Abstract
IMPORTANCE: Cyclin-dependent kinase (CDK) 4 and 6 inhibitors (CDK4/6i) combined with endocrine therapy are widely used in hormone receptor (HR)-positive, ERBB2-negative advanced breast cancer (ABC). The SONIA trial evaluates the optimal timing of CDK4/6i administration, either in first-line or second-line setting. OBJECTIVE: To determine whether first-line CDK4/6i use is superior to second-line use in terms of overall survival (OS) and to provide an updated analysis of the primary end point of progression-free survival (PFS) after 2 lines of therapy. DESIGN, SETTING, AND PARTICIPANTS: The phase 3 SONIA randomized clinical trial is a multicenter trial in the Netherlands. Patients with HR-positive, ERBB2-negative ABC who did not receive prior treatment for ABC were randomized 1:1 to receive CDK4/6i added to first-line or second-line endocrine therapy. Patients were enrolled between November 23, 2017, and September 1, 2021. Data cutoff for this prespecified updated analysis was September 1, 2024. Data were analyzed from February to May 2025. INTERVENTIONS: Aromatase inhibitor plus CDK4/6i as first-line treatment followed by fulvestrant as second-line treatment (CDK4/6i first-line group) vs aromatase inhibitor as first-line treatment followed by fulvestrant plus CDK4/6i as second-line treatment (CDK4/6i second-line group). MAIN OUTCOMES AND MEASURES: The primary end point was PFS after 2 lines of therapy. OS was a key secondary end point, with a prespecified analysis when all patients had 3 or more years of follow-up. RESULTS: Of 1050 enrolled patients, the median (IQR) age was 64 (16) years. A total of 524 were randomized to the CDK4/6i first-line group and 526 patients to the CDK4/6i second-line group. At a median follow-up of 58.5 months (95% CI, 57.0-60.9), 606 deaths (57.7%) had occurred. The median OS was 47.9 months (95% CI, 44.0-54.3) with first-line CDK4/6i and 48.1 months (95% CI, 44.7-52.0) with second-line CDK4/6i (hazard ratio [HR], 0.91; 95% CI, 0.77-1.07; P = .24). A post hoc subgroup analysis suggested an OS benefit with first-line use in premenopausal patients (HR, 0.53; 95% CI, 0.32-0.87) but not in postmenopausal patients (HR, 1.00; 95% CI, 0.84-1.19; P for interaction = .01). Among patients who discontinued second-line treatment, 257 of 303 in the first-line group (84.8%) and 303 of 360 in the second-line group (84.2%) received subsequent anticancer therapy, with similar treatment patterns. First-line CDK4/6i use was associated with more grade 3 or higher adverse events than second-line use (3400 vs 2242, respectively). CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, first-line CDK4/6i use did not improve OS compared with second-line use but did increase treatment-related toxic effects. Post hoc analysis suggests an OS benefit with first-line use in premenopausal patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03425838.