On August 8, 2025, Arvinas and Pfizer announced that the U.S. Food and Drug Administration (FDA) has accepted their New Drug Application (NDA) for vepdegestrant (ARV-471) for the treatment of patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), ESR1-mutated advanced or metastatic breast cancer who have previously received endocrine-based therapy. The PDUFA date for this application is June 5, 2026. [1]

Figure 1. Structure of vepdegestrant (ARV-471) [2]

Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader jointly developed by Arvinas and Pfizer. It is designed to harness the body’s natural protein disposal system to specifically target and degrade the ER. If approved, it will become the first PROTAC® ER degrader approved by the US FDA.

VERITAC-2: Impressive Efficacy Data for Vepdegestrant

The new drug application is primarily supported by positive results from the pivotal Phase III clinical trial VERITAC-2 (NCT05654623). This study aimed to evaluate the efficacy and safety of Vepdegestrant compared with the standard therapy fulvestrant (Faslodex).

Results showed that in the subgroup of patients with ESR1 mutations, Vepdegestrant demonstrated remarkable efficacy:

• In patients treated with Vepdegestrant (n=136), the median progression-free survival (PFS) reached 5.0 months, compared with only 2.1 months in the control group receiving fulvestrant (n=134) (stratified HR: 0.57; 95% CI: 0.42–0.77; P < .001).

• The 6-month PFS rate was 45.2% (95% CI, 36.1%-53.9%) for vepdegestrant vs 22.7% (95% CI, 15.1%-31.2%) for fulvestrant.

• The objective response rate (ORR) was 18.6% in the Vepdegestrant group versus only 4.0% in the fulvestrant group.

These findings provide strong evidence that for breast cancer patients with ESR1 mutations, Vepdegestrant can deliver superior disease control compared with the current standard of care.

About PROTAC

The PROTAC concept was initially proposed and validated in 2001 by Professor Crews from Yale University and Professor Deshaies from Caltech. In 2008, Crews's group reported the first example of a bifunctional small molecule-based PROTAC capable of targeting and degrading the androgen receptor.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that utilize the ubiquitin proteasome system (UPS) to degrade proteins of interest (POI). Each PROTAC molecule is composed by a ligand that recruits the target protein of interest (POI), a ligand specific for an E3 ubiquitin ligase enzyme, and a linker that connects these units. Upon binding to the POI, the PROTAC recruits the E3 inducing ubiquitylation-dependent proteasome degradation of the POI. This process is catalytic—a single PROTAC molecule can repeatedly degrade multiple target proteins, allowing for potent activity at low doses.

Advantages Beyond Traditional Drugs

• Target “undruggable” proteins: Unlike conventional small molecules that must bind to the active site of a protein, PROTACs can bind to any accessible surface, enabling the degradation of traditionally  "undruggable" targets such as transcription factors and scaffold proteins.

• Overcome the drug resistance: PROTAC degrades POI rather than occupies the active site of POI, so PROTAC can not only overcome drug resistance but also improve target selectivity.

• Lower doses and reduced adverse effects: Thanks to its catalytic mechanism, the PROTAC approach allows these compounds to be administered at significantly lower doses, known as catalytic doses, thereby reducing adverse effects while maintaining optimal pharmacological efficacy.

Clinical Development of PROTACs

Since the first two small-molecule PROTAC degraders entered clinical trials in 2019, the field has expanded rapidly, with more than 40 candidates now in development worldwide. While oncology remains the primary focus, clinical programs also target immune-inflammatory disorders and neurodegenerative diseases. Current targets include AR, ER, BTK, EGFR, and IRAK4.

Table 1. PROTACs in Clinical Trials for Diseases (Note: Data not exhaustive; for reference only.)

Arvinas is leading multiple PROTAC initiatives, such as ARV-766, a second-generation androgen receptor degrader developed with Novartis.

Other companies, including Kymera Therapeutics and Nurix Therapeutics, are advancing PROTAC candidates for conditions such as hidradenitis suppurativa, atopic dermatitis, and relapsed/refractory Waldenström macroglobulinemia.

Conclusion

Over the past two decades, PROTAC technology has evolved from an academic curiosity into a rapidly advancing therapeutic platform. By proving the feasibility of degrading disease-causing proteins, it has opened the door to a new drug discovery paradigm. While challenges remain—such as controlling toxicity and improving delivery—ongoing innovation and investment could establish PROTACs as the third major drug modality, alongside small molecules and antibody therapeutics.

References:
[1] https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-fda-acceptance-new-drug-application Arvinas Announces FDA Acceptance of the New Drug Application for Vepdegestrant for the Treatment of ESR1m, ER+/HER2- Advanced Breast Cancer
[2] Cantrill C, Chaturvedi P, Rynn C, et al. Fundamental aspects of DMPK optimization of targeted protein degraders. Drug Discov Today. 2020 Jun;25(6):969-982.
[3] Sincere, N. I., Anand, K., Ashique, S., Yang, J., & You, C. (2023). PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies. Molecules (Basel, Switzerland), 28(10), 4014. https://doi.org/10.3390/molecules28104014