Results from VERITAC-2, the first global phase 3 clinical trial of a PROTAC, a targeted therapy that breaks down the oestrogen receptors found on cancer cells, showed that the PROTAC vepdegestrant could extend progression-free survival for people with previously treated oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer with an ESR1 mutation.

The research was presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 30-June 3 in Chicago.

“Patients with oestrogen receptor-positive, human epidermal growth factor receptor 2 -negative advanced breast cancer whose tumours harbor ESR1 mutations have limited treatment options if the disease progresses and becomes resistant to available endocrine therapies.

Newer therapies with differentiated mechanisms of action, longer clinical benefit, and tolerable safety profiles that can improve outcomes are now emerging. The findings from the VERITAC-2 study provide support for vepdegestrant as a potential oral treatment option,” said lead study author Erika P. Hamilton, MD, Sarah Cannon Research Institute, Nashville, Tennessee.

Vepdegestrant is a type of investigational drug called a proteolysis-targeting chimera, or PROTAC. It works by targeting and breaking down the oestrogen receptors found on cancer cells, which can shrink or stop ER-positive breast cancers from growing.

Previous phase 1/2 research has shown that vepdegestrant might help improve outcomes in people with advanced breast cancer who have received other treatments, but VERITAC-2 is the first global phase 3 clinical trial to study the safety and efficacy of vepdegestrant in these patients.

VERITAC-2 enrolled 624 patients with ER-positive, HER2-negative advanced breast cancer. The patients, 99.5% of whom were women, ranged in age from 26 to 89 years old, with a median age of 60.

The patients in the study had already received treatment with hormone therapy and a CDK4/6 inhibitor. One additional line of hormone therapy was also allowed. Patients who previously received chemotherapy for advanced disease or who had already received fulvestrant were not eligible to enroll in the study.

Fulvestrant is a type of hormone therapy called a selective oestrogen receptor degrader (SERD) that indirectly leads to oestrogen receptor degradation.

In contrast, vepdegestrant directly degrades the oestrogen receptor because of its binding properties.

Key Findings

The patients were randomly assigned to receive treatment with either vepdegestrant (313 patients) or fulvestrant (311 patients). Vepdegestrant was taken orally each day, while fulvestrant was given intramuscularly on days 1 and 15 of the first cycle of treatment and day 1 of each subsequent treatment cycle. A total of 43.3% of patients had ESR1 mutations (136 patients in the vepdegestrant group and 134 in the fulvestrant group).

The researchers found that:

• For patients with ESR1 mutations, the median PFS for those who received vepdegestrant was 5 months vs. 2.1 months for those who received fulvestrant. However, the same PFS benefit was not seen when looking at vepdegestrant vs. fulvestrant in all patients regardless of ESR1 mutational status.
• The clinical benefit rate was 42.1% in the vepdegestrant group vs. 20.2% in the fulvestrant group.
• The overall response rate was 18.6% in the vepdegestrant group vs. 4% in the fulvestrant group.

Most of the side effects in the vepdegestrant group were mild or moderate, but severe side effects were slightly more common in this group. In these patients, 23.4% experienced a grade 3 or higher adverse event vs. 17.6% of those in the fulvestrant group.

Finally, few patients from either group discontinued treatment due to side effects, but more patients in the vepdegestrant group stopped treatment because of side effects (2.9% of patients vs. 0.7% in the fulvestrant group).

“In patients with hormone-sensitive metastatic breast cancers that harbored ESR1 mutations, the VERITAC-2 clinical trial found that vepdegestrant worked better than fulvestrant, making it a potential new option for patients in this setting. However, on average, patients did not have prolonged responses on either agent, highlighting the need for combination therapies and continued development in this space,” said Jane Lowe Meisel, MD, FASCO, Co-Director, Breast Medical Oncology, at the Winship Cancer Institute of Emory University School of Medicine, and an ASCO Expert in breast cancer.

Source: ASCO