Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomized, phase 3 VERITAC-2 study.

Abstract

LBA1000 Background: Vepdegestrant, an oral PROTAC (PROteolysis TArgeting Chimera) ER degrader, showed encouraging clinical activity and was well tolerated in a phase 1/2 study in pretreated patients (pts) with aBC, and is the first PROTAC to be evaluated in a phase 3 trial (VERITAC-2). Methods: Eligible pts (aged ≥18 y) had ER+/HER2- aBC, 1 prior line of a cyclin-dependent kinase (CDK)4/6 inhibitor plus endocrine therapy (ET) and ≤1 additional line of ET (most recent ET given for ≥6 mo before disease progression); pts with prior chemotherapy in the advanced setting or prior fulvestrant were excluded. Pts were randomized 1:1 to vepdegestrant 200 mg orally once daily continuously or fulvestrant 500 mg intramuscularly (days 1 and 15 of cycle 1; day 1 of subsequent cycles); pts were stratified by ESR1 mutation status and presence of visceral disease. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in pts with ESR1 mutations ( ESR1m ) and all pts. Overall survival (OS) was a key secondary endpoint. PFS was tested by stratified 1-sided log-rank. Median PFS (mPFS) was estimated by Kaplan-Meier method and hazard ratio (HR) by a stratified Cox proportional hazard model; study was designed to detect HR<0.60 with 88% power in pts with ESR1m and HR<0.67 with 92.5% power in all pts (1-sided α=0.01875). Results: 624 pts (median age: 60.0 y [range 26–89]) were randomized (n=313 vepdegestrant; 311 fulvestrant); 43.3% had ESR1m tumors (n=136 vepdegestrant; 134 fulvestrant). PFS by BICR was significantly longer with vepdegestrant vs fulvestrant among pts with ESR1m (174 events, HR=0.57 [95% CI 0.42–0.77]; P =0.0001); mPFS (95% CI) was 5.0 mo (3.7–7.4) vs 2.1 (1.9–3.5). PFS by BICR in all pts was not significantly different (384 events, HR=0.83 [95% CI 0.68–1.02]; P =0.0358); mPFS (95% CI) was 3.7 mo (3.6–5.3) vs 3.6 (2.2–3.8). OS data are immature (20% of targeted events in all pts). In 619 treated pts, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. Grade ≥3 TEAEs occurred in 23.4% of pts in the vepdegestrant arm (vs 17.6% fulvestrant). The most common TEAEs in the vepdegestrant arm were fatigue (26.6% vs 15.6% fulvestrant), increased ALT (14.4% vs 9.8%), increased AST (14.4% vs 10.4%) and nausea (13.5% vs 8.8%). TEAEs led to discontinuation of vepdegestrant in 2.9% of pts (vs 0.7% fulvestrant). Conclusions: Vepdegestrant demonstrated statistically significant and clinically meaningful improvement in PFS vs fulvestrant in the ESR1m population. No statistically significant improvement in PFS was observed in the all-pt population. Vepdegestrant was generally well tolerated with low discontinuation rates due to TEAEs. Results support vepdegestrant as a potential oral treatment option for previously treated pts with ESR1m ER+/HER2- aBC. Clinical trial information: NCT05654623 .