Vepdegestrant Shows Promise for ESR1-Mutant breast Cancer

​ Updated‍ June 01, 2025
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A new drug, vepdegestrant, is showing promise in treating advanced breast cancer, ​specifically in patients with ‍estrogen receptor 1 (ESR1) mutations. The drug, an investigational estrogen receptor degrader, ⁤outperformed fulvestrant⁤ in a phase ‌3 trial.

The VERITAC-2 trial ⁣focused on patients with ER-positive/HER2-negative breast cancer who⁤ had previously been treated ⁤with cyclin-dependent kinase 4/6 inhibitors and endocrine⁣ therapy. The study revealed that vepdegestrant led ​to a ‌statistically significant and clinically meaningful⁢ advancement in progression-free survival (PFS) in the subset of patients with ESR1-mutant disease.

dr. erika ‌P. Hamilton, director of Breast Cancer​ and Gynecologic Cancer Research at Sarah Cannon Research Institute, presented the findings ‍at the 2025⁢ American Society of Clinical Oncology (ASCO) Annual Meeting. She noted that the results ‌support‍ vepdegestrant as a⁢ potential monotherapy option for patients ⁣with previously treated ESR1-mutant ER+/HER2- advanced breast cancer.

Vepdegestrant, currently under review by the FDA, has received fast-track status as a monotherapy for this patient population. It represents⁤ a‍ novel class of therapeutic⁢ agents known as PROTACs, which selectively degrade target proteins.

Hamilton‌ explained that there is no established consensus for second-line ⁤treatment after progression on endocrine therapy and a⁣ CDK 4/6 inhibitor. Fulvestrant, a common treatment, has limitations, including intramuscular governance and⁣ short progression-free survival.

The trial included 624 patients with advanced ER+/HER2-⁢ disease who had​ progressed following one or two lines of endocrine therapy and ‌a CDK 4/6 inhibitor. Patients had⁣ to ⁣have benefited from their previous line of endocrine⁤ therapy for at least 6⁢ months ‍to enter the study.

Patients were randomly ⁣assigned to receive either 200 ‌mg oral vepdegestrant once daily or 500 mg intramuscular fulvestrant.The⁤ primary endpoint was PFS in patients with ​ESR1‍ mutations and then in the entire cohort.

The study met its primary ⁤endpoint, demonstrating a median PFS of 5.0 ⁣months​ with vepdegestrant compared to 2.1 months with fulvestrant in​ patients ⁢with ESR1 mutations. However, this endpoint was not‌ significantly‍ different between groups when calculated for the entire patient ⁣population.

In patients with ESR1 mutations, the ⁢clinical benefit rate was more then double in those receiving vepdegestrant (42.1% vs 20.2%), and the objective‌ response rate was ⁢more than ⁢four times higher (18.6% vs 4%).

“These results support vepdegestrant as a potential monotherapy treatment option for patients with previously treated ESR1-mutant‍ ER+/HER2- advanced breast cancer,”‌ said lead author Erika P. Hamilton,⁢ MD.

Jane ‍Lowe ⁢Meisel,an ASCO breast cancer expert,commented ⁣that ‍while vepdegestrant worked better than fulvestrant in patients ‌with ESR1 mutations,patients did not have prolonged ⁣responses on either agent,highlighting the ‍need for combination therapies.

Treatment-emergent adverse events led to discontinuation in 3% of patients taking vepdegestrant and 1% of patients taking fulvestrant. the‍ most common adverse events were fatigue and increased aspartate aminotransferase and alanine aminotransferase levels.

Hamilton noted that vepdegestrant‌ has a favorable side effect profile compared to oral‍ SERDs, which often cause gastrointestinal issues.Rates of vomiting‌ and diarrhea were only 6% with vepdegestrant.

“Oral SERDs have prominent GI side effects as their most frequent side effect,” Hamilton said.

Dr. William John Gradishar emphasized the importance of reducing side effects, noting that‌ vepdegestrant ​joins a growing list ⁣of drugs that perform better than​ current standard of ​care monotherapy in the ESR1-mutant population.

“Vepdegestrant now joins a growing list ‌of drugs that perform better than current standard of care monotherapy” ⁤in the⁢ ESR1-mutant population, noted Dr. William John Gradishar.

Albert Grinshpun,⁣ head of the Breast Cancer Service at Shaare Zedek Medical Center, stated that vepdegestrant has ‍established⁣ itself as a promising endocrine backbone for future combination strategies‌ due to ⁤its favorable toxicity profile.

“Vepdegestrant has demonstrated compelling preclinical activity and encouraging early clinical​ data supporting its efficacy ⁢in degrading ER,” ​said ‌Albert Grinshpun, ⁣MD.

What’s next

Researchers are‍ now focusing ⁤on exploring combination therapies involving‌ vepdegestrant to further improve outcomes for patients with⁣ advanced breast cancer and ESR1 mutations. The ‌favorable toxicity profile of vepdegestrant⁤ makes it a promising​ candidate ‌for pairing ​with other targeted agents.