Abstract PD10-03: Subgroup analyses of VERITAC-2: A phase 3 trial of vepdegestrant, a PROTAC estrogen receptor (ER) degrader, versus fulvestrant in ER-positive/ human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC)

Abstract Background: Vepdegestrant is an oral PROTAC ER degrader. The VERITAC-2 study (NCT05654623), the first phase 3 trial of a PROTAC, demonstrated statistically significant and clinically meaningful prolongation of progression-free survival (PFS) with vepdegestrant versus fulvestrant in patients (pts) with ER+/HER2- aBC who were previously treated with endocrine therapy (ET) and a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and had ESR1 mutations (ESR1m). Here, we report the results of prespecified subgroup analyses of PFS among pts with ESR1m. Methods: Eligible pts (aged ≥18 years) with ER+/HER2- aBC had received 1 prior line of CDK4/6i + ET, and ≤1 additional line of ET (the most recent line of ET must have been given for ≥6 months before disease progression); pts with prior chemotherapy in the metastatic setting or prior fulvestrant were excluded. Pts were randomized (1:1) to receive vepdegestrant 200 mg orally once daily or fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles; randomization was stratified by ESR1m status and the presence of visceral disease. The primary endpoint, PFS by blinded independent central review (BICR), was assessed across prespecified clinically relevant subgroups without adjustments for multiplicity. Results: In total, 270 pts with ESR1m were randomized to vepdegestrant (n=136) or fulvestrant (n=134). Across groups, the median age was 60.0 years, 21% of pts were premenopausal or perimenopausal, 80% had received prior CDK4/6i therapy for ≥12 months, 45% had liver metastases, and 42% had a PIK3CA, AKT1, or PTEN mutation at baseline. Consistent with the primary analysis, benefit was observed in PFS by BICR with vepdegestrant versus fulvestrant across all prespecified subgroups ( Table ). Conclusions: Vepdegestrant demonstrated PFS benefit compared with fulvestrant across all prespecified, clinically relevant subgroups of previously treated pts with ESR1m ER+/HER2- aBC. These analyses provide further information in key prognostic patient subgroups that may inform clinical treatment decisions for pts with ESR1m. Citation Format: E. P. Hamilton, M. De Laurentiis, K. Jhaveri, X. Hu, S. Ladoire, A. Patsouris, C. Zamagni, J. Cui, M. Cazzaniga, T. Cil, K. J. Jerzak, C. Fuentes, T. Yoshinami, A. Rodriguez-Lescure, O. Valota, D. R. Lu, M. Martignoni, S. Dychter, M. Lachowicz, X. Zhi, M. Campone. Subgroup analyses of VERITAC-2: A phase 3 trial of vepdegestrant, a PROTAC estrogen receptor (ER) degrader, versus fulvestrant in ER-positive/ human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD10-03.