Vepdegestrant: First PROTAC at the FDA Gate — Promise Meets Clinical and Commercial Hurdles

Vepdegestrant (ARV-471), an investigational oral PROTAC (PROteolysis TArgeting Chimera) estrogen receptor (ER) degrader, has been at the center of high expectations for targeted breast cancer therapy. Developed by Arvinas and Pfizer, it is the first PROTAC to enter clinical testing (2019) and the first to reach a New Drug Application (NDA, 2025) — a historic milestone for the modality.

On September 17, 2025, Arvinas announced strategic updates on vepdegestrant. The company and Pfizer plan to out-license commercialization rights to a third party, with the aim of maximizing its potential in ESR1-mutant ER+/HER2– advanced breast cancer and possibly expanding into new settings. This move comes as vepdegestrant looks likely to be the third-to-market ER degrader, following Menarini’s elacestrant (Orserdu, approved 2023) and Lilly’s imlunestrant, which recently posted positive EMBER-3 results and is expected to be filed with the FDA. Alongside this, Arvinas outlined cost optimization measures expected to save over $100 million annually vs FY 2024, a $100 million stock repurchase program, and reaffirmed cash runway through H2 2028 [1].

This combination of scientific milestone and strategic pivot reflects the dual reality of vepdegestrant: strong promise in ESR1-mutant disease, but significant clinical and commercial hurdles that temper Pfizer’s enthusiasm.

Key Takeaways

• First PROTAC NDA: Vepdegestrant is the first PROTAC drug to reach FDA submission, a milestone for the modality.
• Mixed Phase 3 results: VERITAC-2 failed to improve PFS in the ITT population (HR 0.83; P = 0.07) but showed clear benefit in ESR1-mutant patients (median PFS 5.0 vs 2.1 months; HR 0.58; P < 0.001).
• Pfizer steps back: Despite a billion-dollar 2021 partnership, Pfizer and Arvinas now seek a third-party commercial partner.
• Commercial outlook: Competition is tightening, with elacestrant already approved and Lilly’s imlunestrant likely to be submitted for FDA review ahead of vepdegestrant’s Q2 2026 PDUFA. Approval would be symbolic for PROTACs, but uptake may be modest unless clear superiority is shown.

Mechanism of Action: Why ER Degradation Matters

Endocrine therapy resistance in ER+/HER2– breast cancer is often driven by mutations in ESR1, leading to constitutive ER activity and treatment failure with aromatase inhibitors or SERMs.

Vepdegestrant employs the PROTAC mechanism: a bifunctional small molecule that simultaneously binds ER and an E3 ubiquitin ligase, triggering ubiquitination and proteasomal degradation of the receptor. Unlike selective estrogen receptor degraders (SERDs), which only inhibit and partially degrade ER, PROTACs can achieve complete target removal, theoretically overcoming ESR1-mediated resistance [2,3].

Why PROTACs were hot: In the early 2020s, PROTACs became one of the most hyped platforms in drug discovery, with partnerships across big pharma (Bayer, Novartis, Biogen) and IPOs from Arvinas, Kymera, and C4 Therapeutics. The technology promised to vastly expand the druggable proteome by targeting proteins previously considered “undruggable.” Vepdegestrant was the flagship molecule expected to validate the modality in oncology.

Pfizer–Arvinas Collaboration: From Billion-Dollar Bet to Strategic Pivot

Pfizer and Arvinas entered a landmark collaboration in July 2021 for the co-development and co-commercialization of vepdegestrant, with Pfizer committing over $1 billion, including $650M upfront and a $350M equity stake [6].

At the time, vepdegestrant was positioned as a potential cornerstone asset in Pfizer’s oncology pipeline. Yet by September 2025, Pfizer and Arvinas jointly agreed to seek a third-party partner for commercialization. This shift underscores Pfizer’s tempered commercial expectations, likely due to:

• The failure of VERITAC-2 in the ITT population.
• Abandonment of first-line and combo expansion strategies.
• A narrowed regulatory indication with limited market size.
  - Competitive pressure from Orserdu and imlunestrant, both of which may capture a significant portion of the ESR1-mutant market before vepdegestrant reaches approval.

For Pfizer, which is now focusing on ADCs, bispecifics, and next-gen CDK inhibitors, vepdegestrant may no longer justify the same level of investment.

Clinical Development: The VERITAC Program

VERITAC-2 (2L+ ER+/HER2– advanced breast cancer)

• Design: Compared vepdegestrant monotherapy (200 mg daily) vs fulvestrant in 624 patients previously treated with endocrine therapy and a CDK4/6 inhibitor.
• Primary endpoint: Progression-free survival (PFS) in the intent-to-treat (ITT) population.
• Secondary endpoints: Overall response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), safety.

