Abstract PS5-07-26: Ribociclib with fulvestrant versus physician's choice treatments in patients who recurred after completion of adjuvant cyclin-dependent kinase 4/6 inhibitors as first-line treatment in HR+, HER2- advanced breast cancer

Abstract Background: The NATALEE phase 3 trial demonstrated a significant reduction in the risk of invasive disease recurrence when ribociclib was added to endocrine therapy in patients with early-stage hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer at intermediate to high risk of recurrence, which supports the expanding therapeutic role of ribociclib from the advanced to the adjuvant setting. However, optimal treatment after recurrence following adjuvant cyclin dependent kinase 4/6 (CDK4/6) inhibitor remains a clinical concern. While postMONARCH and EMBER3 showed benefits of maintaining CDK4/6 inhibitors after disease progression in advanced setting, there remains an unmet need to determine the optimal treatment after recurrence after adjuvant CDK4/6 inhibitor therapy. Method: This randomized, phase 2, open-label, multicenter trial aims to compare the efficacy and safety of ribociclib plus fulvestrant versus physician’s choice treatments (PCT) in patients with distant recurrent HR+/HER2- breast cancer after completing adjuvant CDK4/6 inhibitor therapy. Patients will be randomized in a 1:1 ratio to either the treatment arm (ribociclib and fulvestrant) or the control arm (PCT: fulvestrant or exemestane plus everolimus). Leuporelin will be incorporated into peri and premenopausal patients. Eligible participants include men or pre-, peri-, postmenopausal women aged ≥19 with HR+/HER2- advanced breast cancer based on most recently analyzed biopsy that recurred at least one year after the last dose of adjuvant CDK4/6 inhibitor. The patients must have had previously received at least 1 year of adjuvant abemaciclib or ribociclib and a minimum of 2 years of adjuvant endocrine therapy (either alone or in combination with CDK4/6 inhibitors). Additional inclusion criteria include Eastern Cooperative Oncology Group performance status of 0 or 1 and evidence of at least one measurable lesion according to RECIST v1.1. Patients whose cancer recurs 1 year or later after completing adjuvant endocrine therapy or those who have been free from endocrine therapy for at least 2 years will be excluded. The primary objective is to determine whether ribociclib with fulvestrant prolongs progression-free survival (PFS) compared to PCT. PFS will be determined based on local tumor assessment using RECIST v1.1. Assuming a median PFS of 6.75 months in the control arm and 9 months in the treatment arm, the target hazard ratio was 0.75. Using the O'Brien-Fleming boundary with a one-sided type I error rate of 10% and 80% power, the total required sample size was 272 patients (136 per arm). The planned overall study duration is 72 months (36 months for accrual and randomization, 36 months of follow-up for primary endpoint PFS). This trial received local Institutional Review Board approval and is registered in ClinicalTrials.gov (NCT06849947). Citation Format: H. Ahn, J. Shin, J. Kim, J. Ahn, Y. Park. Ribociclib with fulvestrant versus physician's choice treatments in patients who recurred after completion of adjuvant cyclin-dependent kinase 4/6 inhibitors as first-line treatment in HR+, HER2- advanced 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 PS5-07-26.