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Overall Survival With First-Line vs Second-Line CDK4/6 Inhibitor Use in Advanced Breast Cancer: A Randomized Clinical

Noor Wortelboer¹, Annemiek van Ommen-Nijhof², Inge R Konings³

¹Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.

|February 19, 2026

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.

Insights

First-line cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) did not improve overall survival in advanced breast cancer compared to second-line use. However, first-line CDK4/6i showed a survival benefit in premenopausal patients and increased toxic effects.

Area of Science:

Oncology
Clinical Trials
Pharmacology

Background:

Cyclin-dependent kinase (CDK) 4 and 6 inhibitors (CDK4/6i) are standard treatment for hormone receptor (HR)-positive, ERBB2-negative advanced breast cancer (ABC).
The optimal timing for initiating CDK4/6i therapy (first-line vs. second-line) in combination with endocrine therapy remains under investigation.

Purpose of the Study:

To compare the efficacy of first-line versus second-line CDK4/6i administration in patients with HR-positive, ERBB2-negative ABC.
To evaluate overall survival (OS) and progression-free survival (PFS) after two lines of therapy.

Main Methods:

The SONIA trial is a phase 3, multicenter, randomized clinical trial comparing first-line CDK4/6i plus endocrine therapy versus second-line CDK4/6i plus endocrine therapy.
Patients with HR-positive, ERBB2-negative ABC who had not received prior treatment for ABC were randomized 1:1.
Data from 1050 enrolled patients were analyzed with a median follow-up of 58.5 months.

Main Results:

No significant difference in median OS was observed between the first-line (47.9 months) and second-line (48.1 months) CDK4/6i groups (HR, 0.91; P=.24).
A post hoc subgroup analysis indicated a potential OS benefit for first-line CDK4/6i in premenopausal patients (HR, 0.53).
First-line CDK4/6i use was associated with a higher incidence of grade 3 or higher adverse events.

Conclusions:

Initiating CDK4/6i in the first-line setting did not improve OS compared to second-line use in HR-positive, ERBB2-negative ABC.
First-line CDK4/6i use led to increased treatment-related toxic effects.
The findings suggest a potential benefit of first-line CDK4/6i in premenopausal patients, warranting further investigation.

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