Results (NEJM 2025):

• ITT population: Median PFS 3.8 vs 3.6 months; HR 0.83 (95% CI 0.69–1.01); P = 0.07 → not statistically significant.
• ESR1-mutant subgroup (n=270): Median PFS 5.0 vs 2.1 months; HR 0.58 (95% CI 0.43–0.78); P < 0.001 → statistically significant benefit.
• Safety: Grade ≥3 adverse events: 23.4% (vepdegestrant) vs 17.6% (fulvestrant); discontinuation due to AEs: 2.9% vs 0.7% [7].

This confirms the rationale for narrowing the NDA to ESR1-mutant patients.

VERITAC-3 (1L combo with palbociclib)

Originally planned as a registrational trial in first-line ER+/HER2– disease. However, the study was abandoned in January 2025, reportedly due to strategic reprioritization after weaker than hoped monotherapy signals [5].

Other Planned Trials

According to clinical registries and pipeline trackers, additional trials — including combinations with atirmociclib and other CDK4/6 inhibitors — were abandoned in May 2025 before enrollment began [5].

Regulatory Development

In mid-2025, Arvinas and Pfizer submitted an NDA for vepdegestrant in ESR1-mutant, ER+/HER2– advanced or metastatic breast cancer after CDK4/6 inhibitor therapy. The PDUFA date is set for Q2 2026.

Notably, this marks the first PROTAC NDA ever filed with the FDA. However, the indication is narrow, restricted to ESR1-mutant patients (~40% of ER+ MBC), reflecting the limitations of the VERITAC-2 data.

By contrast, imlunestrant’s EMBER-3 trial (imlunestrant ± abemaciclib) showed significant PFS benefit in ESR1-mutant patients and in the abemaciclib combination arm, though monotherapy did not significantly improve PFS in the overall ITT population, raising the risk that vepdegestrant enters the market as a later and narrower option.

Competitive Landscape

• SERDs: Oral SERDs like elacestrant (FDA-approved in ESR1-mutant ER+ MBC) already provide competition. While vepdegestrant may show deeper degradation, head-to-head differentiation remains modest. Imlunestrant (Lilly): The Phase 3 EMBER-3 trial met its primary endpoint of PFS improvement in ESR1-mutant patients, with additional benefit seen in the combination arm with abemaciclib. However, imlunestrant monotherapy did not significantly improve PFS in the overall ITT population. Lilly has not announced a PDUFA date, and while regulatory submission is expected, the NDA has not yet been confirmed as accepted for review.
• Next-gen ER degraders: Other modalities, including selective ER covalent antagonists (SERCAs) and complete ER antagonists (CERANs), are advancing in early-mid stage development.
• PROTAC pipeline: Vepdegestrant’s NDA filing sets a precedent for the field, but other PROTACs (C4T, Kymera) are still in early oncology or immunology studies, years away from regulatory submission.

The commercial opportunity for vepdegestrant thus depends heavily on whether its clinical advantage over SERDs is persuasive enough for oncologists — and whether a commercial partner can position it as a best-in-class ESR1-mutant option.

Outlook

Vepdegestrant’s path illustrates both the scientific achievement of advancing the first PROTAC to NDA and the commercial realities of oncology drug development. Its approval in ESR1-mutant ER+/HER2– breast cancer would be a symbolic breakthrough for the PROTAC modality, but without clear superiority over existing agents, uptake may be modest.

For Arvinas, finding the right commercialization partner will be critical. For Pfizer, the decision to step back highlights shifting priorities and the unforgiving nature of oncology investment — even for first-in-class assets.

Sources

1. Arvinas Inc. Press Release. Sept 17, 2025.
2. Burslem, G.M.; Crews, C.M. Chem. Rev. 2017, 117, 11269–11301.
3. Gao, H. et al. Targeting estrogen receptor degradation with PROTACs. Nat. Chem. Biol. 2019, 15, 1023–1030.
4. Pfizer & Arvinas. Press Release. June 2025.
5. Oncologypipeline.com, “Vepdegestrant’s Promise Narrows,” Jan–May 2025 updates.
6. Arvinas Inc. Press Release. July 22, 2021.
7. Campone, M.; De Laurentiis, M.; Jhaveri, K.; Hu, X.; Ladoire, S.; Patsouris, A.; Zamagni, C.; Cui, J.; Cazzaniga, M.; Ciȧ Ricci; et al. Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer. N. Engl. J. Med. 2025, 393 (6), 556-568. DOI: 10.1056/NEJMoa2505725.
8. Ma, Z.; et al. NDA Submission of Vepdegestrant (ARV-471) to U.S. FDA. J. Med. Chem. 2025, DOI:10.1021/acs.jmedchem.5c01818
9. Abstract 297O. ESMO Breast Cancer Annual Congress.
10. Jhaveri KL, et al. N Engl J Med. 2025 Mar 27;392(12):1189-1202. doi:10.1056/NEJMoa2410858.

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