Rationale and trial design of RIBOLARIS: A phase II trial of neoadjuvant and adjuvant ribociclib plus endocrine therapy for clinically high-risk HR+/HER2-negative breast cancer.

Background: Despite advances in endocrine therapy, patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (eBC) remain at risk of recurrence (ROR). Chemotherapy is often used in high-risk cases, but not all patients benefit. Objectives: To evaluate whether chemotherapy can be safely omitted in patients with stage II, grade 2/3 HR+/HER2- eBC who convert to low genomic risk (ROR-low) following neoadjuvant ribociclib plus letrozole. Methods: RIBOLARIS (NCT05296746) is an open-label, multicenter phase II trial in patients with stage II, grade 2 or 3, HR+/HER2- eBC defined as high risk based on a Ki-67 index ⩾20% and/or high genomic risk by a validated gene expression signature. All patients receive six 28-day cycles of neoadjuvant ribociclib (600 mg/day, 3 weeks on/1 week off) plus letrozole (2.5 mg/day). Following surgery, patients with ROR-low or pathological complete response continue adjuvant ribociclib (400 mg/day for 30 months) and endocrine therapy (⩾5 years), whereas patients with ROR-medium/high receive standard chemotherapy followed by ribociclib and endocrine therapy. The primary endpoint is 5-year distant metastasis-free survival (DMFS) in the ROR-low cohort. Interim futility analyses are planned at 300 and 800 patient-years (PYs), with the primary analysis after 1300 PYs. The study targets enrollment of 1100 patients, anticipating 400 ROR-low cases, providing ⩾90% power to detect a 5-year DMFS of 96% versus a benchmark of 90.6% (MINDACT trial high-risk subgroup). Discussion: RIBOLARIS is the first prospective trial to evaluate a chemotherapy-free, ribociclib-based strategy in high-risk HR+/HER2- eBC based on neoadjuvant molecular response. By integrating genomic risk reclassification into treatment decision-making, this study aims to demonstrate that patients achieving ROR-low status can maintain excellent long-term outcomes without chemotherapy, while avoiding unnecessary exposure to adjuvant chemotherapy, and to highlight the role of tumor profiling after neoadjuvant endocrine therapy plus cyclin-dependent kinase 4 and 6 inhibitors in optimizing post-neoadjuvant therapy. Trial registration: NCT05296746; EudraCT# 2021-002322-24.