Veppanu (vepdegestrant) / Arvinas, Pfizer, Rigel Pharmaceuticals - LARVOL DELTA

ARV-471, an estrogen receptor (ER) PROTAC degrader, combined with palbociclib in advanced ER+/human epidermal growth factor receptor 2–negative (HER2-) breast cancer: Phase 1b cohort (part C) of a phase 1/2 study. (ASCO 2022) - P1/2 | "In xenograft models, ARV-471 demonstrated substantially greater ER degradation and antitumor activity compared with the selective ER degrader fulvestrant. Primary objectives are to evaluate the safety and tolerability of ARV-471 plus palbociclib and select the recommended phase 2 dose and schedule of the combination (based on the incidence of dose-limiting toxicities during the first cycle and the frequency and severity of adverse events and laboratory abnormalities). Secondary objectives are to assess preliminary antitumor activity of ARV-471 plus palbociclib (based on overall response rate per Response Evaluation Criteria in Solid Tumors v1.1, clinical benefit rate, progression-free survival, and duration of response) and pharmacokinetic parameters."

P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ER • HER-2

Phase 1/2a trial of prifetrastat in combination with vepdegestrant in patients (pts) with ER+/HER2− advanced/metastatic breast cancer (ABC): Results from dose escalation (ESMO 2026) - No abstract available

Clinical • Combination therapy • Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive 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) - 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

Oral selective estrogen receptor degraders in ER+/HER2- breast cancer: a systematic review with pooled analysis of metastatic randomized trials and narrative synthesis of adjuvant evidence. (PubMed, Front Oncol) - "We searched PubMed, Cochrane CENTRAL, and conference abstract archives (SABCS, ESMO, ASCO; 2020-2026) for Phase II/III randomized controlled trials comparing oral SERDs (giredestrant, imlunestrant, elacestrant, camizestrant, vepdegestrant, amcenestrant) with standard endocrine therapy in ER-positive, HER2-negative breast cancer. This evidence synthesis across the full breast cancer continuum offers a framework for clinical decision-making as oral SERDs expand from advanced to early-stage disease. https://www.crd.york.ac.uk/prospero/display_record.php, identifier CRD420261358420."

Journal • Retrospective data • Review • 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-U Sub-Study A: 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 A) (clinicaltrials.gov) - P1/2 | N=37 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Sep 2026 ➔ Mar 2027 | Trial primary completion date: Sep 2026 ➔ Mar 2027

Trial completion date • Trial primary completion date • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • HER-2

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

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

ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study (SABCS 2022) - P1/2 | "Patients had received a median of 4 prior regimens in all settings (range: 1–10); 100% had prior CDK4/6 inhibitors, 78.9% had prior fulvestrant, and 73.2% had prior chemotherapy. In the phase 2 VERITAC expansion cohorts of patients with ER+/HER2- locally advanced/metastatic breast cancer and prior CDK4/6 inhibitor treatment, ARV-471 monotherapy showed evidence of clinical activity based on CBR, which was further enhanced in the subgroup with ESR1 mutations. The manageable AE profile observed in the phase 1 portion of the study was maintained during cohort expansion at doses of 200 mg QD and 500 mg QD. Additional analyses are ongoing.Table."

P1/2 data • P2 data • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Global phase III studies evaluating vepdegestrant in estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: VERITAC-2 and VERITAC-3 (ESMO Asia 2023) - P1, P1/2, P3 | "VERITAC-3 will compare vepdegestrant + palbociclib vs letrozole + palbociclib as 1st-line treatment in pts with ER+/HER2- locoregional recurrent/metastatic breast cancer; no prior treatment in the advanced setting; and no prior treatment in any setting with CDK4/6 inhibitors, vepdegestrant, fulvestrant, elacestrant, or other investigational agents. In the phase 3 portion, pts (N≈1130) will be randomized to vepdegestrant + palbociclib or letrozole + palbociclib. The primary endpoint is PFS by BICR."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • 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 | "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

VERITAC-2: a Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer. (PubMed, Future Oncol) - P3 | "Progression-free survival by blinded independent central review (primary end point) will be assessed in the intention-to-treat population and ESR1 mutation-positive subpopulation. Secondary end points include overall survival, tumor response, safety, pharmacokinetics, patient-reported outcomes, and circulating tumor DNA biomarkers.Clinical trial registration: NCT05654623 (ClinicalTrials.gov)."

Journal • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ER • HER-2

Effects of intestinal permeation enhancers on solubilization and epithelial transport of the proteolysis targeting chimera (PROTAC) ARV-471 in rats. (PubMed, J Control Release) - "C10 demonstrated only modest effects on absorption, likely related to membrane perturbation. Collectively, these findings demonstrate that permeation-enhancing excipients may improve the oral bioavailability of PROTACs and other BCS Class IV compounds by enhancing luminal solubilization and/or epithelial permeability."

Journal • Preclinical • 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

Vepdegestrant: First Approval. (PubMed, Drugs) - "In May 2026, vepdegestrant received its first global approval in the USA for adults with ER+, HER2-, 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. This article summarizes the milestones in the development of vepdegestrant leading to its first approval in this indication."

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

Elucidating the molecular basis of ATP synthase inhibition: A virtual screening framework for next-gen selective acaricides. (PubMed, Sci Adv) - "Using these mechanistic insights, we developed a structure-based virtual screening pipeline to identify selective small-molecule inhibitors, including Vepdegestrant (ARV-471) and ICG-001, that exploit binding-site variation to achieve robust species specificity. This target-centric discovery framework not only advances the mechanistic understanding of ATP synthase inhibition but also establishes a scalable strategy for the rational design of environmentally safe and precision-oriented acaricides."

