Syndrome of Inappropriate Antidiuretic Hormone Secretion and Thrombotic Microangiopathy as Paraneoplastic Syndromes Complicating BRCA2-Mutated Metastatic Prostate Cancer

Background: Metastatic prostate cancer with BRCA2 mutation is associated with aggressive clinical behavior and poor outcomes with standard systemic therapy. While the BRCA2 mutation predicts response to PARP inhibitors and platinum agents, its association with paraneoplastic syndromes is not well described.Case Presentation: We report a 72-year-old male who presented with altered sensorium with severe hyponatremia who was diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the context of newly diagnosed metastatic prostate adenocarcinoma. He was treated with free water restriction, hypertonic saline, and triplet systemic therapy (docetaxel, androgen deprivation, and darolutamide) and discharged in stable condition. After one year of disease remission, he developed generalized weakness, hematuria, thrombocytopenia, hemolytic anemia, and renal impairment. Peripheral smear demonstrated schistocytes, consistent with thrombotic microangiopathy (TMA). Bone marrow biopsy confirmed metastatic adenocarcinoma with a BRCA2 frameshift mutation (p. Trp1692MetfsTer3). ADAMTS13 activity was normal, excluding thrombotic thrombocytopenic purpura. He received five cycles of carboplatin/docetaxel chemotherapy along with blood and platelet support, with clinical and hematologic recovery, and was discharged on Olaparib, abiraterone, and leuprolide. Despite initial improvement, he succumbed to the disease within two months. Discussion: This case illustrates the aggressive biology of BRCA2-mutated prostate cancer, characterized by rapid progression and limited durability of standard therapies. While SIADH and TMA have been individually reported in prostate cancer, their sequential occurrence in a BRCA2-mutated setting is unique. The case highlights the vigilance for atypical paraneoplastic manifestations, the need for early genomic testing, and the exploration of novel therapeutic strategies in BRCA2-driven disease.Conclusion: We present the first reported case of BRCA2-mutated metastatic prostate cancer complicated by the sequential development of SIADH and TMA, underscoring the aggressive clinical trajectory and poor prognosis associated with this molecular subtype.