FDA Accepts NDA for Vepdegestrant in ER+/HER2- Metastatic Breast Cancer

The US FDA has accepted a new drug application (NDA) for vepdegestrant, an investigational oral PROteolysis TArgeting Chimera (PROTAC) being developed by Arvinas and Pfizer.¹

The application seeks approval for vepdegestrant as a monotherapy for patients with estrogen receptor-positive (ER+), HER2-negative (HER2–), ESR1-mutated advanced or metastatic breast cancer who have progressed on prior endocrine-based therapy. This development marks a significant step forward in providing a new, targeted treatment option for a patient population that often faces limited therapeutic choices after first-line treatment.

The Prescription Drug User Fee Act action date for the FDA's decision is set for June 5, 2026.

“Patients often face limited treatment options after first-line treatment, and vepdegestrant demonstrated improved progression-free survival [PFS] in patients with ESR1-mutated ER+/HER2– advanced breast cancer,” said John Houston, CEO and president of Arvinas, in a press release. “With the efficacy and [favorable] tolerability seen in VERITAC-2 [NCT05654623], we believe vepdegestrant, if approved, has [the] potential to be a best-in-class treatment option for patients in the second-line ESR1-mutant setting.”

Study Design and Key Findings

The NDA submission is supported by data from the VERITAC-2 trial, a randomized, global phase 3 study that compared vepdegestrant with fulvestrant (Faslodex), a commonly used selective estrogen receptor degrader (SERD).² In the trial, patients were randomly assigned to receive either vepdegestrant orally once daily or fulvestrant intramuscularly. The primary end point of the study was PFS as assessed by blinded independent central review, both in the overall trial population and specifically in patients with detectable ESR1 mutations.

Data presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting showed that vepdegestrant achieved a median PFS of 5.0 months vs 2.1 months with fulvestrant (stratified HR, 0.57; 95% CI, 0.42-0.77; P <.001) in this genetically defined subgroup.³ Six-month PFS rates favored vepdegestrant at 45.2% compared with 22.7% for fulvestrant. These findings support the potential of vepdegestrant as a targeted treatment option in a post-CDK4/6 setting, where therapeutic consensus remains limited.

While the all-comer population did not reach statistical significance (HR, 0.83; P =.07), the robust efficacy observed in the ESR1-mutant subgroup, along with favorable tolerability and low discontinuation rates, underscores the relevance of biomarker-driven therapy selection.

“One of the challenges is that we don’t have consensus in the post-CDK4/6 landscape on what patients should receive. We’re doing profiling for ESR1; we’re looking at PIK3CA, AKT, [and] PTEN alterations, and we have CDK after CDK,” said Erika Hamilton, MD, director of breast cancer research at Sarah Cannon Research Institute. “What’s really unique about this trial is it’s very similar to the EMERALD trial [NCT03778931], where everyone had already had a CDK4/6 inhibitor. And remember, that trial showed 1.9 vs 3.8 months. So, if we do the dreaded cross-trial comparison, our 5.0 months does compare favorably. And our fulvestrant arm at 2.1 months vs EMERALD’s 1.9 performed very similarly—telling me this was a similar population.”

A subgroup analysis of EMERALD did show an improved PFS of 8.6 months vs the standard-of-care 1.9 months, higher than 3.9 months reported originally. Additionally, Although VERITAC-2 enrolled 100% of patients with prior exposure to CDK4/6 inhibitors, the trial excluded patients who had received prior chemotherapy or fulvestrant, as well as those with primary endocrine resistance (defined as patients who had fewer than 6 months on CDK4/6 inhibitor treatment). In contrast, EMERALD included a broader and more heterogeneous population—23% had prior chemotherapy, 23% had prior fulvestrant, and patients with primary endocrine resistance were eligible to participate. The patient population in EMERALD was a more heavily pretreated population than VERITAC-2, making cross-trial comparisons challenging.

Vepdegestrant's mechanism of action as a PROTAC molecule is distinct from traditional endocrine therapies. It is designed to induce the degradation of estrogen receptors, thereby reducing their levels and inhibiting the proliferation of ER-dependent cancer cells.¹ This targeted degradation offers a new therapeutic strategy that may overcome resistance mechanisms commonly associated with conventional endocrine therapies, particularly in the presence of ESR1 mutations. The trial results demonstrated improved PFS with vepdegestrant in patients with ESR1-mutated ER+/HER2– advanced breast cancer. This finding is particularly notable, as ESR1 mutations are a common driver of endocrine resistance in this disease setting.

REFERENCES:

1. FDA gives Arvinas and Pfizer’s vepdegestrant NDA for breast cancer. News release. Pharmaceutical Technology. August 11, 2025. Accessed August 11, 2025. https://tinyurl.com/yc7v9yfj

2. A Study to Learn About a New Medicine Called Vepdegestrant (ARV-471, PF-07850327) in People Who Have Advanced Metastatic Breast Cancer (VERITAC-2). ClinicalTrials.gov. Updated July 3, 2025. Accessed August 11, 2025. https://clinicaltrials.gov/study/NCT05654623

3. Hamilton E, De Laurentiis M, Jhaveri K, et al. Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: results of the global, randomized, phase 3 VERITAC-2 study. J Clin Oncol. 2025;43(suppl 17):LBA1000. doi:10.1200/JCO.2025.43.17_suppl.LBA1000