THU617 Prolonged Exposure to Target Mitotane Concentrations is Associated with Better Recurrence-free Survival in Patients with Adrenocortical Carcinoma on Adjuvant Treatment

Disclosure: S. Puglisi: None. A. Calabrese: None. V. Basile: None. O. Kimpel: Speaker; Self; HRA Pharmaceuticals. B. Altieri: None. A. Angelousi: None. G. Kaltsas: None. U. Ambroziak: None. M.L. Appetecchia: None. M. Arosio: None. A. Berruti: Advisory Board Member; Self; HRA Pharmaceuticals. D. Cosentini: None. L. Canu: None. F. Ceccato: None. G. Di Dalmazi: None. L. Bouys: None. R. Libè: None. K. Nowak: None. L. Papierska: None. J. Pittaway: None. T. Kienitz: None. M. Quinkler: None. Y. Elhassan: None. C. Ronchi: None. L. Saiegh: None. A. Stigliano: None. T. Dusek: None. D. Kastelan: None. M. Fassnacht: None. M. Terzolo: Advisory Board Member; Self; HRA Pharmaceuticals. Grant Recipient; Self; HRA Pharmaceuticals. Background: The management of adjuvant mitotane therapy in patients with adrenocortical carcinoma (ACC) is challenging. Plasma mitotane concentrations >14 mg/L have been associated with efficacy in the treatment of advanced ACC; however, data in the adjuvant setting are mixed. Moreover, there is no consensus on how to assess the optimal exposure to mitotane and all the proposed methods have inherent limitations. We have recently proposed a new method analogous to what is established for the anticoagulant warfarin, the time in target range (TTR). We aimed to evaluate whether the TTR is a factor influencing recurrence-free survival (RFS) in patients with ACC on adjuvant mitotane. Methods: This is an international, retrospective, cohort study undertaken in 18 centers in 8 countries, under the auspices of the European Network for the Study of Adrenal Tumors (ENSAT), including adult patients with ACC treated with adjuvant mitotane for at least 1 year following tumor resection, with the availability of at least 3 mitotane measurements per year. TTR was calculated with the Rosendaal method and expressed as the number of months with plasma mitotane concentration >14 mg/L. The following potential predictive factors for RFS have been investigated: patient sex and age, ENSAT stage, hormone secretion, resection status, Weiss score, Ki67 index, and TTR. Data are expressed as median and interquartile range. Results: From a total of 254 patients, 157 fulfilled inclusion criteria and were analyzed (F/M 94/63; age 49, 41-58 years), with a follow-up of 49 (33-92) months. The key baseline features were: 7.0% stage I, 69.4% II, 22.3% III, 1.3% IV; 51.6% secreting tumors; 87.2% R0, 2.6% R1, 10.2% RX; Weiss score 5 (4-7); Ki67 index 11 (5-20). All patients were treated with mitotane for 25 (22-36) months, with a TTR of 14 (6-21) months. At multivariate analysis, Ki67 index (HR 1.07, 95%CI, 1.02-1.12; p<0.01) and Weiss score (HR 1.7, 95%CI, 1.16-2.47; p<0.01) were associated with an increased risk of recurrence, while female sex (HR 0.14, 95%CI, 0.04-0.58; p<0.01) and TTR (HR 0.80, 95%CI, 0.70-0.90; p<0.001) were associated with a reduced risk. Conclusions The present findings show that the patients who are exposed to plasma mitotane >14 mg/L for longer periods have better RFS. These findings provide indirect evidence of the value of adjuvant therapy with mitotane and support the importance of drug monitoring to guide dose adjustment in clinical practice and improve patient outcome. Presentation: Thursday, June 15, 2023