FDA Approves First PROTAC Drug VEPPANU for ESR1-Mutated Breast Cancer

The U.S. Food and Drug Administration has granted approval for VEPPANUSearch drug (vepdegestrantSearch drug), marking a historic milestone as the first PROteolysis TArgeting Chimera (PROTAC) therapy to receive regulatory approval. Developed jointly by ArvinasSearch company and PfizerSearch company, VEPPANU is indicated for adults with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-), ESR1Search term-mutated advanced or metastatic breast cancer who have experienced disease progression following at least one line of endocrine therapy.

Breakthrough PROTAC Technology

"Today's FDA approval is a transformative moment for ArvinasSearch company as we achieve our first approved medicine and the first-ever approved PROTAC therapy based on the technology we've pioneered since 2013," said Randy Teel, Ph.D., President and Chief Executive Officer at Arvinas. The approval represents the culmination of research that originated at Yale UniversitySearch company, where Professor Craig Crews, Ph.D., co-authored the first-ever paper on PROTAC protein degraders.

PROTAC technology represents a novel therapeutic approach that harnesses the body's natural protein disposal system to selectively degrade disease-causing proteins. Unlike traditional small molecule inhibitors that block protein function, PROTAC degraders eliminate the target protein entirely, potentially offering advantages in overcoming resistance mechanisms.

Addressing Critical Unmet Need

The approval addresses a significant gap in treatment options for patients with ESR1Search term-mutated breast cancer. While endocrine therapy remains a cornerstone of metastatic ER+/HER2- breast cancer treatment, up to 40-50% of patients treated with endocrine therapy and a CDK4/6 inhibitor develop ESR1 mutations, resulting in endocrine resistance and poor prognosis. These patients often experience rapid disease progression and face limited options after first-line therapy.

"For patients living with ESR1Search term mutant, ER+/HER2 advanced breast cancer, there have been minimal second-line treatment options once standard therapies are no longer effective," said Erika Hamilton, M.D., Chief Development Officer, Late Phase, and Director, Breast Cancer Research, Sarah Cannon Research InstituteSearch company, who served as a principal investigator of the VERITAC-2 trial. "The introduction of a new, targeted treatment is an encouraging development for this community and highlights meaningful innovation in the way this disease is treated."

Robust Clinical Evidence

FDA approval was granted based on data from VERITAC-2 (NCT05654623), a global, randomized, open-label, pivotal Phase 3 clinical trial that enrolled 624 patients at 213 sites across 25 countries. The trial evaluated vepdegestrantSearch drug versus fulvestrantSearch drug in patients with ER+/HER2- advanced or metastatic breast cancer previously treated with a CDK4/6 inhibitor plus endocrine therapy.

Among the 270 patients with ESR1Search term mutations, vepdegestrantSearch drug demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS). The treatment reduced the risk of disease progression or death by 43% compared to fulvestrantSearch drug, with a median PFS of 5 months (95% CI: 3.7, 7.4) versus 2.1 months (95% CI: 1.9, 3.5) for fulvestrant (hazard ratio 0.57 [95% CI: 0.42, 0.77]; p-value 0.0001).

Safety Profile and Administration

The majority of adverse events with vepdegestrantSearch drug were low grade (Grade 1-2). The most common adverse reactions (≥10%) included decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased blood potassium, increased bilirubin, decreased appetite, electrocardiogram QT prolonged, decreased platelets, and constipation.

VEPPANUSearch drug offers practical advantages as an oral therapy administered once daily on a 28-day continuous dosing schedule, compared to fulvestrantSearch drug's intramuscular injection regimen. "Today's approval provides a new oral treatment option that showed improved progression free survival when compared to the current standard of care, fulvestrant, which is administered via an intramuscular injection," noted Noah Berkowitz, M.D., Ph.D., Chief Medical Officer at ArvinasSearch company.

Commercial Strategy and Future Outlook

The approval came ahead of the FDA-assigned PDUFA date of June 5, 2026, demonstrating the agency's recognition of the drug's clinical significance. ArvinasSearch company and PfizerSearch company plan to jointly identify and select a third-party partner with the capabilities and expertise to maximize VEPPANUSearch drug's commercial potential, with the companies on track to announce their selection.

Beyond VEPPANUSearch drug, ArvinasSearch company is advancing multiple investigational PROTAC degraders through clinical development, including ARV-102Search drug targeting LRRK2Search term for neurodegenerative disorders, ARV-806Search drug targeting KRAS G12DSearch term for mutated cancers, ARV-393Search drug targeting BCL6Search term for relapsed/refractory non-Hodgkin lymphoma, and ARV-027Search drug targeting polyglutamine-expanded androgen receptor in skeletal muscle.

The approval establishes PROTAC technology as a validated therapeutic modality and positions ArvinasSearch company at the forefront of protein degradation medicine, with potential applications extending across oncology, neurodegenerative, and neuromuscular diseases.