A new oral therapy may significantly delay disease progression in patients with ESR1-mutated, ER-positive, HER2-negative advanced breast cancer, according to results presented at the 2025 ASCO Annual Meeting. The phase 3 VERITAC-2 trial found that vepdegestrant, an investigational proteolysis-targeting chimera (PROTAC), nearly doubled progression-free survival (PFS) in this patient population compared to standard therapy with fulvestrant.
ESR1 mutations are associated with resistance to existing endocrine therapies, leaving few effective options for patients whose disease has advanced. Vepdegestrant, which directly degrades estrogen receptors on cancer cells, offers a novel mechanism of action distinct from selective estrogen receptor degraders like fulvestrant, which degrade receptors indirectly.
In the VERITAC-2 study, 624 patients with previously treated ER-positive, HER2-negative advanced breast cancer were randomized to receive either oral vepdegestrant or intramuscular fulvestrant. Among patients with ESR1 mutations, present in 43.3% of the cohort, median PFS was 5.0 months with vepdegestrant, compared to just 2.1 months with fulvestrant. However, the PFS advantage was not observed in the overall population regardless of mutation status.
Clinical benefit and response rates also favored vepdegestrant. The clinical benefit rate reached 42.1% with vepdegestrant versus 20.2% with fulvestrant. The overall response rate was 18.6% versus 4.0%, respectively.
Adverse events were mostly mild to moderate across both groups, although grade 3 or higher events occurred in 23.4% of vepdegestrant-treated patients, compared to 17.6% in the fulvestrant group. Discontinuation due to side effects remained low, though slightly higher for vepdegestrant (2.9% vs. 0.7%).
Researchers intend to submit these findings to regulatory authorities to support potential approval of vepdegestrant as a targeted treatment for patients with ESR1-mutated breast cancer.
Reference:
American Society of Clinical Oncology. Vepdegestrant Could Extend Progression-Free Survival for Some People With ESR1-Mutated Advanced Breast Cancer. May 31, 2025. Available at: https://asco1.sharefile.com/share/view/6ee8af44187f42b3/fod471b5-6c79-44e5-babd-39022782c4e4. Last accessed: 31 May, 2025. [Press release].
