Randomization is 1:1. 13.3 Statistical Analysis Plan Primary Endpoint: Previous publications suggest 8% were unable or unwilling to receive all three infusions of Sipuleucel-T. We will stop accrual at any time if more than 2 patients are unable to receive all three infusions and more than 30% of the patients are unable to receive all three infusions. This rule has a 4% of stopping if 8% are unable or unwilling to receive all three infusions, and a 82% chance of stopping early if 33% are unable or unwilling to receive all three infusions (based on 1000 simulations). In addition, if 3 patients in the first 10 are unable to initiate Sipulecel-T immunotherapy on Arm B, the study will hold accrual pending review by the COH DSMB, sponsor and PI. This slightly increase the chance of early stopping (3 of 10 is not “more than 30%” but equal to 30%). Previous publications suggest only 2% of patients are unwilling or unable to begin Sipuleucel-T immunotherapy. In addition, to the above stopping boundaries, there will be a safety review of the toxicities after 10 patients have been treated on Arm B, or after any grade 3 or higher treatment related toxicity on Arm B. These rules are in place to limit patient exposure to arm B if it proves poorly tolerated or too toxic. Secondary Endpoint: From the IMPACT study, titers of antibodies against prostatic acid phosphatase exceed ed 400 in 28.5% of t he patients treated with Sipuleucel-T. By having a control group, a Fisher's exact test with a 0.200 one- sided significance level will have 86% power to detect the difference between non-radiation proportion, 0.285 and a radiation-treated group proportion of 0.570 when the sample size in each group is 25. Also, with 25 patients, if the true proportion about 400 is 28.5% in the control arm, and 48.5% in the radiation arm, there is less than a 5% chance (~1% if the radiation proportion is 57%) that the observed proportion will be higher in the control arm, and there is an 85% chance that difference will exceed 8% between the two arms. In addition, secondary endpoints will include measurements of immune responses to PA2024 and PSA and radiologic responses to therapy with Sipuleucel-T +/- external beam radiation therapy to single metastasis. As a result, by having a concurrently randomized control arm, initial comparisons of Arm A and Arm B including the influence of radiation on PSA kinetics and response, toxicity and tolerability will help Page 39 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 m otivate future studies. For this exploratory secondary analysis, we will not include patients (if any) who do not start Sipuleucel-T immunotherapy, but will include all patients who start. A subset analysis of patients able to complete the planned three infusions will also be conducted. 14.0 Human Subject Issues 14.1 Institutional Review Board In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies with the federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health and Safety code, Title 17, must review and approve this protocol and the informed consent form prior to initiation of the study. All institutional, NCI, Federal, and State of California regulations must be fulfilled. 14.2 Recruitment of Subjects Patients for the study with will be recruited from patients undergoing therapy for metastatic castration resistant prostate cancer at the City of Hope Cancer Center 14.3 Advertisements Advertisements to include print, media (radio, television, billboards), telephone scripts, lay summary to be posted on City of Hope’s public Clinical Trials On-LineSM website, etc., will be reviewed and approved by the IRB prior to their use to recruit potential study subjects. 14.4 Study location and Performance Sites This study will be performed at City of Hope, City of Hope South Pasadena, and Huntsman Cancer Institute, University of Utah. 14.5 Confidentiality This research will be conducted in compliance with federal and state of California requirements relating to protected health information (PHI). The study will record individual immunological response to the Sipuleucel-T +/- radiation and any side effects, and this will be linked to the subject’s identity using a coded study number. The principal investigator, co-investigators, and laboratory technicians will have access to this information, but all information will be treated confidentially. No identifiers will be used in any subsequent publication of these results.} 14.6 Financial Obligations and Compensation Therapy on the protocol utilizes standard of care procedures. The standard of care drug (Sipuleucel-T) and radiation therapy will be the responsibility of the research participant and/or the insurance carrier. The research participant will be responsible for all copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth by the insurance carrier. The research participant and/or the insurance carrier will be billed for the costs of treatment and diagnostic procedures in the same way as if the research participant were not in a research study. However, neither the research participant nor the insurance carrier will be responsible for the research procedures related to this study. In the event of physical injury to a research participant, resulting from research procedures, appropriate medical treatment will be available at th e participating site to the injured research participant, however, financial compensation will not be available. The research participant will not be paid for taking part in this study.