ASCO 2025: PROTAC therapy shows promise for advanced breast cancer patients with ESR1 mutations
The clinically meaningful benefit of vepdegestrant for advanced breast cancer patients with ESR1 mutations has been demonstrated.
A first-of-its-kind Phase III trial, VERITAC-2, has demonstrated that the PROTAC vepdegestrant could extend progression-free survival in patients with previously treated ER-positive, HER2-negative advanced breast cancer harboring ESR1 gene mutations. The data from the trial, presented at the ASCO Annual Meeting (May 30–June 3, IL, USA), highlights the clinically meaningful benefit of this treatment for a patient population currently with limited treatment options.
Estrogen receptor (ER)-positive breast cancer is a subtype of hormone receptor (HR)-positive breast cancer. In the USA, HR-positive, HER2-negative is the most prevalent subtype of breast cancer. Currently, the standard first-line treatment for these patients is hormone therapy combined with a CDK4/6 inhibitor. However, resistance to treatment can develop in many patients with an ESR1 gene mutation, leaving them with limited treatment options if the disease progresses and becomes resistant to available endocrine therapies.
To address this unmet need, studies have been conducted into new treatment options, including proteolysis-targeting chimeras (PROTACs) – a targeted therapy that works by breaking down estrogen receptors found on cancer cells. The VERITAC-2 trial is the first Phase III trial to evaluate a PROTAC, and vepdegestrant is the first PROTAC estrogen-receptor degrader to be evaluated in breast cancer patients.
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The trial enrolled 624 participants with ER-positive, HER2-negative advanced breast cancer who had previously been treated with hormone therapy and a CDK4/6 inhibitor. Participants were randomly assigned to receive either vepdegestrant (313 patients) or the hormone therapy fulvestrant (311 patients), with 43.3% of participants having confirmed ESR1 mutations.
The results demonstrated that the median progression-free survival for patients with an ESR1 mutation was 5 months for those who received vepdegestrant and 2.1 months for those who received fulvestrant. Further to this, the clinical benefit rate and overall response rate for those receiving vepdegestrant were 42.1% and 18.6% respectively, compared to 20.2% and 4% in those receiving fulvestrant.
However, the same progression-free survival benefit was not observed across the entire study population, regardless of ESR1 mutational status. “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 (ASCO Expert in Breast Cancer).
Overall, the results demonstrate the clinically meaningful benefit of vepdegestrant as a potential treatment option for previously treated patients with ESR1-mutated ER-positive, HER2-negative advanced breast cancer. Next, the researchers will share the VERITAC-2 data with global regulatory authorities with the aim of finding support for drug approval.