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

Author(s): Mario Campone, M.D., Ph.D.¹; Michelino De Laurentiis, M.D., Ph.D.²; Komal Jhaveri, M.D.^3,4; Xichun Hu, M.D., Ph.D.⁵; Sylvain Ladoire, M.D., Ph.D.⁶; Anne Patsouris, M.D., Ph.D.⁷; Claudio Zamagni, M.D.⁸; Jiuwei Cui, M.D., Ph.D.⁹; Marina Cazzaniga, M.D.¹⁰; Timucin Cil, M.D.¹¹; Katarzyna J. Jerzak, M.D.¹²; Christian Fuentes, M.D.¹³; Tetsuhiro Yoshinami, M.D., Ph.D.¹⁴; Alvaro Rodriguez-Lescure, M.D., Ph.D.¹⁵; Ahmet Sezer, M.D. https://orcid.org/0000-0002-6445-1439¹⁶; Andrea Fontana, M.D., Ph.D.¹⁷; Valentina Guarneri, M.D., Ph.D.^18,19; Andrea Molckovsky, M.D.²⁰; Marie-Ange Mouret-Reynier, M.D.²¹; Umut Demirci, M.D., Ph.D.²²; Yongqiang Zhang, M.D.²³; Olga Valota, M.S.²⁴; Dongrui R Lu, M.S.²⁵; Marcella Martignoni, Ph.D.²⁴; Janaki Parameswaran, M.D.²⁶; Xin Zhi, Ph.D.²⁶; Erika P. Hamilton, M.D.²⁷; the VERITAC-2 Study Group*²⁸;

Source: N Engl J Med 2025;393:556-568

Dr. Maen Hussein's Thoughts

Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly utilizes the ubiquitin–proteasome system. It was compared to fulvestrant in patients who had received one prior line of hormonal therapy with a CDK4/6 inhibitor. Among patients with ESR1 mutations, Vepdegestrant demonstrated a median progression-free survival (PFS) of 5.0 months versus 2.1 months with fulvestrant. In the overall population, the median PFS was 3.8 months for Vepdegestrant and 3.6 months for fulvestrant, indicating that the drug showed particular efficacy in tumors harboring ESR1 mutations.

BACKGROUND

Vepdegestrant is an oral proteolysis-targeting chimera (PROTAC) estrogen receptor (ER) degrader that directly harnesses the ubiquitin–proteasome system.

METHODS

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 ESR1-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 ESR1 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. Research Summary Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Breast Cancer

RESULTS

A total of 624 patients underwent randomization; 313 were assigned to receive vepdegestrant, and 311 to receive fulvestrant. Among the 270 patients with ESR1 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

CONCLUSIONS

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 ESR1 mutations but not in the full patient population. (Funded by Pfizer and Arvinas Estrogen Receptor; VERITAC-2 ClinicalTrials.gov number, NCT05654623.)

Author Affiliations

¹Institut de Cancérologie de l’Ouest Angers-Nantes, Saint-Herblain, France; ²Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale,” Naples, Italy; ³Memorial Sloan Kettering Cancer Center, New York; ⁴Weill Cornell Medical College, New York; ⁵Shanghai Cancer Center, Fudan University, Shanghai, China; ⁶Centre Georges Francois Leclerc, Dijon, France; ⁷Institut de Cancérologie de l’Ouest Angers-Nantes, Angers, France; ⁸IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy; ⁹First Hospital of Jilin University, Changchun, China; ¹⁰Phase 1 Research Unit, Fondazione IRCCS San Gerardo, Monza, Italy; ¹¹Health and Science University, Adana City Hospital, Adana, Turkey; ¹²Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto; ¹³Fundación Respirar, Buenos Aires; ¹⁴Graduate School of Medicine, Osaka University, Osaka, Japan; ¹⁵Hospital General Universitario de Elche, Elche, Spain; ¹⁶Baskent University Adana Application and Research Center, Adana, Turkey; ¹⁷Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; ¹⁸Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy; ¹⁹University of Padova, Padua, Italy; ²⁰Grand River Regional Cancer Centre, Kitchener, ON, Canada; ²¹Centre Jean Perrin, Clermont-Ferrand, France; ²²Memorial Ankara Hospital, Ankara, Turkey; ²³Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing; ²⁴Pfizer, Milan; ²⁵Pfizer, San Diego, CA; ²⁶Arvinas Operations, New Haven, CT; ²⁷Breast Cancer Research Program, Sarah Cannon Research Institute, Nashville

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