Abstract Advanced prostate cancer is a universally lethal disease and one for which no biomarkers have yet been found to inform therapeutic decision making. DNA repair deficiency in the homologous recombination and CDK12 pathways increases sensitivity of tumors to the DNA damaging effects of high dose testosterone based on early biomarker interrogations of phase II high dose testosterone studies. High dose testosterone is also very well tolerated in appropriately selected patient populations who are asymptomatic. The proposed study is a two arm phase II study of high dose testosterone in men with metastatic, castration resistant prostate cancer containing mutations in ATM or CDK12. Patients would receive intermittent high dose testosterone (intramuscular injections Day 1 of each monthly cycle) until clinical or radiographic progression or intolerance. Androgen deprivation is continued in order to maintain consistent nadir testosterone levels which are critical to the concept of inducing genomic instability by exposing tumor cells to very high and low testosterone levels over the length of the cycle. The primary endpoint will be 50% decline in PSA from baseline. Secondary endpoints are radiographic response per RECIST, radiographic progression free survival, PSA progression free survival, overall survival, PSA50 response rate in each genomic subgroup, quality of life by FACT-P and International Index of Erectile Function (IIEF) surveys and incidence and severity of adverse events according to CTCAE version 4.0. This study will provide critical information regarding efficacy and toxicity of high dose testosterone therapy in a biomarker selected population. High dose testosterone in appropriately selected patients is very well tolerated and would provide treatment options for patients who are otherwise not at the appropriate point in their treatment sequence for other treatments. The importance of this study will be to establish the utility of DNA repair deficiency in specific genes as a predictive biomarker for response to high dose testosterone and to justify larger studies targeting specific subsets, particularly for subsets for which effective therapies have not yet been established such as ATM and CDK12.