Vepdegestrant Improves Outcomes in ESR1-Mutant ER-Positive Metastatic Breast Cancer

Clinical Summary:

• Design/Population: The phase 3 VERITAC-2 trial randomized patients with ER-positive, HER2-negative metastatic breast cancer who had progressed on a CDK4/6 inhibitor to receive either vepdegestrant or fulvestrant.  The study evaluated progression-free survival in the overall population and in the ESR1-mutant subgroup. 
• Key Outcomes: Vepdegestrant improved progression-free survival compared with fulvestrant in patients with ESR1-mutated tumors but did not achieve a statistically significantly benefit in the overall population. Treatment was generally well tolerated, with mostly low-grade toxicities and low discontinuation rates. 
• Clinical Relevance: these findings establish vepdegestrant as the first approved PROTAC for patients with ER-positive, HER2-negative metastatic breast cancer with ESR1 mutations and expand endocrine treatment options following CDK4/6 inhibitor therapy.

Komal Jhaveri, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses results from the phase 3 VERITAC-2 trial, evaluating vepdegestrant, the first proteolysis-targeting chimera (PROTAC) to receive regulatory approval for breast cancer. The study compared vepdegestrant with fulvestrant in patients with ER-positive, HER2-negative metastatic breast cancer following progression on prior CDK4/6 inhibitor therapy.

The trial demonstrated a clinically meaningful progression-free survival benefit among patients with ESR1-mutant disease while maintaining a favorable safety profile. These findings support vepdegestrant as a new endocrine therapy option for patients with ESR1-mutant metastatic breast cancer and add to the growing number of targeted endocrine therapies available in this setting.

Transcript:

Hi, my name is Komal Jhaveri, and I'm a breast medical oncologist at Memorial Sloan Kettering Cancer Center in New York. Today we'll be talking about the phase 3 VERITAC-2 study, the registrational trial that recently led to the approval of the very first-in-human PROTAC of proteolysis-targeting chimera, vepdegestrant for ER-positive HER2-negative metastatic breast cancer whose tumors harbor ESR1 mutations.

The VERITAC-2 study evaluated vepdegestrant against fulvestrant, another SERD. The dose for vepdegestrant in this trial was 200 mg orally daily. These were patients who had had progression on a prior CDK4/6 inhibitor therapy in the metastatic setting and up to 1 additional line of endocrine therapy was also permitted. 

Predominantly this was a second-line trial, 624 patients were randomized 1:1 to receiving vepdegestrant versus fulvestrant for dual primary end points looking at progression-free survival for all patients and those with ESR1 mutations.

What we learned from this study was that the study met its end point in ESR1-mutant tumors, in that there was an improvement in progression-free survival in the order of 5 months with vepdegestrant compared to 2 months with fulvestrant alone. When we looked at all patients, that included the ESR1 as well, there the study did not meet statistical significance. The median PFS was 3.8 for the vepdegestrant arm compared to 3.6 months. Really this is why the drug is now approved for ESR1-mutant tumors. 

It's a very well tolerated therapy, we see predominantly low-grade toxicities. We don't really see a lot of high-grade toxicities. In fact, treatment discontinuation rates were also rather low. The most common toxicities that we would think about with vepdegestrant are a little bit of fatigue. We don't see a whole lot of diarrhea or other GI side effects with this molecule. There was some signal of bradycardia, however, a small study was also done as a substudy to look at QTc prolongation and there we did not see a prolonged QTc clinically impactful QTc prolongation. Overall, very well-tolerated therapy. There's been 3% of the patients that had treatment discontinuations, so this drug, as we said, is approved.

Another option that we have for ESR1 mutant tumors, we already had approval for elacestrant back in January of 2023. More recently, we had approval for imlunestrant, another oral SERD in September of 2025. As of this year now, we have approval for this PROTAC of vepdegestrant.

One would wonder how do we think about vitalizing these drugs? We as oncologists always like options for our patients. While they're all very well tolerated, there are slight differences in their toxicity profiles that one could think about. Some of these drugs such as imlunestrant, we have some combination data available with elacestrant. We also have phase 1/2 combination data. There are ongoing studies for vepdegestrant and some combinations. Currently, the approval for vepdegestrant is as monotherapy. As I said, we have options that we could consider for our patients in clinic.

Source:

US Food and Drug Administration. FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. Accessed on May 1, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vepdegestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast

Campone M, Michelino De Laurentiis, Jhaveri K, et al. Vepdegestrant, a PROTAC estrogen receptor degrader, in advanced breast cancer. N Engl. J Med. Published online: May 31, 2025. doi:10.1056/nejmoa2505725