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

Next-Generation Proteolysis-Targeting Chimeras in Precision Oncology: Multifunctional Designs, Emerging Modalities, and Translational Prospects in Targeted Protein Degradation. (PubMed, Drug Dev Res) - "Furthermore, ARV-110 and ARV-471, as two representative PROTACs, have entered clinical trials, suggesting their potentially broader application. Accordingly, this review provides a critical overview of the design rationales, molecular mechanisms of action, therapeutic utilities, and synthetic issues associated with these innovative modalities, focusing on on their translational implication and pharmacokinetic limitations, as well as potential future clinical applications."

Journal • Review • Oncology • Targeted Protein Degradation

Circulating tumor DNA (ctDNA) biomarker analyses of a phase 1/2 study evaluating vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in ER-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC) (SABCS 2025) - P1/2, P3 | "In a subsequent phase 3 trial (VERITAC-2, NCT05654623), vepdegestrant demonstrated statistically significant and clinically meaningful improvement in progression-free survival vs fulvestrant among pts with previously treated ER+/HER2- aBC and ESR1 mutations (ESR1m). Patients with higher baseline ESR1m VAF/TF, a likely indicator of ESR1m clonality, had better clinical outcomes with vepdegestrant than pts with lower ESR1m VAF/TF. Greater decreases in ctDNA TF after 1 cycle of treatment were associated with increased likelihood of achieving clinical benefit. Overall, these exploratory biomarker analyses provide potentially clinically useful insights on pt responses to vepdegestrant and add to a growing body of evidence on the use of ctDNA in decisions around treatment continuation for pts with ER+/HER2- aBC."

Biomarker • Circulating tumor DNA • Metastases • P1/2 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 • ER • HER-2

I- SPY2 Endocrine Optimization Pilot (EOP): Neoadjuvant vepdegestrant monotherapy or in combination with letrozole or abemaciclib in molecularly selected patients with stage 2/3 HR+ HER2-negative breast cancer (BC) (SABCS 2025) - "Six months of neoadjuvant vepdegestrant, alone or in combination with letrozole or abemaciclib, is feasible and demonstrates robust ER/PR degradation. Encouraging anti-tumor activity through reduction of Ki67 and MRI FTV, ctDNA clearance, and achievement of BCS was seen in pre- and postMN women. The neoadjuvant setting provides a rich platform to identify the dynamic range of response and non-response using a multi-modal approach and can be leveraged to inform future trial design and adjuvant therapy."

Clinical • Combination therapy • Monotherapy • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Dauntless-1: A Phase 2 Clinical Trial to Evaluate PMD-026, a First-in-Class Pan-RSK Inhibitor, Combined with Fulvestrant to Overcome Resistance to CDK4/6 Inhibitors in Advanced or Metastatic HR+/HER2- Breast Cancer (SABCS 2025) - P1/2 | "In addition, PMD-026 inhibits the nuclear translocation of RSK2 (with no change to levels of nuclear ERα), reduces ERα transcription as a single agent equal to or better than fulvestrant or elacestrant, and synergizes with fulvestrant, oral selective estrogen receptor degraders (SERDs) or vepdegestrant to substantially inhibit tumor growth in CDK4/6i sensitive and resistant models. RSK2 is highly expressed in most front-line mBC patients receiving CDK4/6i + ET therapy. PMD-026 inhibits ER signalling and is highly synergistic with fulvestrant in preclinical studies, the translation of which into potentially meaningful clinical benefit is being explored in the Dauntless-1 study."

Clinical • Metastases • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PIK3CA • RPS6KA3 • TP53

Subgroup analyses of VERITAC-2: A phase 3 trial of vepdegestrant, a PROTAC estrogen receptor (ER) degrader, versus fulvestrant in ER-positive/ human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC) (SABCS 2025) - P3 | "Vepdegestrant demonstrated PFS benefit compared with fulvestrant across all prespecified, clinically relevant subgroups of previously treated pts with ESR1m ER+/HER2- aBC. These analyses provide further information in key prognostic patient subgroups that may inform clinical treatment decisions for pts with ESR1m.NE=not estimable."

Metastases • P3 data • 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 • AKT1 • ER • HER-2 • PIK3CA • PTEN

A phase 1/2 trial evaluating the safety, tolerability, and efficacy of the KAT6 inhibitor, PF-07248144, in combination with vepdegestrant in patients with ER+/HER2− locally advanced or metastatic breast cancer (SABCS 2025) - P1 | "Patients may have received fulvestrant. Primary endpoints are dose-limiting toxicities (Part 1E only), safety, and tolerability. Secondary endpoints include pharmacokinetics of PF-07248144 and vepdegestrant in both Parts 1E and 2E, and best overall response, duration of response, clinical benefit rate, progression-free survival, time to progression, and overall survival in Part 2E."

