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

Inclusion Criteria:

* 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