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Micro-Abstract Men with metastatic castration-resistant prostate cancer (CRPC) have a median survival of > 2 years and can experience significant pain. We evaluated oxaliplatin plus pemetrexed (PemOx) in men with metastatic CRPC previously treated with a taxane to determine the clinical response rate, as well as pain palliation, progression-free survival, and overall survival (OS). A Simon optimal 2-stage design was used to distinguish between a response rate unworthy of further study (≤ 14%) or worthy of further study (≥ 30%) with 90% power. With 47 patients treated, we found a response rate of 30%, including 10 men with Response Evaluation Criteria in Solid Tumors (RECIST) responses of the 40 who had measurable disease (25%); overall, 64% had decline of prostate-specific antigen (PSA) levels. Nineteen patients (40%) experienced a grade 3 or 4 hematologic toxicity and 16 (34%) patients experienced a grade 3 nonhematologic toxicity. Although fewer men with CRPC are receiving chemotherapy, the pain palliation and clinical responses observed during the trial would justify studying this regimen in the second- or third-line setting.