CDK4/6 Inhibitors in Advanced Breast Cancer: Is Sooner Really Better?

In hormone receptor (HR)–positive, HER2-negative advanced breast cancer, starting CDK4/6 inhibitors (CDK4/6i) in the first line of therapy did not improve overall survival (OS) compared with reserving them for the second line, according to results of the phase 3 randomized SONIA trial (NCT03425838) published in JAMA Oncology.¹

This result challenges one of oncology’s guiding instincts—that effective drugs should be used as early as possible. In an accompanying editorial, experts note that “a substantial percentage of patients with advanced, ER-positive breast cancer might be appropriately treated with endocrine therapy alone as initial treatment, reserving introduction of CDK4/6i for later in the course of the illness.”²

Conducted across 74 hospitals in the Netherlands, the trial enrolled 1050 women with a median age of 64 years.¹ Patients were randomized to receive either a CDK4/6i added to first-line aromatase inhibitor (AI) therapy, followed by fulvestrant alone at progression, or an AI alone first, with fulvestrant plus a CDK4/6i held for the second line. Nearly all patients (91%) received palbociclib as their CDK4/6i.

At a median follow-up of 58.5 months, median OS was 47.9 months with first-line CDK4/6i use and 48.1 months with second-line use. This difference of less than 2 weeks did not approach statistical significance (P = .24). Treatment patterns and rates of subsequent therapy were nearly identical between groups.

However, first-line use did come with a meaningfully higher toxicity burden: 3400 grade 3 or higher adverse events compared with 2242 in the second-line group, with 86% of first-line patients experiencing at least 1 serious adverse event compared with 76% in the second-line group. Previous analyses from the SONIA program have also shown no quality-of-life advantage as well as significantly higher drug costs with first-line use.

A post hoc subgroup analysis surfaced a potentially important exception. Among the 145 premenopausal women in the trial, those who received CDK4/6i in the first line had dramatically better survival. Their median OS was not reached by the end of the study, compared with 35.3 months for those who received CDK4/6i second. This translates to an approximate 47% reduction in the risk of death with first-line use. No such difference was seen in the 905 postmenopausal patients. The researchers, cautioning that this analysis was not prespecified and involved small numbers with some baseline imbalances, called for further research to validate the finding.

The editorial accompanying the study noted the trial’s broader importance, highlighting that SONIA is one of very few trials designed specifically to evaluate treatment sequencing rather

than efficacy alone. It argues that postmenopausal patients with endocrine-sensitive, lower-burden disease may be good candidates to start with AI monotherapy and receive CDK4/6i at crossover, whereas premenopausal patients or those with greater disease burden may benefit more from early combination.

Key limitations include the predominant use of palbociclib, restriction to a Dutch population with uniform health care access, and a treatment landscape that has evolved since enrollment began in 2017. The authors also note that estrogen/progesterone positivity was defined as greater than 10% expression, limiting generalizability to patients with lower receptor expression.

The findings are particularly relevant for clinicians and health systems weighing both patient outcomes and resource use. Sequencing CDK4/6i to the second line rather than using them immediately appears to produce equivalent survival for most patients but with the added benefit of meaningfully less treatment burden.

References

1. Wortelboer N, van Ommen-Nijhof A, Konings IR, et al. Overall survival with first-line vs second-line CDK4/6 inhibitor use in advanced breast cancer: a randomized clinical trial. JAMA Oncol. Published online February 19, 2026. doi:10.1001/jamaoncol.2025.6585

2. Valenza C, Burstein HJ. Lessons from the SONIA trial on timing of CDK4/6 inhibitors in advanced breast cancer—the sooner, the better? JAMA Oncol. Published online February 19, 2026. doi:10.1001/jamaoncol.2025.6345