Supplementary Material for: Apalutamide-induced toxic epidermal necrolysis in a Caucasian patient with metastatic castration-sensitive prostate cancer: a case report and review of the literature

Apalutamide is a novel nonsteroidal androgen receptor inhibitor that has been shown to improve outcomes for patients with nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer when combined with androgen deprivation therapy. Apalutamide-induced skin rash occurred commonly in clinical trials, with 23.8-27.1% of patients experiencing a rash of any grade, and 5.2-6.3% experiencing a rash of grade three or higher. There were no cases of severe cutaneous adverse events (SCARs) such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) reported in clinical trials, however there are rare cases reported in the literature with the majority occurring in Asian patients. An 83-year-old Caucasian male was commenced on apalutamide, combined with degarelix, for the management of metastatic castration-sensitive prostate cancer. During week five of apalutamide treatment, the patient developed a widespread erythematous maculopapular rash. On presentation, the rash affected 80% of his body surface area (BSA) and a diagnosis of a severe cutaneous drug eruption was made. He was commenced on methylprednisolone (MP) therapy. Despite five days of MP, the rash continued to deteriorate involving 95% of his BSA. Nikolsky’s sign was positive. A diagnosis of overlap SJS/TEN was made, supported by skin biopsy. His SCORTEN score was three. He was then commenced on intravenous immunoglobulin and transferred to the intensive care unit. Over the coming days, the rash began to stabilise, and his steroid dose was weaned. He was discharged from hospital 38 days after rash onset. We report the first suggested case of apalutamide-induced SJS/TEN in a Caucasian patient. We discuss other cases of apalutamide-induced SCARs reported in the literature. Risk factors seem to include low body weight and Japanese race, as well as short time to onset of rash.

阿帕他胺（Apalutamide）是一种新型非甾体类雄激素受体抑制剂，研究证实其联合雄激素剥夺治疗（androgen deprivation therapy）可改善非转移性去势抵抗性前列腺癌（nonmetastatic castration-resistant prostate cancer）及转移性去势敏感性前列腺癌（metastatic castration-sensitive prostate cancer）患者的临床结局。阿帕他胺诱导性皮疹在临床试验中较为常见，23.8%~27.1%的患者会出现任意级别的皮疹，5.2%~6.3%的患者出现3级及以上皮疹。临床试验中未报告史蒂文斯-约翰逊综合征（Stevens-Johnson syndrome, SJS）、中毒性表皮坏死松解症（toxic epidermal necrolysis, TEN）等重度皮肤不良事件（severe cutaneous adverse events, SCARs），但文献中已有少数相关病例报告，且多数病例为亚裔患者。本文报告1例83岁高加索男性患者，因转移性去势敏感性前列腺癌接受阿帕他胺联合地加瑞克（degarelix）治疗。在阿帕他胺治疗第5周，患者出现广泛性红斑丘疹性皮疹。就诊时皮疹累及体表面积（body surface area, BSA）的80%，被诊断为重度药物性皮肤损害。予甲泼尼龙（methylprednisolone, MP）治疗。尽管接受了5天的甲泼尼龙治疗，皮疹仍持续进展，累及体表面积的95%，且尼科尔斯基征（Nikolsky’s sign）阳性。结合皮肤活检结果，确诊为重叠型史蒂文斯-约翰逊综合征/中毒性表皮坏死松解症（overlap SJS/TEN），其SCORTEN评分为3分。随后予静脉注射免疫球蛋白治疗，并转入重症监护病房（intensive care unit, ICU）。后续数日，皮疹趋于稳定，激素剂量逐渐递减，患者于皮疹发作后38天出院。本文报告了全球首例高加索患者阿帕他胺诱导性重叠型SJS/TEN病例，并讨论了文献中报告的其他阿帕他胺诱导性重度皮肤不良事件病例。潜在风险因素可能包括低体重、日本裔及皮疹发作潜伏期较短。