Effect of adjuvant carboplatin intensified chemotherapy versus standard chemotherapy on survival in women with high risk, early stage, triple negative breast cancer (CITRINE): randomised, open label phase 3 trial.

OBJECTIVE: To evaluate the efficacy and safety of epirubicin and cyclophosphamide followed by weekly paclitaxel with or without carboplatin as adjuvant therapy for patients with high risk, early stage, triple negative breast cancer. DESIGN: Randomised, open label, phase 3 trial. SETTING: Fudan University Shanghai Cancer Center in China between March 2020 and March 2022. PARTICIPANTS: Female patients with operable high risk triple negative breast cancer (defined as either regional node positive or node negative with a Ki-67 labelling index of ≥50%) after definitive surgery. INTERVENTIONS: Patients were randomised in a 1:1 ratio into either the carboplatin arm (four cycles of two weekly epirubicin and cyclophosphamide followed by four cycles of weekly paclitaxel combined with carboplatin) or the control arm (four cycles of three weekly or two weekly epirubicin and cyclophosphamide followed by four cycles of weekly paclitaxel). MAIN OUTCOME MEASURES: The primary endpoint was disease-free survival in the intention-to-treat population. Secondary endpoints included recurrence-free survival, distant disease-free survival, overall survival, and safety. RESULTS: Of the 808 enrolled patients, 807 received study treatment. At a median follow-up of 44.7 months, estimated percentages of patients who would be disease-free at three years were 92.3% in the carboplatin arm and 85.8% in the control arm (hazard ratio 0.64, 95% confidence interval (CI) 0.43 to 0.95; P=0.03). However, the assessment of the proportional hazards assumption showed that it was violated (P=0.02). A piecewise hazard model showed that the hazard ratio changed over time: the hazard ratio was 0.31 (95% CI 0.13 to 0.73) for 0-12 months, 0.65 (0.39 to 1.09) for 12-36 months, and 1.98 (0.69 to 5.69) for >36 months. For secondary endpoints, the carboplatin arm was associated with improved outcomes in three year recurrence-free survival (93.8% v 88.3%; hazard ratio 0.59, 95% CI 0.37 to 0.93; P=0.02), three year distant disease-free survival (94.8% v 89.8%; hazard ratio 0.61, 0.37 to 0.98; P=0.04), and three year overall survival (98.0% v 94.0%; hazard ratio 0.41, 0.20 to 0.83; P=0.01). The incidence of grade 3-4 treatment related adverse events was 66.7% (269 of 403 patients) in the carboplatin arm and 55.0% (222 of 404 patients) in the control arm. No treatment related deaths occurred. CONCLUSIONS: The addition of carboplatin to adjuvant anthracycline/taxane based chemotherapy significantly improved survival outcomes in patients with high risk, early stage, triple negative breast cancer, driven by reduction of early recurrence risk without new safety concerns. TRIAL REGISTRATION: ClinicalTrials.gov NCT04296175.