Journal

Oral selective estrogen receptor degraders and biomarker-driven therapy in ER-positive breast cancer: mechanisms, clinical evidence, and future directions. (PubMed, Front Oncol) - "This review comprehensively examines the mechanisms of SERD action, their role in overcoming resistance to conventional endocrine therapy, and clinical applications of approved agents including fulvestrant, elacestrant, imlunestrant, and vepdegestrant, the first FDA-approved PROTAC estrogen receptor degrader. We discuss emerging oral SERDs such as giredestrant and camizestrant, novel PROTAC-based approaches, and combination strategies with CDK4/6 inhibitors, PI3K inhibitors, and other targeted agents. Special attention is given to ESR1 mutations as biomarkers for patient selection and therapy optimization. The review highlights key clinical trials including EMERALD, EMBER-3, SERENA-6, and lidERA that have shaped current treatment guidelines and points toward future directions in SERD development."

Biomarker • Journal • Review • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Gynecology • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ER

Novel Endocrine Therapies: Current Status and Future Directions. (PubMed, Clin Breast Cancer) - "This review outlines key findings from clinical trials of Food and Drug Administration (FDA)-approved selective estrogen receptor degraders (SERDS), including elacestrant and imlunestrant, the newly FDA-approved proteolysis-targeting chimera (PROTAC) vepdegestrant, as well as emerging oral SERDs, PROTACs, complete estrogen receptor antagonists, selective estrogen receptor covalent antagonists (SERCAs), and other targeted therapies. We explore their mechanisms, efficacy, tolerability, and potential to improve treatment options and outcomes in both metastatic and early-stage disease."

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 • HER-2

The PROTAC milestone: FDA approval of vepdegestrant (ARV-471) for ESR1-mutated breast cancer. (PubMed, Drug Discov Today) - "In the Phase III VERITAC-2 trial, vepdegestrant significantly improved progression-free survival versus fulvestrant in ESR1-mutated, endocrine-resistant breast cancer. This milestone approval validates the PROTAC modality as a therapeutic platform, redefining oral beyond-Rule-of-5 design principles and opening new frontiers for induced-proximity medicines."

FDA event • Journal • Review • Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CRBN • ER

A phase 1, open-label study evaluating the pharmacokinetics, safety, and tolerability of vepdegestrant in Chinese patients with ER+/HER2- advanced breast cancer. (PubMed, Cancer Chemother Pharmacol) - P1 | "Vepdegestrant (200 mg QD) demonstrated a PK profile comparable to previous studies, a well-tolerated safety profile, and signs of preliminary antitumor activity in heavily pretreated Chinese patients with ER+/HER2- advanced breast cancer."

Journal • P1 data • PK/PD data • 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

Effect of ESR1 Somatic Mutations on SERM/SERD Binding: Insights from Molecular Docking and Molecular Dynamics Simulations (PubMed, Mol Biol (Mosk)) - "Vepdegestrant and fulvestrant were found to bind far less efficiently with ERα mutants and especially double mutants (e.g., Y537C/D538G) than with the native ERα. The findings elucidate the molecular mechanism of ESR1 mutation-driven resistance and support the promise of ZB716 as a compound capable of overcoming resistance conferred by a subset of the most common somatic ESR1 mutations in BC patients. The results justify the targeted design of new SERDs aimed at interacting with ERα mutants and outline an avenue of further research in the field of personalized therapy for ER+ BC."

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

Rigel Announces Availability of VEPPANU (vepdegestrant) for Patients with ER+/HER2-, ESR1-Mutated Advanced or Metastatic Breast Cancer (PRNewswire) - "The recommended dosage of VEPPANU is 200 mg taken orally once daily. VEPPANU is immediately available through Rigel's network of specialty distributors and specialty pharmacies in the United States and Puerto Rico at $29,400 per 30-day supply."

Launch US • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Population Pharmacokinetics and Exposure-Response Analyses of Vepdegestrant, a First-in-Class PROteolysis-TArgeting Chimera Estrogen Receptor Degrader. (PubMed, J Clin Pharmacol) - P1/2, P3 | "Overall, integrated analyses adequately characterized the PK of vepdegestrant, with no clinically meaningful covariate effects. No exposure-response relationships were identified between vepdegestrant exposure and efficacy or safety outcomes."

Clinical • First-in-human • Journal • PK/PD data • Breast Cancer • Fatigue • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Musculoskeletal Pain • Oncology • Solid Tumor • Targeted Protein Degradation • ER • HER-2

Rigel…expects VEPPANU to be commercially available in the United States for the treatment of second line-plus (2L+) ER+/HER2-, ESR1-mutated mBC in mid-August 2026 (PRNewswire)

Launch US • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Onco360 Has Been Selected as a National Pharmacy Partner for VEPPANU (vepdegestrant) (GlobeNewswire) - "...VEPPANU (vepdegestrant)...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..."

Commercial • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer

Mapping Scientific Landscapes and Therapeutic Innovations of Targeted Protein Degradation: A Scientometric Review. (PubMed, Pharmaceutics) - "Clinical viability is evidenced by the FDA approval of the agent ARV-471 for oncology. Despite this progress, critical challenges remain regarding E3 ligase expansion, molecular design optimization, and off-target toxicity. This review provides a data-driven roadmap for future TPD development, bridging the gap between academic output and real-world translational science to guide researchers, clinicians, and industry partners in navigating this dynamic therapeutic frontier."

Journal • Review • Oncology • Targeted Protein Degradation