FDA issues landmark approval for Arvinas, Pfizer PROTAC Veppanu in breast cancer

Edited by Robert McTiernan··3 min read

Arvinas announced US FDA approval of Veppanu (vepdegestrant), developed with partner Pfizer, for adults with estrogen receptor-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer following at least one prior line of endocrine therapy. The approval marks the first time the FDA has cleared a PROteolysis TArgeting Chimera, or PROTAC — a class of heterobifunctional protein degrader — for any indication, representing a mechanistic milestone for the targeted protein degradation field that Arvinas has pursued since its founding in 2013.

Veppanu is approved as a monotherapy for patients whose tumors carry ESR1 mutations, as detected by an FDA-authorized companion diagnostic test. The drug is administered orally on a continuous 28-day dosing schedule, offering an alternative to fulvestrant, the current injectable standard of care in this setting. The approval was granted ahead of the FDA-assigned PDUFA date of June 5, 2026. Arvinas and Pfizer have separately announced plans to identify a third-party partner for commercialization, with a selection announcement described as on track.

The approval was supported by data from VERITAC-2 (NCT05654623), a global, randomized, open-label Phase III trial enrolling 624 patients with ER+/HER2- advanced or metastatic breast cancer previously treated with a CDK4/6 inhibitor plus endocrine therapy. The primary endpoint was progression-free survival in the ESR1-mutation-positive and intent-to-treat populations, assessed by blinded independent central review. Among the 270 patients with confirmed ESR1 mutations, vepdegestrant reduced the risk of disease progression or death by 43% compared to fulvestrant, with a median PFS of 5.0 months versus 2.1 months (hazard ratio 0.57, 95% CI: 0.42–0.77; p=0.0001). Overall survival data were immature at the time of the PFS analysis, with 16% of deaths recorded in this population.

The safety profile in VERITAC-2 was characterized predominantly by low-grade events. Adverse reactions occurring in 10% or more of patients included decreased white blood cell counts, elevated liver enzymes, musculoskeletal pain, fatigue, nausea, decreased hemoglobin, electrolyte abnormalities, and QT prolongation on electrocardiogram. The prescribing information includes a warning for QTc interval prolongation, with monitoring requirements for cardiac function and electrolyte levels prior to and during treatment.

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Approval context

ESR1 mutations arise predominantly as an acquired resistance mechanism following exposure to aromatase inhibitors, and are detected in an estimated 40%–50% of patients with ER+/HER2- metastatic breast cancer who have received endocrine therapy combined with a CDK4/6 inhibitor. Veppanu joins Orserdu (elacestrant), an oral selective estrogen receptor degrader approved by the FDA in January 2023 for the same ESR1-mutated indication, and Eli Lilly’s Inluriyo (imlunestrant), approved in September 2025 as a monotherapy in patients post-CDK4/6 inhibitor therapy. AstraZeneca’s camizestrant has been filed for approval based on the Phase III SERENA program, including a study specifically evaluating ESR1-mutated patients, but faced a setback last week when an FDA advisory committee voted 6–3 against its benefit-risk profile. Olema Pharmaceuticals’ palazestrant, a Complete Estrogen Receptor Antagonist (CERAN) and Selective Estrogen Receptor Degrader (SERD), is in Phase III via the OPERA-01 trial.

Arvinas’ PROTAC pipeline

The PROTAC modality works by recruiting an E3 ubiquitin ligase to a target protein, directing it for degradation via the cell’s proteasome system rather than simply inhibiting its function. The FDA’s clearance of vepdegestrant provides the first clinical validation of this mechanism at a regulatory level, with implications for other PROTAC programs in Arvinas’ pipeline and across the industry. Arvinas is also advancing PROTAC-based programs targeting LRRK2 in neurodegeneration, KRAS G12D in solid tumors, BCL6 in non-Hodgkin lymphoma, and a polyglutamine-expanded androgen receptor in neuromuscular disease.

Arvinas and Pfizer entered a global co-development and co-commercialization agreement in July 2021, and in September 2025 announced a plan to bring in a third party for commercialization and potential further development. That deal focused solely on vepdegestrant, with Pfizer paying USD 650 million upfront and committing to up to USD 1.4 billion in milestone payments, alongside a USD 350 million equity investment in Arvinas.

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