAC) and GlueTAC. This review focuses on recent advancements in covalent degraders beyond covalent PROTACs and examines obstacles and future directions pertinent to this field."

Journal • Review • Oncology • Solid Tumor • Targeted Protein Degradation • BTK • DDB1 • EGFR • KEAP1 • KRAS

Arvinas Updates Guidance for First- and Second-Line Phase 3 Combination Trials with Vepdegestrant, Highlights Upcoming Milestones, and Provides Corporate Update (GlobeNewswire) - "As part of Arvinas’ global collaboration with Pfizer, in 2025 the companies plan to: Announce topline data for the VERITAC-2 Phase 3 monotherapy clinical trial in patients with second-line-plus ER+/HER2- metastatic breast cancer (mBC) (1Q25). Initiate two new Phase 3 combination trials in patients with ER+/HER2- mBC (pending emerging data and regulatory feedback): First-line Phase 3 combination trial with Pfizer’s novel investigational CDK4 inhibitor, atirmociclib. Second-line Phase 3 combination trial with a CDK4/6 inhibitor. With the prioritization of the vepdegestrant plus atirmociclib combination for the first-line setting, the VERITAC-3 trial evaluating vepdegestrant plus palbociclib in the first-line will not proceed beyond the study lead-in."

New P3 trial • P3 data: top line • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

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

Enrollment open

PRISM high-throughput screening to elucidate how tumor microenvironments modulate drug responses of breast cancer cells (SABCS 2024) - "Media filtering reduced the drug effects of fulvestrant but not ARV-471, suggesting that ARV-471 efficacy may be less sensitive to the tumor microenvironment than fulvestrant. Lapatinib (HER2/neu and EGF receptor inhibitor) was more effective in killing HER2+ than HER2- negative breast cancer cells, with cells cultured in EGF-spiked media being more sensitive to lapatinib, whereas media filtration diminished its effects. We did not observe breast cancer subgroup specific killing by alpelisib (PI3K inhibitor) or olaparib (PARP inhibitor), but breast cancer cells became less sensitive to alpelisib when cultured in either insulin- or EGF-spiked media, and less sensitive to olaparib in EGF-spiked media. Overall, our study highlights how the PRISM 900+ cell panel can provide insights into drug specificity, cancer subtype selectivity, and to uncover clinically relevant targets. The breast cancer specific pool can further increase the throughput of understanding how drug..."

Biomarker • Tumor microenvironment • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Oncology • Solid Tumor • ABCB1 • ER

Vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor (ER) Degrader, Plus Abemaciclib in ER-Pos/Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced or Metastatic Breast Cancer: TACTIVE-U Prelim Phase 1b Results (SABCS 2024) - P1/2 | "All pts (100%) received prior CDK4/6 inhibitors (ribociclib [n=8], palbociclib [n=7], and abemaciclib [n=1]), 14 (88%) prior aromatase inhibitors, 11 (69%) prior chemotherapy, and 5 (31%) prior fulvestrant. The safety profile of vepdegestrant plus abemaciclib in pts with ER+/HER2- advanced or metastatic breast cancer was generally consistent with the known profiles of each agent, and no DLTs were observed. Neutropenia was manageable with dose modifications. The impact of vepdegestrant on abemaciclib exposure was minor and indicated no significant drug interaction."

Metastases • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2