Clinical • Combination therapy • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • KAT6A • KAT6B

Vepdegestrant Overcomes Endocrine and CDK4/6i Resistance to Enhance Radiosensitivity in ESR1 mutant ER+ Breast Cancer (SABCS 2025) - "Given this synergy, we hypothesized that targeted ER degradation using Vepdegestrant (ARV-471), a potent PROTAC-based ER degrader, would further augment radiosensitization in models resistant to CDK4/6 inhibition and endocrine therapy.We evaluated ARV-471 in ER⁺ breast cancer cell lines, including wild-type MCF-7, tamoxifen-resistant ESR1 Y537S-mutant MCF-7, and CDK4/6i-resistant variants, with and without radiation. ARV-471 effectively radiosensitizes ER⁺ breast cancer cells, including ERi and CD4/6i resistant models, through ER degradation and disruption of DNA repair mechanisms, overcoming critical resistance to endocrine therapy and CDK4/6 inhibitors. Building upon prior evidence of radiosensitization achieved by combined ER and CDK4/6i inhibition, these findings highlight ER degradation as a potentially effective therapeutic approach to enhance radiotherapy efficacy in resistant ER⁺ breast cancer, addressing an unmet clinical need, especially in women with..."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CD4 • CDK4 • ER

Dual-drug codelivery gelatin-based hydrogel of ARV-471 and Palbociclib enhances synergistic effect in breast cancer treatment. (PubMed, Sci Rep) - No abstract available

Journal • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Oncology • Solid Tumor

Arvinas Announces Data Presentations from the Vepdegestrant (ARV-471) Clinical Development Program at the 2025 San Antonio Breast Cancer Symposium (SABCS) (GlobeNewswire)

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

A Study to Learn How the Body Processes the Study Medicine Called Vepdegestrant in People With Loss of Liver Function (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Pfizer

New P1 trial • Hepatology

Vepdegestrant in Advanced Breast Cancer. Reply. (PubMed, N Engl J Med) - No abstract available

Journal • Breast Cancer • Oncology • Solid Tumor

Vepdegestrant in Advanced Breast Cancer. (PubMed, N Engl J Med) - No abstract available

Journal • Breast Cancer • Oncology • Solid Tumor

PROTAC: a revolutionary technology propelling small molecule drugs into the next golden age. (PubMed, Front Oncol) - "Recent clinical studies on compounds such as ARV-471 have yielded encouraging results, validating the efficacy of this approach. Over the past decade, PROTAC technology has garnered widespread attention in biomedicine for its promise in developing novel targeted therapies. This review will elucidate the broad therapeutic prospects and future challenges of PROTACs by detailing their mechanism of action, recent advances, progress in targeted therapy research, and current clinical trial landscape."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Targeted Protein Degradation

Vepdegestrant in Advanced Breast Cancer. (PubMed, N Engl J Med) - No abstract available

Journal • Breast Cancer • Oncology • Solid Tumor

Announced agreement with Pfizer to jointly select a third party for the commercialization and potential further development of vepdegestrant (Arvinas Press Release)

Commercial • Estrogen Receptor Positive Breast Cancer • HER2 Negative 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 | Trial completion date: Nov 2025 ➔ Apr 2026 | Trial primary completion date: Nov 2025 ➔ Apr 2026

Trial completion date • Trial primary completion date • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

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) - P2 | "Conclusions Neoadjuvant vepdegestrant was well tolerated and demonstrated biological and clinical activity in postmenopausal women with ER+/HER2- localized BC. Vepdegestrant led to robust ER protein degradation in tumor tissue, supporting its pharmacodynamic effect in pts with BC."

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

Vepdegestrant, a PROteolysis Targeting Chimera (PROTAC) estrogen receptor (ER) degrader, induces greater ER degradation and antitumor activity relative to selective ER degraders (SERDs) in preclinical ER+ breast cancer models (AACR-NCI-EORTC 2025) - "Here, we report preclinical ER degradation and antitumor activity of vepdegestrant compared with FDA-approved (fulvestrant and elacestrant) and investigational oral SERDs (giredestrant, camizestrant, amcenestrant, and imlunestrant). Our results indicate that vepdegestrant induces greater maximal ER degradation than investigational oral SERDs, elacestrant, or fulvestrant in WT ER+ breast cancer cell lines. Vepdegestrant also demonstrated greater TGI and ER degradation in vivo compared with fulvestrant in a WT ER+ breast cancer CDX model."

