Rationale and Trial Design of DAWNA‐FES Trial: Single‐Arm Phase Ⅱ Study of Endocrine Therapy With Dalpiciclib After Progression on CDK4/6 Inhibition Based on [¹⁸F]FES PET/CT in Patients With HR+/HER2− Advanced Breast Cancer

Cyclin‐dependent kinase 4/6 (CDK4/6) inhibitors have become a cornerstone in the first‐line management of hormone receptor‐positive, human epidermal growth factor receptor 2‐negative (HR+/HER2−) advanced breast cancer. Despite their clinical efficacy, most patients eventually experience disease progression, and optimal treatment strategies following CDK4/6 inhibitor resistance remain unclear. Emerging evidence suggests that switching endocrine therapy (ET) while continuing cyclin inhibition may provide additional clinical benefit. Dalpiciclib, a selective CDK4/6 inhibitor, in combination with physician‐selected ET, represents a potential option in this setting. Concurrently, 16α‐[¹⁸F]fluoro‐17β‐estradiol ([¹⁸F]FES) PET/CT, a novel imaging modality targeting estrogen receptors (ER), enables non‐invasive, whole‐body assessment of ER expression in metastatic lesions, offering a personalized approach to treatment selection.

This is a prospective, single‐center, single‐arm Phase Ⅱ clinical trial evaluating the efficacy and safety of dalpiciclib plus ET in HR+/HER2− advanced breast cancer patients who progressed on prior CDK4/6 inhibitor therapy. Forty eligible patients with confirmed metastases and at least one [¹⁸F]FES‐positive lesion will be enrolled. Participants will receive dalpiciclib combined with ET as determined by the treating physician. The primary endpoint is progression‐free survival (PFS). Secondary endpoints include objective response rate (ORR), disease control rate (DCR), and overall survival (OS).

Beyond evaluating efficacy, this single‐center phase Ⅱ trial will provide practical insight into the feasibility of [¹⁸F]FES PET/CT‐guided patient selection, including standardized imaging workflows and multidisciplinary implementation in routine clinical research. Positive outcomes may support a personalized, imaging‐guided strategy to prolong disease control after prior CDK4/6 inhibitor progression.

Approved by the Ethics Committee of Peking Union Medical College Hospital (Approval number: K3629); registered at ClinicalTrials. gov (NCT05613270).