Inclusion Criteria:
Target Population: Cohort A Patients with castration-sensitive oligometastatic prostate cancer who have not received primary local therapy (radiation or surgery), and no more than 5 months of prior androgen deprivation therapy.
* The subject must be age 18 or older, and be willing and able to provide informed consent.
* The subject must have histologically confirmed adenocarcinoma of the prostate with tissue confirmation at selected study site.
* The subject must have newly diagnosed prostate cancer with a metastatic site(s).
* The subject must have a history or presence of ≤ 10 bony metastatic lesions
* Note: bone mets that are not clearly identified on bone imaging, but are biopsy proven are allowed
* History or presence of distant metastatic lymph node(s) (e.g., retroperitoneal or non-regional pelvic lymph nodes) are allowed
* History or presence of regional pelvic lymph nodes (as per AJCC Cancer Staging \[7th edition\]) will be considered a metastatic site if greater than 1.5cm in shortest dimension.
* The subject must have Karnofsky performance status of 80-100.
* Normal organ function with acceptable initial laboratory values:
* WBC ≥ 2000/μL
* ANC ≥ 1000/ μL
* Platelets ≥ 75 x 103/μL
* Creatinine ≤ 2.0 x ULN
* AST/ALT ≤ 2.5 x ULN
* Bilirubin ≤ 1.5 x ULN (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
* No active or chronic infection with HIV, Hepatitis B or Hepatitis C (negative screening tests required).
* The subject must be deemed medically fit for radical prostatectomy by the attending urologic surgeon at the selected study site.
* Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study \[and for up to 26 weeks after the last dose of ipilimumab\] in such a manner that the risk of pregnancy is minimized.
Exclusion Criteria:
* Patients that meet any of the criteria listed below will not be eligible for Cohort A entry:
* Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer or superficial bladder cancer
* Major surgery within 4 weeks of enrollment (Week 1 Visit).
* Current or prior radiation therapy to the prostate Prior radiation to a metastatic site (e.g., palliative radiation) is allowed..
* More than 5 months of prior hormonal therapy (e.g., gonadotropin hormone releasing analogs, megestrol acetate, or casodex) . There is no washout period required for GnRH analogs. A two week washout is required for megestrol or anti-androgen.
* Prior use of an 5 alpha reductase inhibitor is allowed (no limit on duration of use), however a two week washout is required.
* Prior ketoconazole, abiraterone acetate, or enzalutamide for the treatment of prostate cancer.
* Current or prior investigational therapies for prostate cancer, or chemotherapy administered with the intent to treat prostate cancer.
* Concomitant therapy with any other experimental drug.
* Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's granulomatosis\]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis).
* Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
* Patients with underlying heart conditions who are deemed ineligible for surgery.
* Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab).
* Note: Inactivated vaccines are allowed at any time on study.
* A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 inhibitor or agonist.
* Concomitant or prior therapy with any of the following: IL-2, interferon, or other nonstudy immunotherapy regimens; immunosuppressive agents; ; or chronic use of systemic corticosteroids within 6 weeks of study entry.
* Persons of reproductive potential unwilling to use an adequate method of contraception throughout treatment and for at least 26 weeks after ipilimumab is stopped.
* Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation.
Inclusion Criteria:
Target Population: Cohort B
* The subject must be age 18 or older, and be willing and able to provide informed consent.
* Histologically confirmed prostate cancer with progressive disease, defined as:
* Rising PSA (50% or more increase to a level of 1 ng/mL or more, based on at least 3 PSA determinations obtained at least 1 week apart). The 50% rise in PSA is across the 3 determinations, and these determinations do not need to be sequential.
* PSA doubling time of ≤ 12 months as calculated according to the Memorial Sloan-Kettering Cancer Center nomogram (http://www.mskcc.org/mskcc/html/10088.cfm)
* The subject must have Karnofsky performance status of 80-100.
* Normal organ function with acceptable initial laboratory values:
* WBC ≥ 2000/μL
* ANC ≥ 1000/ μL
* Platelets ≥ 75 x 103/μL
* Creatinine ≤ 2.0 x ULN
* AST/ALT ≤ 2.5 x ULN
* Bilirubin ≤ 1.5 x ULN (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
* No active or chronic infection with HIV, Hepatitis B or Hepatitis C (negative screening tests required).
* Prior radiotherapy to the prostate (adjuvant or salvage radiotherapy) is allowed
* Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study \[and for up to 26 weeks after the last dose of ipilimumab\] in such a manner that the risk of pregnancy is minimized.
Exclusion Criteria:
Target Population: Cohort B
Patients that meet any of the criteria listed below will not be eligible for Cohort B entry:
* Any other malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer or superficial bladder cancer
* Major surgery within 4 weeks of enrollment (Week 1 Visit).
* Visceral metastatic disease
* More than 3 cycles of intermittent hormones (for the treatment of biochemical recurrence or castration sensitive metastatic disease), with a cycle defined as a period of consistent androgen deprivation therapy (generally 3-12 months) followed by intentional cessation of ADT without reinitiation of ADT until the PSA rises.
* Prior use of an 5 alpha reductase inhibitor is allowed (no limit on duration of use), however a two week washout is required.
* Current or prior investigational therapies for prostate cancer, or chemotherapy administered with the intent to treat prostate cancer.
* Concomitant therapy with any other experimental drug.
* Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's granulomatosis\]); motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis).
* Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
* Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month before or after any dose of ipilimumab).
* Note: Inactivated vaccines are allowed at any time on study.
* A history of prior treatment with ipilimumab or prior CD137 agonist or CTLA-4 inhibitor or agonist.
* Concomitant or prior therapy with any of the following: IL-2, interferon, or other non-study immunotherapy regimens; immunosuppressive agents; ; or chronic use of systemic corticosteroids within 6 weeks of study entry.
* Persons of reproductive potential unwilling to use an adequate method of contraception throughout treatment and for at least 26 weeks after ipilimumab is stopped.
* Patients who have had a history of acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation.
