Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC).

LBA1000 Background: The phase-3, randomized, investigator-initiated, nationwide SONIA trial is evaluating the efficacy, safety and cost-effectiveness of CDK4/6i added to either first- or second-line endocrine therapy (ET) in patients with HR+, HER2- ABC who have received no prior therapy for ABC. The addition of CDK4/6i to ET improves progression-free (PFS) and overall survival (OS) in HR+, HER2- ABC, as initial treatment (first-line) and after prior endocrine monotherapy (second-line). Most international guidelines advice first-line use, despite prolonged toxicity and a steep increase in costs compared to use in second-line. Evidence of superiority of first-line use over second-line based on a head-to-head comparison is lacking. Methods: Pre- and postmenopausal women (N=1050), who received no prior therapy for ABC, with measurable or evaluable disease and WHO performance status 0-2 were enrolled in 74 Dutch hospitals. (Neo)adjuvant therapy was allowed (disease-free interval after non-steroidal aromatase inhibitor (NSAI) >12 months). Patients were randomized 1:1 to receive strategy A (first-line treatment with an NSAI + CDK4/6i, followed on progression by fulvestrant (F)) or strategy B (first-line treatment with an NSAI, followed on progression by F + CDK4/6i). Choice between one of the available CDK4/6i (abemaciclib, palbociclib, ribociclib) was a stratification factor and left to the discretion of the treating physician. The primary endpoint is time from randomization to second objective disease progression, as assessed by local investigators, or death (PFS2). Secondary endpoints include OS, safety, quality of life, and cost-effectiveness. Results: After a median follow-up of 37.3 months (data cut-off 1 December 2022), median PFS2 was 31.0 months in strategy A versus 26.8 months in strategy B (hazard ratio 0.87; 95% confidence interval, 0.74 to 1.03; P=0.10). The treatment effect was consistent across the levels of pre-defined subgroups. The safety profile was characteristic for ET + CDK4/6i. Median time on CDK4/6i was 24.64 months in strategy A and 8.08 months in strategy B (Δ 16.56 months). The number of grade ≥3 adverse events was 2782 for strategy A and 1620 for strategy B. Conclusions: First-line use of CDK4/6i + ET does not provide statistically significant, nor clinically meaningful PFS benefit compared to second-line use in women with HR+, HER2- ABC. Use in first-line prolongs the time on CDK4/6i by 16.56 months and increases toxicity and costs. Second-line use may thus be a preferred option for the majority of patients. (Funded by The Netherlands Organisation for Health Research and Development and Dutch Health Insurers; ClinicalTrials.gov number, NCT03425838). Clinical trial information: NCT03425838 .