This study is designed to test the hypothesis that using Sipuleucel-T (Provenge) in combination with new hormonal agents (NHA) (abiraterone, enzalutamide, apalutamide) for the treatment of participants with asymptomatic metastatic castration resistant prostate cancer (mCRPC) and no visceral metastases would enhance the activation of antigen presenting cells (APC) by sipuleucel-T.

Inclusion Criteria:

• Asymptomatic or minimally symptomatic metastatic prostate cancer, and the diagnosis of prostate cancer needs to be histologically confirmed by biopsy of the prostate or a metastatic lesion
• On combined ADT with LHRH analog and a NHA (enzalutamide, apalutamide or abiraterone) for metastatic prostate cancer with PSA progression, but no imaging progression based on the prostate cancer working group (PCWG) 3 criteria
• Age 18 or above
• ECOG performance status 0 or 1
• Participants must have adequate organ and marrow function as defined below:
• Absolute neutrophil count ≥1,000/mcL
• Platelets ≥100,000/mcL
• Hemoglobin > 10 g/dl
• AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN
• Creatinine 1.5 ≤ institutional ULN
• Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of sipuleucel-T are eligible for this trial
• No uncontrolled arrhythmia: patients with h/o myocardial infarction or history of congestive heart failure, need to have estimated left ventricle ejection fraction above 40% either on echocardiogram or MUGA scan within 6 months of study enrollment
• Non-sterilized men who are sexually active with a female partner of childbearing potential must agree to use adequate contraception prior to the study enrollment, and for the duration of study participation
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Participants who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study
• Prior treatment with sipuleucel-T
• Participants who have not recovered from adverse events (AEs) due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 2).
• Participants who require > 50% dose reduction of NHA are excluded from the study except for taking abiraterone at 250 mg with low fat food
• Documented brain metastases or liver metastases
• Treatment with any investigational compound within 30 days prior to the first dose of Sipuleucel-T
• Documented brain metastases or liver metastases
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for sipluleucel-T to be less clinically active in this population
• Inability to comply with protocol requirements