Changing the Landscape of ESR1-Mutant Breast Cancer Treatment

In an interview with Targeted Oncology, Erika Hamilton, MD, director, breast cancer research, Sarah Cannon Research Institute, discusses how vepdegestrant changes the treatment landscape for ESR1-mutated breast cancer.

Earlier this month, the FDA accepted the new drug application for vepdegestrant, an investigational oral PROteolysis TArgeting Chimera (PROTAC), as a monotherapy for patients with estrogen receptor (ER)-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer who have progressed on prior endocrine-based therapy. The Prescription Drug User Fee Act action date for the FDA's decision is set for June 5, 2026.

This followed positive data out of the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting where vepdegestrant demonstrated clinically meaningful and statistically significant improvements in progression-free survival compared with fulvestrant (Faslodex) in the intent-to-treat population. At a median follow-up of 7.4 months in the vepdegestrant arm (n = 136) and 6.0 months in the fulvestrant arm (n = 134), the median PFS was 5.0 months (95% CI, 3.7–7.4) and 2.1 months (95% CI, 1.9–3.5), respectively (stratified HR, 0.57; 95% CI, 0.42-0.77; 2-sided P < .001). At the time of the analysis, 58% of PFS events had occurred in the vepdegestrant arm vs 71% in the fulvestrant arm; treatment was ongoing in 33% and 12% of patients, respectively. The 6-month PFS rates with vepdegestrant and fulvestrant were 45.2% (95% CI, 36.1%–53.9%) and 22.7% (95% CI, 15.1%–31.2%), respectively.

A subgroup analysis of the EMERALD study (NCT03778931) 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 is the first PROTAC to be evaluated in a phase 3 study,” Hamilton said in a press briefing ahead of the meeting. “These results support vepdegestrant as a potential treatment option for previously treated [patients with] ESR1-mutant ER-positive, HER2-negative advanced breast cancer.”

In February 2024, the FDA granted fast track designation to vepdegestrant for the treatment of patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with endocrine-based therapy.