Abstract Understanding the molecular underpinnings of sensitivity to specific therapies will advance the goal of precision medicine in prostate cancer (PCa). We identified three patients with metastatic castration-resistant PCa (mCRPC) who achieved an exceptional response to platinum chemotherapy (not first-line treatment for PCa), despite disease progression on prior standard therapies. Using targeted next-generation sequencing on the primary and metastatic tumors, we found that all three patients had biallelic inactivation of BRCA2 , a tumor suppressor gene critical for homologous DNA repair. Notably, two had germline BRCA2 mutations, including a patient without compelling family history who was diagnosed at age 66 yr. The third patient had somatic BRCA2 homozygous copy loss. Biallelic BRCA2 inactivation in mCRPC warrants further exploration as a predictive biomarker for sensitivity to platinum chemotherapy.