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

Insights Into Vepdegestrant (ARV-471): The First-in-Class Estrogen Receptor Proteolysis-Targeting Chimera Approaching Food and Drug Administration Approval for Breast Cancer. (PubMed, ChemMedChem) - "On June 6, 2025, Arvinas and Pfizer submitted a New Drug Application (NDA) for vepdegestrant to the U.S. Food and Drug Administration (FDA), representing an important step in the clinical translation of PROTAC technology. This review summarizes the design, synthesis, degradation mechanism, preclinical pharmacology, and clinical development of vepdegestrant and discusses the broader implications and future prospects of oral PROTAC-based ER degraders in breast cancer therapy."

Journal • Review • 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

Palazestrant directly recruits the corepressor protein NCoR1 in vitro leading to complete antagonism of estrogen receptor alpha (AACR 2026) - "Contrarily, selective estrogen receptor modulators (SERMs) such as 4-OH-tamoxifen and vepdegestrant either do not induce recruitment or are incomplete recruiters, in line with previous data indicating that SERMs are not complete antagonists...CERAN molecules palazestrant and fulvestrant consistently demonstrate greater suppression of GREB1 and PGR as compared to SERMs in both ESR1 wildtype and mutant ER+ breast cancer models.Functionally, treatment with palazestrant leads to antiproliferative activity in ER+ breast cancer models comparable or superior to investigational and approved anti-estrogens...When cells are not stimulated with E2, SERMs like tamoxifen demonstrate induction of cell proliferation where CERANs do not. Palazestrant is a promising therapeutic strategy for treating ER+/HER2- breast cancer patients and is being evaluated clinically, both as monotherapy and combination."

Preclinical • 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 • ER • HER-2 • NCOR1

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

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

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

Integrated organoid screening approaches enable preclinical assessment of protein degrader efficacy and target engagement (AACR 2026) - "Two cereblon (CRBN)-mediated protein degrader candidates, CC-885 (GSPT1 degrader; molecular glue) and ARV-471 (estrogen receptor (ER) degrader; PROTAC), were evaluated using patient-derived organoids to address the unmet need for physiologically relevant platforms in preclinical protein degrader development. CC-885 was screened using the OrganoidXplore™ CellTiterGlo assay at 6 doses across 98 NGS characterized organoids derived from six tissue types (colorectal, cervical, gastric, head and neck, lung, and pancreatic cancer), including non-diseased models... Organoids offer genomically stable, patient-derived models that capture patient diversity and tumor heterogeneity, enabling clinically translatable insights for precision medicine. Our results establish organoid-based screening platforms (OrganoidXploreTM), combining CTG and HCI modalities, as robust tools for preclinical protein degrader evaluation. These platforms uniquely enable identification of tumor subtypes..."

Preclinical • Oncology • Pancreatic Cancer • Solid Tumor • CRBN • ER • GSPT1

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

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

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=71 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Mar 2026 ➔ Sep 2026

Trial completion date • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Anticipated Upcoming Milestones and Expectations (GlobeNewswire) - "Continue enrollment in the Phase 1 trial of ARV-806 in patients with solid tumors harboring KRAS G12D mutations (ClinicalTrials.gov Identifier: NCT07023731); Share initial clinical data in patients with solid tumors harboring KRAS G12D mutations (2026)...Anticipate sharing updated clinical data from the ongoing Phase 1 clinical trial in patients with relapsed/refractory non-Hodgkin’s lymphoma (ClinicalTrials.gov Identifier: NCT06393738) at a medical congress (2H 2026); Initiate enrollment of a combination cohort with glofitamab in patients with DLBCL in the ongoing Phase 1 clinical trial (1H 2026)....Identify and select a partner with the capabilities and expertise to maximize the commercial potential of vepdegestrant; Advance towards Prescription Drug User Fee Act (PDUFA) action date on June 5, 2026."

Clinical data • Commercial • PDUFA • Trial status • Angioimmunoblastic T-cell Lymphoma • Estrogen Receptor Positive Breast Cancer • HER2 Negative Breast Cancer • Non-Hodgkin’s Lymphoma • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Effect of carbamazepine on the pharmacokinetics of vepdegestrant, a PROteolysis TArgeting Chimera estrogen receptor degrader, in healthy adults. (PubMed, Br J Clin Pharmacol) - P1 | "Coadministration of multiple doses of carbamazepine 200 mg, a strong CYP3A4 inducer, with a single dose of vepdegestrant 200 mg resulted in a modest (36%) decrease in plasma vepdegestrant exposure. A single dose of vepdegestrant 200 mg was well tolerated in healthy adult participants."

Journal • PK/PD data • Breast Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CYP3A4 • ER

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: Mar 2026 ➔ Sep 2026 | Trial primary completion date: Mar 2026 ➔ Sep 2026

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

Preclinical translational physiologically based pharmacokinetic modeling for predicting human pharmacokinetics of proteolysis targeting chimeras: Case studies of vepdegestrant (ARV-471) and bavdegalutamide (ARV-110). (PubMed, Drug Metab Dispos) - "Incorporating mechanistic absorption modeling and permeability data from modified in vitro assays (Genentech Madin-Darby canine kidney cells with 4% bovine serum albumin) improved oral absorption predictions, whereas the integration of multispecies preclinical PK data enhanced the translational accuracy of human PK predictions. Together, these findings establish a translational physiologically based PK framework for estimating oral exposure in first-in-human studies and supporting model-informed development of proteolysis targeting chimeras drug candidates."

First-in-human • Journal • PK/PD data • Preclinical • Targeted Protein Degradation

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

The Effect of Itraconazole on the Pharmacokinetics of Vepdegestrant, a PROteolysis TArgeting Chimera Estrogen Receptor Degrader, in Healthy Adult Participants. (PubMed, Clin Ther) - P1, P3 | "Coadministration of multiple doses of itraconazole, a strong CYP3A4 inhibitor, increased vepdegestrant exposure by 69%, suggesting the involvement of CYP3A4-mediated metabolism, albeit not predominantly, in vepdegestrant elimination."

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

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

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

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

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

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

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

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

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