VERITAC-2: A global, randomized phase 3 study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer.

TPS1122 Background: ARV-471 is an oral PROTAC ER degrader that binds to and degrades wild-type ER and clinically relevant mutants. ARV-471 directly recruits the ubiquitin-proteasome system to degrade ER, whereas selective ER degraders (SERDs) indirectly cause ER degradation. In a first-in-human phase 1/2 study, ARV-471 monotherapy was well tolerated and showed clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. The phase 3 monotherapy dose (200 mg once daily QD) was chosen due to comparable efficacy and favorable tolerability relative to 500 mg QD and robust ER degradation in paired tumor biopsies. The randomized phase 3 VERITAC-2 study (NCT05654623) will compare efficacy and safety of ARV-471 vs the SERD fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy and endocrine therapy (ET). Methods: Eligible patients (aged ≥18 years) have a confirmed diagnosis of ER+/HER2- locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation; 1 prior line of combination CDK4/6 inhibitor therapy and ET; ≤1 additional line of ET; most recent ET given for ≥6 months before disease progression; and radiological disease progression during or after the last line of therapy. Prior chemotherapy in the locally advanced or metastatic setting and prior fulvestrant are not permitted. Patients (N~560) are randomized 1:1 to receive 200 mg ARV-471 orally QD continuously or fulvestrant intramuscularly on days 1 and 15 in the first 28-day cycle and on day 1 in subsequent cycles; patients are stratified by ESR1 mutation status and presence of visceral disease. The primary endpoint, progression-free survival, will be assessed by blinded independent central review in the intention-to-treat population and the ESR1 mutation sub-population. Secondary outcome measures include overall survival, antitumor activity (objective response rate, duration of response, and clinical benefit rate), safety, and quality of life assessments. Clinical trial information: NCT05654623 .