PROTAC therapy vepdegestrant improves progression-free survival in ERS1-mutated breast cancer

MedNet.nl: Vepdegestrant, a PROTAC (proteolysis-targeting chimera), provides improved progression-free survival compared with fulvestrant as a treatment for ESR1-mutated, HER2-negative, advanced breast cancer,  according to the phase 3 VERITAC-2 study.

PROTACs are a new type of drug that can selectively deactivate proteins. They do this by, as it were, earmarking these proteins, so that they are recognized by the ubiquitin-proteasome system, which is responsible for the breakdown of proteins in the cell. With vepdegestrant, the estrogen receptor can be selectively degraded, and in a phase 1/2 study, this strategy was effective in patients with previously treated advanced breast cancer. The VERITAC-2 trial examined efficacy in patients who had received one previous treatment with a CDK4/6 inhibitor plus endocrine therapy (ET), and up to one additional treatment with ET. Patients who previously received chemotherapy or fulvestrant were excluded. The primary endpoint was progression-free survival (PFS) in patients with an ESR1 mutation. After randomization, patients were treated with vepdegestrant (n=313) or fulvestrant (n=311).

Although the PFS did not differ between the overall groups treated with vepdegestrant or fulvestrant (median 3.7 and 3.6 months, respectively), there was a significant difference in the groups with an ESR1 mutation. Here, the median PFS was 5.0 months in the vepdegestrant group versus 2.1 months in the fulvestrant group (HR=0.57). At 6 months, the percentage of patients without progression was about two times higher in the vepdegestrant group than in the fulvestrant group: 45.2% versus 22.7%. The objective response rate was also higher: 18.6% versus 4.0%.

The adverse event profile of vepdegestrant was relatively mild. Grade 3 or higher adverse events occurred in 23% and 18%, respectively, and in the vepdegestrant group, 3% of patients discontinued treatment due to adverse events.

Vepdegestrant is a potential new treatment option for previously treated ESR1-mutated, hormone receptor-positive, HER2-negative, advanced breast cancer, the researchers said.

Hamilton E, De Laurentiis M, Jhaveri, 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. ASCO 2025, abstract LBA1000.

This article was originally published in Dutch on MedNet.nl