Abstract PO2-19-10: CAPItello-292 Phase 3: An open-label, randomized study of capivasertib, fulvestrant, and investigator’s choice of CDK4/6 inhibitor (palbociclib or ribociclib) in HR+/HER2– advanced breast cancer
Authors: Rugo Hope , Pistilli Barbara , Collins Julie , D’Cruz Celina , Gresty Christopher , Sommavilla Roberto , Sudhan Dhivya , Miller Claire , Ha Juyoung , Neven Patrick 
Published: May 2024

Abstract
Background: Overcoming resistance to endocrine therapy in advanced breast cancer (ABC) is a major challenge, and there remains an unmet need for safe and efficacious treatment options. AKT pathway activation is implicated in resistance to endocrine therapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) ABC. In the Phase 3 CAPItello-291 study, capivasertib (a potent inhibitor of all three AKT isoforms) plus fulvestrant significantly improved progression-free survival (PFS) versus fulvestrant in patients with aromatase inhibitor-resistant HR+/HER2– ABC. Simultaneous inhibition of the AKT and CDK4/6 pathways may delay CDK4/6 inhibitor resistance or re-sensitize tumors to endocrine therapy plus CDK4/6 inhibitors, leading to improved clinical outcomes. CAPItello-292 is an ongoing Phase 1b/3 study examining the efficacy and safety of adding capivasertib to fulvestrant plus a CDK4/6 inhibitor in HR+/HER2– ABC. Phase 1b has previously confirmed the recommended Phase 3 dose (RP3D) in combination with palbociclib to be tolerable with preliminary signals of clinical activity; determination of the RP3D in combination with ribociclib is currently being explored.
Trial design: The Phase 3 component of CAPItello-292 is an open-label, randomized study assessing the efficacy of the addition of capivasertib to fulvestrant and the investigator’s choice of CDK4/6 inhibitors (either palbociclib or ribociclib) in patients with HR+/HER2− ABC following recurrence or progression on or within 12 months of the end of (neo)adjuvant endocrine therapy (HER2− defined as immunohistochemistry [IHC] 0, or 1-positive or IHC2-positive/in situ hybridization-negative). Approximately 628 patients will be randomized 1:1 to receive capivasertib (400 mg, oral twice daily, 4 days on and 3 days off) plus fulvestrant (500 mg intramuscularly every 28 days plus loading dose on cycle 1, day 15) and investigator’s choice of CDK4/6 inhibitor (125 mg palbociclib once daily for 21 days of each 28-day cycle or ribociclib at the determined RP3D) or fulvestrant plus investigator’s choice of CDK4/6 inhibitor alone. Patients will be treated until disease progression, unacceptable tolerability, or withdrawal of consent. Treatment beyond progression is permitted for patients with clinical benefit at the investigator’s discretion.
The primary endpoint is PFS (by blinded independent central review [BICR]). The secondary endpoints include PFS in patients with AKT pathway-altered tumors, overall survival, time to second progression or death, objective response rate, duration of response, clinical benefit rate (all by BICR), physical functioning, global health status/quality of life and safety.
The study plans to enroll patients from 23 countries and is planned to start at the end of 2023.
Clinical trial identification: NCT04862663.
Funding: CAPItello-292 is supported by AstraZeneca
Editorial acknowledgment: AstraZeneca-funded medical writing support was provided by Suzanne Patel, Ph.D., from BOLDSCIENCE Inc.
Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).
Citation Format: Hope Rugo, Barbara Pistilli, Julie Collins, Celina D’Cruz, Christopher Gresty, Roberto Sommavilla, Dhivya Sudhan, Claire Miller, Juyoung Ha, Patrick Neven. CAPItello-292 Phase 3: An open-label, randomized study of capivasertib, fulvestrant, and investigator’s choice of CDK4/6 inhibitor (palbociclib or ribociclib) in HR+/HER2– advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-10.