Clinical Study of Local and Systemic Biological Impact of GLP1/GIP-Receptor Agonists in Patients With Breast Cancer: the CLARA Trial

CLARA is a randomized, controlled, phase IIb window‐of‐opportunity trial designed toevaluate the biological effects and safety of tirzepatide, alone or in combination withletrozole, in postmenopausal women with hormone receptor‐positive (HR+), HER2‐negative,treatment‐naïve breast cancer scheduled for primary surgery, who meet the EMA‐approvedobesity criteria for tirzepatide prescription (BMI ≥30 kg/m² or BMI ≥27 kg/m² withweight‐related comorbidities).168 participants will be randomized equally into four arms: Arm A (Control): Immediatesurgery Arm B: 3 weeks of neoadjuvant letrozole alone Arm C: 3 weeks of neoadjuvanttirzepatide alone Arm D: 3 weeks of neoadjuvant tirzepatide combined with letrozolePrimary objective is to compare anti‐proliferative tumor response in patients receivingimmediate surgery, GLP1/GIP RA, letrozole and combined treatment.Secondary objectives are: ‐ To compare adherence to the GLP1/GIP RA, letrozole and combined treatment. ‐ To compare safety ‐ To compare perioperative complications ‐ To explore the feasibility and utility of circulating tumour DNA (ctDNA) in plasmasamples collected throughout the study.Exploratory objectives are: ‐ To compare fatigue ‐ To compare body composition changes ‐ To compare changes in genomic risk score ‐ To compare postoperative nausea and vomiting ‐ To compare gastric emptying delays prior to surgery ‐ To compare anti‐proliferative tumor response as complete cell cycle arrest (CCCA) ‐ To compare endocrine response ‐ To compare concentrations of letrozole ‐ To compare impact of stress on tumor biology and on clinical and biological effectsof treatment