Introduction: The Standard of Care Dilemma in Advanced Breast Cancer
For nearly a decade, the combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and endocrine therapy (ET) has served as the cornerstone of treatment for hormone receptor (HR)-positive, ERBB2-negative advanced breast cancer (ABC). Pivotal trials such as PALOMA-2, MONALEESA-2, and MONARCH-3 established the superiority of first-line (1L) CDK4/6i plus an aromatase inhibitor (AI) over AI monotherapy in terms of progression-free survival (PFS). However, the optimal sequencing of these potent agents has remained a subject of intense clinical debate. Specifically, whether the immediate use of CDK4/6i in the 1L setting offers a long-term survival advantage over reserving these agents for the second-line (2L) setting—after progression on ET monotherapy—has been an unanswered question with significant implications for patient quality of life and healthcare economics.
Highlights of the SONIA Trial
The SONIA trial (NCT03425838) provides critical, practice-informing data regarding the sequencing of CDK4/6i. The main highlights include:
1. No Overall Survival Benefit: The study found no statistically significant difference in overall survival (OS) between starting a CDK4/6i in the first-line versus the second-line setting.
2. Increased Toxicity: Patients in the first-line CDK4/6i group experienced a significantly higher burden of grade 3 or higher adverse events compared to those who received the inhibitor only in the second line.
3. Premenopausal Subgroup Divergence: A post hoc analysis suggested a potential survival benefit for first-line CDK4/6i use specifically in premenopausal patients, contrasting with the postmenopausal cohort.
Study Design and Methodology
The SONIA trial was a phase 3, investigator-initiated, multicenter, randomized clinical trial conducted across the Netherlands. It enrolled 1050 patients with HR-positive, ERBB2-negative ABC who had not received prior systemic treatment for advanced disease.
Patient Randomization and Interventions
Participants were randomized 1:1 into two distinct treatment strategies:
1. CDK4/6i First-Line Group (n=524): Patients received an aromatase inhibitor (AI) plus a CDK4/6i (abemaciclib, palbociclib, or ribociclib) as 1L therapy. Upon progression, they transitioned to fulvestrant as 2L therapy.
2. CDK4/6i Second-Line Group (n=526): Patients received AI monotherapy as 1L therapy. Upon progression, they received fulvestrant combined with a CDK4/6i as 2L therapy.
Endpoints and Statistical Analysis
The primary endpoint was PFS after two lines of therapy (PFS2), defined as the time from randomization to progression on the second-line treatment or death from any cause. Overall survival (OS) was a key secondary endpoint. The prespecified analysis for OS occurred once all patients had at least three years of follow-up. Data cutoff for this updated analysis was September 1, 2024, with a median follow-up of 58.5 months.
Key Findings: Survival and Efficacy Outcomes
The results of the SONIA trial challenge the current paradigm of universal upfront CDK4/6i use. At the time of analysis, 606 deaths (57.7% of the total cohort) had occurred.
Overall Survival (OS)
In the intention-to-treat population, the median OS was 47.9 months (95% CI, 44.0-54.3) for the first-line CDK4/6i group and 48.1 months (95% CI, 44.7-52.0) for the second-line group. The hazard ratio (HR) was 0.91 (95% CI, 0.77-1.07), with a P-value of .24, indicating no significant survival advantage for the upfront strategy.
Progression-Free Survival (PFS2)
Previous reports from SONIA indicated that the primary endpoint of PFS2 also showed no significant difference between the two strategies. The updated analysis confirms that delaying CDK4/6i until the second line does not compromise the total time a patient remains on endocrine-based therapies before moving to chemotherapy.
Subsequent Therapy Patterns
One concern in sequencing trials is whether patients in the delayed arm actually receive the intended rescue therapy. In SONIA, treatment patterns were remarkably consistent. Among patients who discontinued second-line treatment, 84.8% in the first-line group and 84.2% in the second-line group received subsequent anticancer therapy, ensuring that the OS results were not confounded by a lack of access to further care.
Safety and Toxicity: The Burden of Early Intervention
A pivotal finding of the SONIA trial is the disparity in treatment-related toxicity. Because the first-line use of CDK4/6i typically results in a longer duration of exposure to the drug than second-line use, the cumulative toxicity is higher.
Patients in the first-line CDK4/6i group experienced 3400 grade 3 or higher adverse events, compared to 2242 in the second-line group. This increased toxicity profile, coupled with the lack of survival benefit, suggests that for many patients, starting with endocrine monotherapy may spare them significant side effects for a period of time without negatively impacting their long-term prognosis.
The Premenopausal Exception: A Post Hoc Insight
While the overall study was negative, a post hoc subgroup analysis revealed a potential interaction with menopausal status.
1. Premenopausal Patients: The HR for OS was 0.53 (95% CI, 0.32-0.87), favoring first-line CDK4/6i use.
2. Postmenopausal Patients: The HR for OS was 1.00 (95% CI, 0.84-1.19).
The P-value for interaction was .01, suggesting that the biology of ABC in younger, premenopausal women may necessitate more aggressive upfront inhibition of the cell cycle. However, as this was a post hoc analysis, these results should be interpreted as hypothesis-generating rather than definitive.
Expert Commentary: Reevaluating Clinical Guidelines
The SONIA trial is one of the few large-scale randomized trials to address the strategy of treatment sequencing rather than drug efficacy alone. Its findings are provocative because they suggest that the widespread practice of prescribing CDK4/6i to every treatment-naive patient with HR+/ERBB2- ABC may lead to over-treatment.
Impact on Quality of Life and Cost
By utilizing CDK4/6i in the second line, clinicians can potentially reduce the duration of exposure to these agents by 14 to 16 months on average. In many healthcare systems, this represents a massive reduction in drug costs and a significant period where patients can avoid the hematological and gastrointestinal toxicities associated with these inhibitors. This “ET-first” approach aligns with the principle of therapy escalation—starting with the least toxic effective therapy and intensifying as needed.
Limitations and Generalizability
Critics of the SONIA trial point out that the study included all three available CDK4/6 inhibitors, and while they are often grouped together, their individual OS data from other trials (like MONALEESA-2) have shown distinct advantages. Furthermore, the trial was conducted in the Netherlands, where treatment patterns and patient populations may differ slightly from other global regions. The post hoc nature of the premenopausal benefit also requires cautious application in clinical practice.
Conclusion and Clinical Summary
The phase 3 SONIA trial provides robust evidence that for the general population of patients with HR-positive, ERBB2-negative advanced breast cancer, initiating CDK4/6 inhibitors in the second-line setting is a viable and safe strategy that does not compromise overall survival. While the first-line use of these agents remains a standard of care, the trial highlights that this approach comes at the cost of increased toxicity and longer treatment duration.
Clinicians should engage in shared decision-making with patients, particularly postmenopausal women, discussing the option of starting with endocrine therapy alone. For premenopausal patients, the potential survival benefit noted in the subgroup analysis supports the continued preference for upfront CDK4/6i use.
Funding and Clinical Trial Information
This study was funded by the Dutch Health Care Insurance Board and the Dutch Cancer Society.
ClinicalTrials.gov Identifier: NCT03425838.
References
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2. Finn RS, Martin M, Rugo HS, et al. Palbociclib and Aromatase Inhibitor in Advanced Breast Cancer. N Engl J Med. 2016;375(20):1925-1936.
3. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med. 2022;386(10):942-950.
4. Turner NC, Slamon DJ, Ro J, et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2018;379(20):1926-1936.
