VEPDEGESTRANT, an investigational oral therapy, extended progression-free survival (PFS) in patients with ESR1-mutated, estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, according to results from a global Phase III study presented at the ASCO 2025 Annual Meeting.
The VERITAC-2 trial evaluated vepdegestrant, a proteolysis-targeting chimera (PROTAC) that degrades estrogen receptors, in patients with advanced ER-positive, HER2-negative breast cancer previously treated with hormone therapy and a CDK4/6 inhibitor. Of the 624 enrolled participants, 270 had confirmed ESR1 mutations, a known mechanism of resistance to standard endocrine therapies. Patients were randomly assigned to receive either vepdegestrant orally or intramuscular fulvestrant, a selective estrogen receptor degrader.
Among those with ESR1 mutations, vepdegestrant demonstrated a median PFS of 5 months, compared to 2.1 months with fulvestrant. This benefit was not observed in the overall study population when stratified by ESR1 mutational status. The clinical benefit rate in the ESR1-mutant subgroup was 42.1% for vepdegestrant, versus 20.2% for fulvestrant. Objective response rates were 18.6% and 4.0%, respectively.
Vepdegestrant is the first PROTAC estrogen receptor degrader evaluated in a phase 3 setting for breast cancer, representing a novel approach to targeting receptor-driven tumor growth. By binding and degrading the estrogen receptor directly, the agent differs mechanistically from traditional endocrine therapies.
The study enrolled patients aged 26 to 89, with a median age of 60. Eligibility required prior treatment with a CDK4/6 inhibitor and hormone therapy, but excluded prior use of fulvestrant or chemotherapy for advanced disease.
In terms of safety, Grade 3 or higher adverse events occurred in 23.4% of patients treated with vepdegestrant and 17.6% in the fulvestrant arm. Discontinuations due to adverse events were uncommon, although more frequent in the vepdegestrant group (2.9% vs. 0.7%).
These findings suggest that vepdegestrant may offer a targeted therapeutic option for patients with ESR1-mutated, ER-positive, HER2-negative advanced breast cancer following prior endocrine therapy. The data are being submitted to regulatory authorities to support potential approval.
Reference:
ASCO 2025. Vepdegestrant Could Extend Progression-Free Survival for Some People With ESR1-Mutated Advanced Breast Cancer. May 31, 2025. Available at: https://www.asco.org/about-asco/press-center/news-releases/vepdegestrant-could-extend-progression-free-survival-some. Last accessed: June 1, 2025.
