Abstract PS4-04-09: Activity of capivasertib in a panel of ER+ breast XPDX models harboring PI3-K/Akt pathway and other known mutations

Abstract Background: Therapies targeting the PI3-K/Akt pathway are an active field of research. Capivasertib in combination with fulvestrant was recently approved in endocrine therapy-resistant, advanced or metastatic ER+/HER2- breast cancer patients harboring hotspot mutations in AKT, PIK3CA or PTEN genes. However, sensitivity to capivasertib therapy in ER+ breast cancers without these specific mutations is unclear. To this end, we established a panel of ER+ breast XPDX models with or without PI3-K/Akt pathway mutations and evaluated each in vivo with capivasertib alone or in combination with fulvestrant. Methods: Fifty-six previously developed XPDX models representing ER+ breast cancer were evaluated in this study. Models were grown subcutaneously in female athymic nude mice supplemented with estradiol in drinking water when necessary and ER expression confirmed at multiple passes; mutations in and out of the PI3-K/Akt pathway were determined by WES and RNAseq. For in vivo studies, capivasertib was administered twice daily by oral gavage at 100 mg/kg/dose on a four-days on/ three-days off cycle through study completion. Endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C<0%) versus Day 0 tumor volume was also reported. Results: Identified PI3-K/Akt pathway mutations included AKT1E17K (N=3), PIK3CAE542X/E545X/H1047X (N=17) and other PIK3CA variants (N=8); alterations in PTEN were also reported in some models. In this study, capivasertib was found active in 12/56 models, including partial or complete tumor regressions in 3/12 and tumor stasis in 2/12 models. 1/12 models with AKT1E17K, 5/17 models with PIK3CAE542X/E545X/H1047X and 3/8 models with other PIK3CA variants were found sensitive to single agent capivasertib. Interestingly, the most sensitive model tested harbored only a PTEN deletion in the PI3-K/Akt pathway and 2/3 of the most sensitive models were established from HER2+ patients. In addition, co-treatment with fulvestrant antagonized efficacy in several of the sensitive models. Conclusion: We have benchmarked a panel of ER+ breast XPDX models with capivasertib alone and in combination with fulvestrant and compared activity of models based on mutations in and out of the PI3-K/Akt pathway. This data is a valuable tool in developing PI3-K/Akt pathway therapies in ER+ breast cancer. Citation Format: C. Nelson, J. Flores, M. Lopez, A. Simonson, A. Nunez, S. Johnson, A. Rojas, A. Stackpole, J. Lund, P. Forofontov, L. Wilson, J. Garcia, I. Sturgill, A. Cunningham, M. Wick. Activity of capivasertib in a panel of ER+ breast XPDX models harboring PI3-K/Akt pathway and other known mutations [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 PS4-04-09.