Abstract OT3-02-04: <u>S</u>electing the <u>o</u>ptimal positio<u>n</u> of CDK4/6 <u>i</u>nhibitors in hormone-receptor-positive <u>a</u>dvanced breast cancer: The BOOG 2017-03 <u>SONIA</u> study
Authors: A van Ommen - Nijhof, A van der Voort, IR Konings, A Jager, GS Sonke
Journal: Cancer Research (2019)

Abstract BACKGROUND Combining cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with endocrine therapy (ET) is an effective strategy to improve progression-free survival (PFS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). There is a lack of comparative data to help clinicians decide whether CDK4/6 inhibitors can best be added to first- or second-line ET. The former strategy may provide longer PFS benefit, but is associated with longer use of the drug, which results in more toxicity and costs, whereas no clear benefit on overall survival (OS) or quality of life (QoL) has been proven thus far. No predictive biomarker exists to select patients who are most likely to benefit from the addition of CDK4/6 inhibition. TRIAL DESIGN AND AIMS The SONIA study is an investigator-initiated, multicenter, randomized phase III study, funded by 'ZonMw' and 'Zorgverzekeraars Nederland'. Patients are randomly assigned to receive either strategy A (first-line treatment with a non-steroidal aromatase inhibitor (NSAI) + CDK4/6 inhibition, followed on progression by fulvestrant) or strategy B (first-line treatment with NSAI, followed on progression by fulvestrant + CDK4/6 inhibition). Each CDK4/6 inhibitor can be used according to its approved EMA label. The primary objective is to test whether strategy A is superior to strategy B. The primary endpoint is time from randomization to second objective progression (PFS2). Secondary endpoints include OS, safety, QoL, and cost-effectiveness. Additional biomarker analyses will be performed to optimize patient selection. ELIGIBILITY CRITERIA Patients with a proven diagnosis of HR+/HER2-negative advanced breast cancer without prior systemic therapy for advanced disease who are candidates to receive NSAIs as first-line treatment, are eligible for the study. Exclusion criteria include advanced visceral spread with the risk of life-threatening complications in the short term. Other conditions excluding a patient from participating are other malignancies, prolonged QTc time (&amp;gt;480ms) or any other medical condition that interferes with study procedures or compliance. STATISTICAL METHODS The difference in PFS2 will be estimated using the intention-to-treat population in a Cox proportional hazards model accounting for all stratification factors (visceral versus non-visceral disease, yes versus no prior ET in (neo)adjuvant setting, hospital, and type of CDK4/6 inhibitor). Five-hundred seventy-four primary outcome events yield 89% power to show that strategy A has statistically significant, clinically meaningful (according to European Society for Medical Oncology - Magnitude of Clinical Benefit Scale) superior PFS2 in a log-rank test at the two-sided 95% confidence level. ACCRUAL TARGET: with an accrual period of 42 months and an additional 18 months follow-up, inclusion of 1050 evaluable patients is required. A total of 76 Dutch hospitals will participate. PRESENT: the study is open in 51 hospitals and 106 patients are included. Citation Format: van Ommen - Nijhof A, van der Voort A, Konings IR, Jager A, Sonke GS, On behalf of the SONIA Investigators (SONIA Steering Committee), And the Dutch Breast Cancer Research Group (BOOG). Selecting the optimal position of CDK4/6 inhibitors in hormone-receptor-positive advanced breast cancer: The BOOG 2017-03 SONIA study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-04.