NATALEE: Phase III study of ribociclib (RIBO) + endocrine therapy (ET) as adjuvant treatment in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) early breast cancer (EBC).

TPS597 Background: RIBO is a selective inhibitor of CDK4/6 with demonstrated efficacy and is well tolerated when combined with ET in pre-/peri- and postmenopausal women with HR+, HER2– advanced breast cancer. Given these findings and considering the role of CDK4/6–Rb–E2F pathway dysregulation in ET resistance, there is a rationale for evaluating whether RIBO + ET prevents, or delays acquired resistance to ET in the adjuvant setting, to improve invasive disease-free survival (iDFS). Methods: The phase 3 multicenter, randomized, open-label NATALEE trial will evaluate the efficacy and safety of RIBO + ET as adjuvant treatment in patients with HR+, HER2– EBC. Eligible women (any menopausal status) and men aged ≥ 18 years will be randomized to RIBO 400 mg/day (3 weeks on/1 week off) + ET or ET alone. In both arms, ET will comprise daily continuous letrozole 2.5 mg/day or anastrozole 1 mg/day; men and premenopausal women will also receive goserelin 3.6 mg once every 28 days. Treatment with RIBO will last 36 months whereas treatment with ET (in both arms) will last 60 months. Patients must have had American Joint Committee on Cancer (8 th ed.) Anatomic Stage II (either N0 with grade 2-3 and/or Ki67 ≥ 20% or N1) or III EBC, with an initial diagnosis ≤ 18 months prior to randomization, and completed chemotherapy and radiotherapy (if indicated). Patients receiving standard (neo)adjuvant ET are eligible only if this treatment was initiated within 12 months of randomization. Key exclusion criteria include previous CDK4/6 inhibitor treatment and clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality. The primary endpoint is iDFS using STEEP (Standardized Definitions for Efficacy End Points) criteria as assessed by the investigator; secondary endpoints include recurrence-free survival, distant DFS, overall survival, patient-reported outcomes, and RIBO pharmacokinetics. Safety and tolerability will also be evaluated. Estimated enrollment is 4000 patients from 425 sites in 21 countries. Recruitment is ongoing. Clinical trial information: NCT03701334.