Adjuvant mitotane in low-risk adrenocortical carcinoma: A reconstructed IPD analysis of the ADIUVO randomized and observational studies

BACKGROUND: The benefit of adjuvant mitotane after complete resection of low-risk adrenocortical carcinoma (ACC) remains uncertain. The ADIUVO randomized trial was underpowered due to low event rates. We conducted a reconstructed individual patient data (IPD) analysis to provide a comprehensive reassessment of treatment effects. METHODS: IPD were reconstructed from published Kaplan-Meier curves of the ADIUVO randomized trial and its parallel prospective observational cohort using the Guyot algorithm. Overall survival (OS) and recurrence-free survival (RFS) were analysed using Cox proportional hazards models, restricted mean survival time (RMST), and accelerated failure time (AFT) models. Pooled analyses were stratified by study design. Exposure-response analyses evaluated therapeutic mitotane levels (≥14 mg/L) and early target attainment. RESULTS: The reconstructed randomized cohort included 91 patients (18 RFS events; 19 deaths). In intention-to-treat analysis, no clear evidence of a benefit with mitotane was observed for RFS (HR=0.99, 95%CI 0.39-2.50; p = 0.99) or OS (HR=0.98, 95%CI 0.40-2.42; p = 0.97). RMST differences at 60 months were negligible (-0.05 months for RFS; -0.19 months for OS). In the observational cohort (n = 95), no significant differences were observed for RFS (HR=0.90, 95%CI 0.32-2.47) or OS (HR=0.75, 95%CI 0.31-1.84). Pooled analysis (n = 186; 39 OS events; 33 RFS events) likewise showed no clear evidence of improved OS (HR=0.86, 95%CI 0.45-1.61) or RFS (HR=1.05, 95%CI 0.53-2.08). Exposure-based analyses did not demonstrate a consistent survival advantage associated with therapeutic drug levels or early target attainment, although these analyses were limited by small sample sizes. INTERPRETATION: Across complementary modelling approaches, no clear evidence of a clinically meaningful survival benefit with adjuvant mitotane was observed. While small effects cannot be definitively excluded, the overall consistency of findings suggests that any potential benefit is likely marginal. Active surveillance therefore represents an evidence-aligned management strategy in this population.