Journal Article

Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer

Jerzak, Katarzyna J., Ladoire, Sylvain, Lu, Dongrui R, Molckovsky, Andrea, Fontana, Andrea, Zhang, Yongqiang, Cui, Jiuwei, Cil, Timucin, Martignoni, Marcella, Zamagni, Claudio, Zhi, Xin, Rodriguez-Lescure, Alvaro, Guarneri, Valentina, Hamilton, Erika P., De Laurentiis, Michelino, Cazzaniga, Marina, Sezer, Ahmet, Demirci, Umut, Patsouris, Anne, Parameswaran, Janaki, Fuentes, Christian, Jhaveri, Komal, Yoshinami, Tetsuhiro, Valota, Olga, Campone, Mario, Hu, Xichun, Mouret-Reynier, Marie-Ange

2025

Overview

Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly harnesses the ubiquitin-proteasome system. In this phase 3, open-label, randomized trial, we enrolled patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer who had received one previous line of cyclin-dependent kinase 4 and 6 inhibitor therapy plus one line of endocrine therapy (and up to one additional line of endocrine therapy). Patients were randomly assigned in a 1:1 ratio to receive vepdegestrant at a dose of 200 mg orally once every day of each 28-day cycle or fulvestrant at a dose of 500 mg, administered intramuscularly, on day 1 and day 15 of cycle 1 and on day 1 of subsequent cycles, with randomization stratified according to -mutation status and presence or absence of visceral disease. The primary end point was progression-free survival as assessed by blinded independent central review among the patients with mutations and among all the patients who underwent randomization. Progression-free survival was estimated with Kaplan-Meier methods and hazard ratios with a stratified Cox proportional-hazards model. A total of 624 patients underwent randomization; 313 were assigned to receive vepdegestrant, and 311 to receive fulvestrant. Among the 270 patients with mutations, the median progression-free survival was 5.0 months (95% confidence interval [CI], 3.7 to 7.4) with vepdegestrant and 2.1 months (95% CI, 1.9 to 3.5) with fulvestrant (hazard ratio, 0.58 [95% CI, 0.43 to 0.78]; P<0.001). Among all the patients, the median progression-free survival was 3.8 months (95% CI, 3.7 to 5.3) with vepdegestrant and 3.6 months (95% CI, 2.6 to 4.0) with fulvestrant (hazard ratio, 0.83 [95% CI, 0.69 to 1.01]; P = 0.07). Adverse events of grade 3 or higher occurred in 23.4% of the patients in the vepdegestrant group and in 17.6% of the patients in the fulvestrant group. Adverse events led to treatment discontinuation in 2.9% and 0.7% of the patients, respectively. Among patients with ER-positive, HER2-negative advanced breast cancer, vepdegestrant was associated with significantly longer progression-free survival than fulvestrant in the subgroup with mutations but not in the full patient population. (Funded by Pfizer and Arvinas Estrogen Receptor; VERITAC-2 ClinicalTrials.gov number, NCT05654623.).

• Publisher: Massachusetts Medical Society
• Subject: Administration, Oral / Adult / Adverse events / Aged / Aged, 80 and over / Antineoplastic Agents, Hormonal / Antineoplastic Agents, Hormonal - administration & dosage / Antineoplastic Agents, Hormonal - adverse effects / Breast Cancer / Breast Neoplasms / Breast Neoplasms - drug therapy / Breast Neoplasms - genetics / Breast Neoplasms - mortality / Breast Neoplasms - pathology / Breast Neoplasms, Male / Breast Neoplasms, Male - drug therapy / Breast Neoplasms, Male - genetics / Breast Neoplasms, Male - mortality / Breast Neoplasms, Male - pathology / Cancer / Cancer therapies / Chimeras / Cyclin-dependent kinase / Cyclin-dependent kinase 4 / Cyclin-dependent kinases / Endocrine therapy / ErbB-2 protein / Estrogen Receptor alpha / Estrogen Receptor alpha - antagonists & inhibitors / Estrogen Receptor alpha - genetics / Estrogen Receptor alpha - metabolism / Estrogen Receptor Antagonists / Estrogen Receptor Antagonists - administration & dosage / Estrogen Receptor Antagonists - adverse effects / Estrogen receptors / Estrogens / Female / Fulvestrant / Fulvestrant - administration & dosage / Fulvestrant - adverse effects / Genetics / Genetics General / Hematology / Humans / Injections, Intramuscular / International organizations / Kaplan-Meier Estimate / Kinases / Life Sciences / Male / Metastasis / Middle Aged / Mutation / Oncology / Patients / Progression-Free Survival / Proteasomes / Proteolysis / Proteolysis Targeting Chimera / Proteolysis Targeting Chimera - administration & dosage / Proteolysis Targeting Chimera - adverse effects / Statistical analysis / Survival / Treatment Outcome / Treatment resistance / Treatments in Oncology / Tumors / Ubiquitin