Provenge With or Without pTVG-HP DNA Booster Vaccine in Prostate Cancer

• Histologically confirmed diagnosis of prostate cancer (adenocarcinoma of the prostate)
• Metastatic disease as evidenced by the presence of soft tissue and/or bone metastases on imaging studies (computed tomography [CT] of abdomen/pelvis, bone scintigraphy)

• Castrate-resistant disease, defined as follows:

  • All patients must have received standard of care androgen deprivation treatment before trial entry (surgical castration versus gonadotropin-releasing hormone [GnRH] analogue or antagonist treatment), and subjects receiving GnRH analogue or antagonist must continue this treatment throughout the time on this study

  • Patients may have been treated previously with a nonsteroidal antiandrogen, with evidence of disease progression subsequently; subjects must be off use of anti-androgen for at least 4 weeks (for flutamide) or 6 weeks (for bicalutamide or nilutamide) prior to registration

    ** Subjects who demonstrate an anti-androgen withdrawal response, defined as a >= 25% decline in PSA within 4-6 week of stopping a nonsteroidal antiandrogen are not eligible until the PSA rises above the nadir observed after antiandrogen withdrawal

  • Castration levels of testosterone (\< 50 ng/dL) within 2 weeks of registration

• Progressive disease while receiving androgen deprivation therapy defined by any one of the following as per the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) bone scan criteria or Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 during or after completing last therapy:

  • PSA: at least two consecutive rises in serum PSA, obtained at a minimum of 1-week intervals, and each value >= 2.0 ng/mL
  • Measurable disease: >= 50% increase in the sum of the cross products of all measurable lesions or the development of new measurable lesions; the short axis of a target lymph node must be at least 15 mm by spiral CT to be considered a target lesion
  • Non-measurable (bone) disease: the appearance of two or more new areas of uptake on bone scan consistent with metastatic disease compared to previous imaging during castration therapy; the increased uptake of pre-existing lesions on bone scan will not be taken to constitute progression, and ambiguous results must be confirmed by other imaging modalities (e.g. X-ray, CT or magnetic resonance imaging [MRI])
• Must have >= 3 serum PSA values obtained over at least a 12 week period of time prior to registration, including the day of screening, to calculate a PSA doubling time; Note: PSA's are not required to be obtained at the same laboratory; use all PSA values that have been done in last 6 months to calculate PSA doubling time
• Life expectancy of at least 6 months
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• White blood cell >= 2000/mm\^3
• Absolute neutrophil count >= 1000/mm\^3
• Hemoglobin (HgB) >= 9.0 mg/dL
• Platelets >= 100,000/mm\^3
• Creatinine =\< 2.0 mg/dL
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =\< 2.5 x institutional upper limit of normal
• Negative serology tests for human immunodeficiency virus (HIV) 1 and 2, and for active hepatitis B or hepatitis C, within 14 days of first peripheral blood collection for sipuleucel-T
• Patients must be at least 4 weeks from any prior treatments and have recovered (to \< grade 2) from acute toxicity attributed to this prior treatment
• Patients must be informed of the experimental nature of the study and its potential risks, and must sign an Institutional Review Board (IRB)-approved written informed consent form indicating such an understanding

Exclusion Criteria:

• Small cell or other variant prostate cancer histology
• Patients may not be receiving other investigational agents or be receiving concurrent anticancer therapy other than androgen deprivation
• Symptomatic metastatic disease, as defined by the need for opioid analgesics for the treatment of pain attributed to a prostate cancer metastatic lesion; patients receiving opioids must receive approval from the principal investigator (PI) for eligibility
• Patients may not have been treated with prior sipuleucel-T

• Treatment with any of the following medications within 28 days of registration, or while on study, is prohibited:

  • Systemic corticosteroids (at doses over the equivalent of 1 mg prednisone daily); inhaled, intranasal or topical corticosteroids are acceptable
  • Prostate cancer (PC)-SPES
  • Saw palmetto
  • Megestrol
  • Ketoconazole
  • 5-alpha-reductase inhibitors-patients already taking 5-alpha-reductase inhibitors prior to 28 days prior to registration may stay on these agents throughout the course of therapy, but these should not be started while patients are on study
  • Diethyl stilbestrol
  • Abiraterone
  • Any other hormonal agent or supplement being used with the intent of cancer treatment
• External beam radiation therapy within 4 weeks of registration is prohibited, or anticipated need for radiation therapy (e.g. imminent pathological fracture or spinal cord compression) within 3 months of registration
• Major surgery within 4 weeks of registration is prohibited
• Prior cytotoxic chemotherapy (e.g. docetaxel, mitoxantrone, cabazitaxel) within 6 months of registration is prohibited
• Patients with a history of life-threatening autoimmune disease
• Patients who have undergone splenectomy
• Patients must not have other active malignancies other than non-melanoma skin cancers or carcinoma in situ of the bladder; subjects with a history of other cancers who have been adequately treated and have been recurrence-free for >= 3 years are eligible
• Patients with known brain metastases
• Any antibiotic therapy or evidence of infection within 1 week of registration
• Any other medical intervention or condition, which, in the opinion of the PI could compromise patient safety or adherence with the study requirements
• Patients cannot have concurrent enrollment on other phase I, II, or III investigational treatment studies