This trial will evaluate the use of one versus two DNA vaccines, delivered concurrently with PD-1 blockade using pembrolizumab followed by treatment with pembrolizumab alone, and delivered over a prolonged period of time (for a maximum of 2 years (32 cycles) or until radiographic progression) on the treatment of castrate-resistant, metastatic prostate cancer. The hypothesis to be tested is that delivering two vaccines with PD-1 blockade will elicit a greater frequency and magnitude of tumor-directed CD8+ T cells, and thereby increase the percentage of patients experiencing objective anti-tumor effect as measured by PSA declines and/or objective radiographic responses. Participants must be 18 years of age or older and can expect to be on treatment for 2 years (32 cycles) and on study for up to 4 years (including 2 years of follow up via phone).