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.

2 months ago

Review • Journal

KRAS (KRAS proto-oncogene GTPase) • STAT3 (Signal Transducer And Activator Of Transcription 3)

KRAS mutation • KRAS G12C • KRAS G12 • STAT3 mutation

bavdegalutamide (ARV-110) • vepdegestrant (ARV-471)

2ms

TACTIVE-E: ARV-471 in Combination With Everolimus for the Treatment of Advanced or Metastatic ER+, HER2- Breast Cancer (clinicaltrials.gov)

P1, N=32, Completed, Arvinas Estrogen Receptor, Inc. | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Aug 2025

2 months ago

Trial completion • Trial completion date

HER-2 (Human epidermal growth factor receptor 2)

everolimus • vepdegestrant (ARV-471)

3ms

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, Pfizer | Trial completion date: Sep 2025 --> Mar 2026 | Trial primary completion date: Sep 2025 --> Mar 2026

3 months ago

Trial completion date • Trial primary completion date

HER-2 (Human epidermal growth factor receptor 2)

HER-2 negative

Verzenio (abemaciclib) • vepdegestrant (ARV-471)

4ms

Effect of vepdegestrant, a PROTAC oestrogen receptor degrader, on dabigatran and rosuvastatin pharmacokinetics in healthy participants. (PubMed, Br J Clin Pharmacol)

Coadministration with vepdegestrant doubled dabigatran exposure and resulted in a minor increase (11%) in rosuvastatin exposure in humans.

4 months ago

PK/PD data • Journal

ER (Estrogen receptor)

vepdegestrant (ARV-471)

4ms

C4551001: Study of PF-07248144 in Advanced or Metastatic Solid Tumors (clinicaltrials.gov)

P1, N=320, Recruiting, Pfizer | Trial completion date: Jan 2028 --> Sep 2029

4 months ago

Trial completion date

HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A)

ER positive • HER-2 negative • HER-2 negative + ER positive

Ibrance (palbociclib) • fulvestrant • letrozole • vepdegestrant (ARV-471) • atirmociclib (PF-07220060) • prifetrastat (PF-07248144)

4ms

TACTIVE-U Sub-Study B: 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 B) (clinicaltrials.gov)

P1/2, N=20, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=47 --> 20

4 months ago

Enrollment closed • Enrollment change

HER-2 (Human epidermal growth factor receptor 2)

HER-2 negative

Kisqali (ribociclib) • vepdegestrant (ARV-471)

5ms

Advancing Predictions of Oral Drug Absorption, CYP3A4 Induction, and Transporter-Mediated Interactions Using a Human Primary Intestinal 3D Model (EpiIntestinal™). (PubMed, Clin Pharmacol Ther)

However, PBPK modeling, using EpiIntestinal™ permeability data, accurately predicted the clinical maximum plasma concentration (Cmax) of the P-gp substrates digoxin and dabigatran etexilate, unlike the significant underpredictions from Caco-2 data...Combining induction parameters of rifampicin from EpiIntestinal™ with those from the TruVivo (human hepatic model) into PBPK modeling accurately captured DDI effects on midazolam, a sensitive CYP3A4/5 substrate. Additionally, the model accurately predicted clinical outcomes of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) mediated DDIs for ARV-471. These data underscore the potential of EpiIntestinal™ in predicting human Fa and Fg, and in quantitatively assessing CYP3A4 induction and transporter-based DDIs.

5 months ago

Journal

CYP3A4 (Cytochrome P450, family 3, subfamily A, polypeptide 4)

vepdegestrant (ARV-471) • midazolam hydrochloride • rifampicin

5ms

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, Completed, Pfizer | Recruiting --> Completed

5 months ago

Trial completion

vepdegestrant (ARV-471)