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

This randomized pilot clinical trial studies sipuleucel-T with or without deoxyribonucleic acid (DNA) vaccine therapy in treating patients with prostate cancer that has not responded to previous treatment with hormones and has spread to other places in the body. Vaccines may help the body build an effective immune response to kill tumor cells. It is not yet known whether giving sipuleucel-T vaccine works better with or without DNA vaccine therapy in treating prostate cancer.


Eligibility Criteria:
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