Based on the findings of the VERITAC-2 trial, treatment with the selective PROTAC (proteolysis targeting chimera) estrogen receptor degrader vepdegestrant yielded statistically significant and clinically meaningful improvement in progression-free survival in patients with ESR1-mutant, estrogen receptor–positive, HER2-negative advanced breast cancer—but not in the all-patient population—compared with the endocrine therapy fulvestrant. These findings were presented at the 2025 ASCO Annual Meeting by Erika P. Hamilton, MD, Director of Breast Cancer Research at the Sarah Cannon Research Institute, Nashville, on behalf of her colleagues.1 In fact, this is the first PROTAC estrogen receptor degrader to be evaluated in a phase III trial. Vepdegestrant targets wild-type as well as mutant estrogen receptor.
Erika P. Hamilton, MD
“These results support vepdegestrant as a potential treatment option for previously treated patients with ESR1-mutated, estrogen receptor–positive, HER2-negative advanced breast cancer,” stated Dr. Hamilton during a press briefing prior to the ASCO Annual Meeting.
Study Details
Patients eligible for this global trial had estrogen receptor–positive, HER2-negative advanced breast cancer. Approximately 80% of patients had received one prior line of therapy (eg, a CDK4/6 inhibitor plus endocrine therapy), and about 20% had received two prior lines of therapy in the advanced or metastatic setting. Excluded from the trial were patients who had received prior chemotherapy in the advanced or metastatic setting or prior fulvestrant. In addition, “patients had to have benefited from their previous line of endocrine therapy for at least 6 months to enter the study,” Dr. Hamilton noted.
A total of 624 patients, with a median age of 60 years, were randomly assigned in a 1:1 fashion: 313 received 200 mg orally once daily continuously of vepdegestrant, and 311 received 500 mg intramuscularly of fulvestrant (days 1 and 15 of cycle 1; day 1 of each subsequent cycle). A total of 43.3% had ESR1-mutated tumors; of these patients, 136 were given vepdegestrant and 134 were given fulvestrant.
Progression-free survival by blinded independent central review in those with ESR1-mutated tumors and in all patients was the primary study endpoint. A key secondary endpoint was overall survival. Progression-free survival was tested by stratified one-sided log-rank. Median progression-free survival was estimated by the Kaplan-Meier method, and the hazard ratio (HR) was estimated by a stratified Cox proportional hazard model. The study was designed to detect a hazard ratio < 0.60 with 88% power in patients with ESR1-mutated tumors and a hazard ratio < 0.67 with 92.5% power in all patients (one-sided α = 0.01875).
Key Results and Safety
The median follow-up in the vepdegestrant arm was 7.4 months, and it was 6.0 months in the fulvestrant arm. Treatment was ongoing in nearly three times as many patients in the vepdegestrant arm as in the fulvestrant arm (33% vs 12%).
Among patients with ESR1-mutated tumors, progression-free survival by blinded independent central review was significantly longer with vepdegestrant than with fulvestrant (174 events, HR = 0.57 [95% confidence interval [CI] = 0.42–0.77]; two-sided P < .001). Specifically, the median progression-free survival was 5.0 months (95% CI = 3.7–7.4 months) vs 2.1 months (95% CI = 1.9–3.5 months), respectively. However, progression-free survival by blinded independent central review in all study patients did not significantly differ (384 events, HR = 0.83 [95% CI = 0.68–1.02]; P = .07); the median progression-free survival was 3.7 months (3.6–5.3 months) vs 3.6 months (2.2–3.8 months). The 6-month progression-free survival rate, however, was 45.2% with vepdegestrantand 22.7% with fulvestrant.
Jane Lowe Meisel, MD, FASCO
In terms of secondary endpoints, “the clinical benefit rate was more than double with vepdegestrant than with fulvestrant (42.1% vs 20.2%),” stated Dr. Hamilton. And, she added, the objective response rate was almost quadrupled with vepdegestrant vs fulvestrant (18.6% vs 4.0%).