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

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) - P3 | "VEP demonstrated numeric benefit in TTDD vs FUL across all scales calculated, with statistically significant differences in TTDD in pain and HRQoL (including role, cognitive, emotional, and social functioning, as well as overall QoL/health status); key PROs are shown in the Table. Table: 489MO Scale TTDD Median, mo VEP vs FUL Hazard ratio (95% CI) VEP n=127 FUL n=129 HRQoL/Functioning EORTC QLQ-C30 Global health status 12.0 4.8 0.60 (0.40–0.91)* Functioning Physical 14.4 NR 0.79 (0.50–1.26) Role 14.0 5.7 0.64 (0.42–0.97)* Cognitive 12.0 10.9 0.53 (0.33–0.84)* Emotional 14.4 NR 0.57 (0.35–0.93)* Social 14.0 4.7 0.52 (0.34–0.81)* EQ-5D-5L VAS 9.2 5.8 0.59 (0.39–0.89)* Symptoms BPI-SF Worst pain NR NR 0.49 (0.29–0.83)* Pain severity NR NR 0.55 (0.31–0.97)* Pain interference 14.4 NR 0.57 (0.32–1.00)* EORTC QLQ-C30 Pain 9.5 4.6 0.64 (0.43–0.96)* Fatigue 15.6 4.7 0.71 (0.47–1.06) Nausea/vomiting 15.8 NR 0.74 (0.43–1.29) Dyspnea 17.0 NR 0.56 (0.34-0.92)* *Log-rank test P..."

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

Patient-Reported Outcomes from VERITAC-2 Clinical Trial Support Clinical Benefit of Vepdegestrant in Patients with ESR1-Mutated, ER+/HER2- Advanced or Metastatic Breast Cancer Previously Treated with Endocrine-Based Therapy (The Manila Times) - "In patients with ESR1-mutated disease, vepdegestrant demonstrated a reduced risk of deterioration compared to fulvestrant which was statistically significant in several PRO domains including overall health status, pain severity, and functioning (including role, cognitive, emotional, and social functioning), and vepdegestrant consistently showed reduced risk of deterioration versus fulvestrant across all PRO domains."

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

Erika Hamiltoon: TACTIVE-N – Vepdegestrant vs. Anazstrazole at ESMO25 (OncoDaily) - "...'Tumor at baseline, wk 2, and at surgery (6mo). Comparable results- Ki-67 declines by about 70% at 2 wks and further ~ 80% at surgery for both drugs. 100% PgR H score decline with vepdeg'."

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

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: Aug 2025 ➔ Nov 2025

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

Arvinas to Present Data from the Vepdegestrant Clinical Development Program at the 2025 European Society for Medical Oncology (ESMO) Congress (The Manila Times) - "Ongoing studies are also evaluating vepdegestrant as a monotherapy and as part of combination therapy for ER+/HER2- breast cancer."

Clinical data • Patient reported outcomes • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Pfizer Highlights Momentum in Redefining Standards of Care in Cancer at ESMO 2025 (Pfizer Press Release) - "Data from more than 45 company-sponsored, investigator-sponsored, and collaborative research abstracts, including 11 oral/mini oral presentations and five late-breaking sessions, will be presented across Pfizer’s core scientific modalities and key tumor areas."

Clinical data • Bladder Cancer • Colorectal Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Hormone Sensitive Prostate Cancer • Non Small Cell Lung Cancer • Squamous Cell Carcinoma of Head and Neck • Urothelial Cancer

Proteolysis-Targeting Chimera (PROTAC): Current Applications and Future Directions. (PubMed, MedComm (2020)) - "We evaluate clinical progression of breakthrough candidates such as ARV-110 for prostate cancer, ARV-471 for breast cancer, and BTK degraders, while discussing critical challenges including the "hook effect" and oral bioavailability limitations. This review provides essential foundations for rational target selection, molecular optimization, and clinical translation strategies. By integrating mechanistic insights with clinical realities, this analysis offers perspectives on PROTAC technology advancement and identifies opportunities for transforming treatment of complex diseases resistant to conventional therapies."

Journal • Review • Breast Cancer • Genito-urinary Cancer • Hormone Receptor Breast Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • KRAS • STAT3