Pituitary carcinoma is a rare and aggressive malignancy with a poor prognosis and few effective treatment options. A 35-year-old woman presented with an aggressive ACTH-secreting pituitary adenoma that initially responded to concurrent temozolomide and capecitabine prior to metastasizing to the liver. Following treatment with ipilimumab and nivolumab, the tumor volume of the dominant liver metastasis reduced by 92%, and the recurrent intracranial disease regressed by 59%. Simultaneously, her plasma ACTH level decreased from 45,550 pg/mL to 66 pg/mL. Both prospective clinical sequencing with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and retrospective whole-exome sequencing were performed to characterize the molecular alterations in the chemotherapy-naive pituitary adenoma and the temozolomide-resistant liver metastasis. The liver metastasis harbored a somatic mutational burden consistent with alkylator-induced hypermutation that was absent from the treatment-naive tumor. Resistance to temozolomide treatment, acquisition of new oncogenic drivers, and subsequent sensitivity to immunotherapy may be attributed to hypermutation. Combination treatment with ipilimumab and nivolumab may be an effective treatment in pituitary carcinoma. Clinical sequencing of pituitary tumors that have relapsed following treatment with conventional chemotherapy may identify the development of therapy-induced somatic hypermutation, which may be associated with treatment response to immunotherapy.