“At the time of this analysis, overall survival was very immature, with only 20% of the anticipated events occurring,” she noted. Follow-up is ongoing.
In 619 treated patients, treatment-emergent adverse events were mostly grade 1 or 2. Grade ≥ 3 treatment-emergent adverse events were reported in 23.4% of patients who received vepdegestrant (vs 17.6% of those who received fulvestrant). In the vepdegestrant arm, the most common treatment-emergent adverse events were fatigue (26.6% vs 15.6% with fulvestrant), increased alanine transaminase (14.4% vs 9.8%), increased aspartate transaminase (14.4% vs 10.4%), and nausea (13.5% vs 8.8%). Treatment-emergent adverse events led to discontinuation of vepdegestrant in 2.9% of patients (vs in 0.7% of those given fulvestrant), and two patients given vepdegestrant required a dose reduction. No treatment-related deaths were reported.
Additional Commentary
ASCO expert Jane Lowe Meisel, MD, FASCO, Co-Director, Breast Medical Oncology, Winship Cancer Institute of Emory University School of Medicine, Atlanta, shared a few comments about the clinical significance of this research. “These results are exciting, and this drug, with its unique mechanism of action, has the potential to be a tolerable, convenient, and effective option for patients with previously treated, ESR1-mutated, estrogen receptor–positive, HER2-negative advanced breast cancer,” she stated. “There are a lot of exciting things happening in this space, and we look forward to seeing the results of studies combining vepdegestrant with other agents as well.”
DISCLOSURE: The study was jointed funded by Arvinas Estrogen Receptor and Pfizer. Dr. Hamilton has received institutional research funding from AbbVie, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Bicycle Therapeutics, Biohaven Pharmaceuticals, BioNTech, Compugen, Cullinan, Daiichi Sankyo, Dantari, Day One Biopharmaceuticals, Duality Biologics, Ellipses Pharma, Elucida Oncology, Exelixis, FujiFilm, Genmab, Gilead Sciences, H3 Biomedicine, Iambic Therapeutics, ImmunoGen, Inspirna, InventisBio, Jacobio, Jazz Pharmaceuticals, K-Group Beta, Kind Pharmaceuticals, Lilly, Loxo Oncology, Mabspace Biosciences, Mabwell Bioscience, Marengo Therapeutics, MediLink Therapeutics, Merck, Mersana, Novartis, Olema, Orinove, Orum Therapeutics, Pfizer, Pionyr Immunotherapeutics, Prelude Therapeutics, Profound Bio, Regeneron, Relay Therapeutics, Rgenix, Roche/Genentech, SeaGen, Shattuck Labs, Simcha Therapeutics, Stemline Therapeutics, Sutro, SystImmune, Taiho Pharmaceutical, Tesaro, TheRas, Treadwell Therapeutics, Verastem, Xadcera Biopharmaceutical, and Zymeworks; and has served as a consultant or advisor (with all payments to her institution) to Arvinas, AstraZeneca, BeiGene, Circle Pharma, Daiichi Sankyo, Entos, Gilead Sciences, Halda Therapeutics, Incyclix Bio, IQVIA, Janssen, Jazz Pharmaceuticals, Jefferies LLC, Johnson & Johnson, Lilly, Medical Pharma Services, Mersana Therapeutics, Novartis, Pfizer, Pyxis Oncology, Roche/Genentech, Samsung Bioepis, Shorla Pharma, Stemline Therapeutics, Tempus Labs, and Zentalis Pharmaceuticals Dr. Meisel has served as an advisor or consultant to Pfizer, AstraZeneca, Olema Pharmaceuticals, Sermonix Pharmaceuticals, Novartis, and Puma Biotechnology; and has received institutional research funding from AstraZeneca, Olema Pharmaceuticals, Sermonix Pharmaceuticals, and Pfizer.
REFERENCE
1. Hamilton EP, et al: 2025 ASCO Annual Meeting. Abstract LBA1000. Presented May 31, 2025.
