Abstract PS5-07-17: A prospective, direct-to-patient study to evaluate clinical and molecular mechanisms of resistance to capivasertib in estrogen receptor-positive metastatic breast cancer

Abstract Background: The PI3K pathway is activated in approximately 40% of estrogen receptor-positive (ER+) breast cancers and is a key therapeutic target in ER+ metastatic breast cancer (MBC). PI3Kα inhibitors including alpelisib and inavolisib improve progression free survival (PFS) in PIK3CA-mutated ER+ MBC, but are often associated with high-grade toxicities such as hyperglycemia. AKT is a key downstream effector in the PI3K pathway, and the AKT inhibitor capivasertib was FDA approved in November 2023 for patients with ER+ MBC harboring mutations in PIK3CA, AKT1, and/or PTEN. In the CAPItello-291 trial, capivasertib combined with fulvestrant more than doubled PFS to 7.3 months versus 3.1 months with fulvestrant alone, and exhibited a favorable toxicity profile. However, despite initial disease responses, almost all patients eventually progress on therapy. Preclinical studies have identified several resistance mechanisms to AKT inhibitors including reactivated PI3K pathway signaling and increased compensatory signaling of parallel pathways. However, there are no validated clinical biomarkers of resistance to capivasertib. Understanding the clinical mechanisms of capivasertib resistance is critical to identifying patients who may not benefit from capivasertib and to informing subsequent therapeutic strategies. Methods: We are conducting a pragmatic, decentralized study enrolling patients treated at any medical institution who are starting capivasertib (n = 20). Eligibility criteria include 1) ER+ MBC with mutations in PIK3CA, AKT1, and/or PTEN, 2) no prior treatment with a PI3K pathway inhibitor, and 3) plans to initiate capivasertib as the next line of therapy. Participants are asked to collect circulating tumor DNA (ctDNA) at two time points: 1) before or within 2 weeks of starting capivasertib and 2) after progression on or discontinuation of capivasertib. The study uses a decentralized design in which participants are mailed liquid biopsy kits to their home and collect blood samples locally, with the goal of facilitating more rapid and inclusive enrollment. Recruitment is under way using social media channels, patient advocacy groups, and multi-institutional collaborative groups. Interim clinical data is collected from local medical records while participants remain on capivasertib. After sample collection is complete, pre- and post-treatment samples will be analyzed using whole exome and whole transcriptome sequencing via the Caris Assure platform. Paired ctDNA samples from each participant will be compared to identify acquired genomic and transcriptomic alterations on capivasertib. We hypothesize that alterations in negative regulators of mTORC1 and parallel pathways such as PIM signaling will drive clinical resistance to capivasertib. The study is approved by the Columbia University Irving Medical Center (CUIMC) Institutional Review Board and was developed in collaboration with the patient advocacy group PIK3CA Pathbreakers. Since January 2025, 10 patients have been enrolled and provided pre-treatment ctDNA samples. Further study details are available at https://contributeher.wixsite.com/capivaresistance. Citation Format: J. J. Tao, E. Harden, A. Johnston, C. M. Sathe, J. E. McGuinness, M. S. Trivedi, M. K. Accordino, K. D. Crew, D. L. Hershman, N. Vasan. A prospective, direct-to-patient study to evaluate clinical and molecular mechanisms of resistance to capivasertib in estrogen receptor-positive metastatic breast cancer 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 PS5-07-17.