Arvinas (ARVN) Study Update summary

Study background and design

• VERITAC-2 was a global, randomized phase III trial comparing vepdegestrant (oral PROTAC ER degrader) to fulvestrant in ER+/HER2- advanced or metastatic breast cancer patients previously treated with endocrine therapy and a CDK4/6 inhibitor.

• 624 patients were enrolled globally, with 43% (n=270) having ESR1 mutations; patients were stratified by ESR1 mutation status and visceral disease.

• The primary endpoint was progression-free survival (PFS) by blinded independent central review in both ESR1 mutant and all-patient populations.

• Secondary endpoints included overall survival, clinical benefit rate (CBR), objective response rate (ORR), and safety.

• The study population reflected real-world second-line settings, with all patients having prior CDK4/6 inhibitor exposure.

Key efficacy results

• In ESR1 mutant patients, vepdegestrant achieved a statistically significant and clinically meaningful 2.9-month improvement in median PFS over fulvestrant (5.0 vs 2.1 months; HR 0.57, p<0.001).

• Six-month landmark PFS was 45.2% for vepdegestrant versus 22.7% for fulvestrant.

• CBR in ESR1 mutant tumors was 42.1% for vepdegestrant versus 20.2% for fulvestrant; ORR was 18.6% vs 4.0%.

• In the all-patient population, median PFS was similar between arms (3.7 vs 3.6 months; HR 0.83, p=0.07).

• PFS benefit was consistent across subgroups, including those with visceral disease, age, menopausal status, and prior therapy lines.

Safety and tolerability

• Vepdegestrant was generally well tolerated, with low rates of discontinuations (2.9-3%) and dose reductions (2%) due to adverse events.

• Most adverse events were grade 1 or 2; nausea occurred in 13-13.5% of patients, vomiting and diarrhea in less than 10%.

• Most common adverse events included fatigue (26.6%), increased ALT/AST (14.4%), anemia, neutropenia, and back pain.

• A small QT prolongation effect (11.1 ms) was observed, with no cases of torsade de pointes or discontinuations due to QT.

• Safety profile was consistent with previous studies and considered manageable.