Using cyclin-dependent kinase (CDK) 4/6 inhibitors as first-line therapy in advanced breast cancer does not improve overall survival (OS) compared with subsequent treatment, but the impact of sequencing might differ according to menopausal status, according to the results of a phase 3 trial.
The randomised SONIA clinical trial, published in JAMA Oncology and conducted across 74 hospitals in the Netherlands, investigated whether adding a CDK4/6 inhibitor to first-line endocrine therapy improved OS compared with delaying its use in advanced breast cancer.
Eligible women aged 18 years or older with hormone receptor-positive, HER2-negative advanced breast cancer who had not previously received systemic treatment were randomly assigned to a CDK4/6 inhibitor combined with an aromatase inhibitor as first-line therapy, followed by fulvestrant alone (n=524) or endocrine therapy alone initially, followed by fulvestrant combined with a CDK4/6 inhibitor at progression (n=526).
Most patients received palbociclib as the CDK4/6 inhibitor and were monitored for 58.5 months. OS was a key secondary outcome, while the study also provided an updated analysis of the primary end point of progression-free survival (PFS) after two lines of therapy.
Earlier CDK4/6 inhibitor use and OS, PFS and toxicity
The median age of participants was 64 years. Approximately 56% had visceral disease, 34.7% presented with de novo metastatic breast cancer and nearly half had previously received adjuvant or neoadjuvant endocrine therapy.
At the time of analysis, 606 deaths had been recorded. The median OS was 47.9 months in the first-line CDK4/6 inhibitor group and 48.1 months in the second-line group, with no statistically significant difference between the strategies (hazard ratio [HR] 0.91; 95% CI 0.77–1.07; P = 0.24).
Results were consistent across predefined subgroups, including disease characteristics and CDK4/6 inhibitor type.
A post hoc subgroup analysis indicated that premenopausal patients might benefit from earlier CDK4/6 inhibitor treatment (HR 0.53 for OS for first-line use; 95% CI 0.32–0.87), whereas no difference was observed among postmenopausal patients.
Although OS was similar across treatment groups, PFS after two lines of therapy was longer in patients receiving the inhibitor as first-line therapy, with a median of 31.9 months versus 26.7 months in the first- and second-line groups, respectively.
However, treatment-related toxicity was greater when CDK4/6 inhibitors were used as first-line treatment, with 3,400 grade 3 or higher adverse events reported compared with 2,242 events in the second-line group.
Implications for advanced breast cancer treatment sequencing
Overall, the findings suggest that introducing CDK4/6 inhibitors in first-line therapy does not improve OS compared with reserving them for second-line treatment, although certain limitations should be considered when interpreting the results.
Most participants received palbociclib, reflecting Dutch reimbursement patterns, which may limit comparisons with other CDK4/6 inhibitors. In addition, the treatment landscape has evolved greatly since the study began in 2017, the authors noted.
They emphasised the importance of carefully assessing treatment sequencing in clinical practice, concluding that future trials of drugs with established OS benefits in later-line settings should include crossover and focus on primary endpoints.
Considering OS, PFS after two lines of therapy and health-related quality of life would provide clearer guidance for management strategies, they concluded.
Reference
Wortelboer N et al. Overall Survival With First-Line vs Second-Line CDK4/6 Inhibitor Use in Advanced Breast Cancer. A Randomized Clinical Trial. JAMA Oncol 2026;Feb 19:e256585.
This article was originally published by our sister publication Hospital Healthcare Europe.
