DOI: 10.6084/m9.figshare.26394822.v2
title: VERITAC-2: a Phase III study of vepdegestrant, a PROTAC ER degrader, versus fulvestrant in ER+/HER2- advanced breast cancer

description: Vepdegestrant (ARV-471) is an oral PROTAC ER degrader that binds an E3 ubiquitin ligase and ER to directly trigger ubiquitination of ER and its subsequent proteasomal degradation. In a first-in-human Phase I/II study, vepdegestrant monotherapy was well tolerated with clinical activity in pretreated patients with ER+/HER2- advanced breast cancer. The global, randomized Phase III VERITAC-2 study compares efficacy and safety of vepdegestrant versus fulvestrant in adults with ER+/HER2- advanced breast cancer after treatment with a CDK4/6 inhibitor plus endocrine therapy. Progression-free survival by blinded independent central review (primary end point) will be assessed in the intention-to-treat population and <i>ESR1</i> mutation-positive subpopulation. Secondary end points include overall survival, tumor response, safety, pharmacokinetics, patient-reported outcomes, and circulating tumor DNA biomarkers. <b>Clinical trial registration:</b>NCT05654623 (ClinicalTrials.gov) <b>VERITAC-2 is a clinical trial comparing vepdegestrant, a new drug that degrades estrogen receptors, to an existing treatment called fulvestrant in patients with ER+/HER2- advanced breast cancer:</b> Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer grows in response to estrogen, a hormone in the body, and has low levels or no HER2 protein. People living with ER+/HER2- advanced breast cancer that has grown, spread to another part of the body, or cannot be removed by surgery are often treated with cyclin-dependent kinase (CDK) 4/6 inhibitors and endocrine therapies, but their cancer may get worse on these treatments and new treatments are needed. Fulvestrant, an endocrine therapy that attaches to estrogen receptors, lowers estrogen's effect on tumors and can slow or stop cancer growth. Vepdegestrant, a new medicine being tested for ER+ breast cancer, is a PROteolysis TArgeting Chimera (PROTAC) protein degrader that attaches to estrogen receptors and causes them to be tagged for removal by the cell's natural protein disposal system. By removing estrogen receptors, vepdegestrant may cause tumors to stop growing or shrink. This paper describes the Phase III VERITAC-2 clinical study comparing vepdegestrant versus fulvestrant in people living with ER+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor and endocrine therapy. Patients will be randomly assigned to receive vepdegestrant (a pill taken once daily by mouth) or fulvestrant (a shot given into the muscle). The purpose of the study is to find out how long people live without their cancer getting worse with vepdegestrant or fulvestrant. VERITAC-2 will also look at how long people live during the study, side effects people may experience, and the overall well-being of people throughout the study. ER-mediated signaling is a key driver of breast cancer pathogenesis in ER+/HER2- breast cancer, which accounts for the majority of all breast cancers. Despite the initial efficacy of first-line treatments that use endocrine therapies (ETs), the acquisition of mutations in <i>ESR1</i> often leads to the development of ET resistance, leading to disease progression and poor outcomes; there is no clear standard of care in the second-line setting. Vepdegestrant is a small-molecule PROteolysis TArgeting Chimera (PROTAC) ER degrader that has a unique mechanism of action that harnesses the ubiquitin-proteasome system to induce direct ubiquitination and subsequent degradation of ER, unlike selective ER degraders, which lead to conformational changes in ER that may indirectly result in ER degradation. In preclinical studies, vepdegestrant demonstrated potent ER degradation and robust tumor growth inhibition and regression. In a first-in-human Phase I/II dose escalation and cohort expansion clinical study, vepdegestrant was well tolerated and demonstrated antitumor activity; the 200-mg once-daily dose of vepdegestrant was chosen as the recommended Phase III monotherapy dose. VERITAC-2 is an open-label, randomized, global, multicenter, Phase III study comparing the efficacy and safety of vepdegestrant with fulvestrant in adults with ER+/HER2- advanced breast cancer. Eligible patients have a confirmed diagnosis of ER+/HER2- locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation. Patients must also have had one line of prior treatment with CDK4/6 inhibitor therapy in combination with ET and no more than one additional line of ET wherein the most recent ET was given for ≥6 months before disease progression. The primary end point is progression-free survival in both the intention-to-treat population and <i>ESR1</i> mutation-positive subpopulation, and key secondary end points include overall survival, objective response rate, duration of response, clinical benefit rate, and safety and tolerability end points. This study plans to enroll 560 patients; enrollment is ongoing at the time of publication.