New Hormonal Therapy Vepdegestrant Promising for Some Metastatic HR+ Breast Cancers

Vepdegestrant, a new oral SERD (called a PROTAC, or proteolosys-targeting chimera), led to better progression-free survival than Faslodex (chemical name: fulvestrant) in people with metastatic hormone receptor-positive, HER2-negative breast cancer with an ESR1 mutation that grew while being treated with hormonal therapy and a CDK4/6 inhibitor.

Progression-free survival is how long people live without the cancer growing.

The results from the VERITAC-2 trial were presented at the 2025 American Society of Clinical Oncology Annual Meeting (ASCO) and published simultaneously in The New England Journal of Medicine.

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  In people with cancers with an ESR1 mutation, progression-free survival was five months for people who received vepdegestrant and two months for people who received Faslodex.

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  More of the cancers responded to vepdegestrant. The overall response rate was about 19% for cancers treated with vepdegestrant compared to 4% for cancers treated with Faslodex.

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  Serious side effects were slightly more common in people who received vepdegestrant (10% vs. 9%), but only 3% of the people stopped treatment.

Vepdegestrant may be a new treatment for metastatic hormone receptor-positive, HER2-negative breast cancer that has stopped responding to hormonal therapy and a CDK4/6 inhibitor, but it isn’t approved by the U.S. Food and Drug Administration (FDA). The researchers plan to share the results of the study to support the drug’s approval.

Faslodex is a common option for treating metastatic hormone receptor-positive, HER2-negative breast cancer that grows while being treated with hormonal therapy and a CDK4/6 inhibitor,.

In many cases, the cancer grows because it develops a mutation in the ESR1 gene. It’s estimated that up to 40% of these types of breast cancers develop an ESR1 mutation. Besides making the cancer resistant to certain hormonal therapy medicines, ESR1 mutations also can make the cancer more likely to grow and spread.

So researchers have been working to develop new treatments for metastatic breast cancers that are resistant to hormonal therapy. Orserdu (chemical name: elacestrant) is another oral SERD that was approved in 2023 for metastatic hormone receptor-positive breast cancer with an ESR1 mutation.

Vepdegestrant is a PROTAC SERD and works to break down estrogen receptors in a different way than Orserdu. Orserdu had not been approved when this study began, so the researchers compared vepdegestrant to Faslodex.

The study included 624 people diagnosed with advanced-stage hormone receptor-positive, HER2-negative breast cancer that had grown during treatment with hormonal therapy and a CDK4/6 inhibitor; 99.5% were women.

The people were randomly assigned to receive one of two treatments:

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  313 people took vepdegestrant once each day; 136 of these people had cancers with ESR1 mutations

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  311 people received Faslodex injections; 134 of these people had cancers with ESR1 mutations

Vepdegestrant improved progression-free survival in people with cancers with ESR1 mutations, but this benefit wasn’t seen in people with cancers without ESR1 mutations.

Most of the side effects experienced by people who took vepdegestrant were mild or moderate, with fatigue, liver problems, and nausea being the most common.

“The findings from the VERITAC-2 study provide support for vepdegestrant as a potential oral treatment option for previously treated ESR1-mutated estrogen receptor-positive, HER2-negative advanced-stage breast cancer,” said Erika Hamilton, MD, director of Breast Cancer and Gynecologic Cancer Research at the Sarah Cannon Research Institute and lead author of the VERITAC-2 trial.

Hamilton, E., 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. 2025 ASCO Annual Meeting. Abstract LBA1000.