The primary objective is to test the following hypothesis: Patients with metastatic castrate resistant prostate cancer that have progressed following at least one line of therapy and have an immunogenic signature will respond to combined PD-1 and CTLA4 inhibition.

This is a two-arm non-randomised, non-comparative phase II trial designed to assess the efficacy of nivolumab + ipilimumab in patients with metastatic castrate resistant prostate cancer that have progressed following at least 1 line of therapy and have an specified immunogenic signature. The immunogenic signature is defined by the presence of at least one of the following:

• Mismatch repair deficiency by IHC
• Defective DNA repair detected by a targeted sequencing panel
• High inflammatory infiltrate defined on multiplexed IHC criteria.

Treatment consists of :

Cohort 1:

• Nivolumab 1 mg/kg + ipilimumab 3 mg/kg every three weeks for a maximum of 4 doses
• 6 week gap after last combination dose
• 480 mg flat dose of nivolumab every 4 weeks for up to one year, or until progression, unacceptable toxicity or withdrawal of consent.

Cohort 2:

• Nivolumab 3 mg/kg + ipilimumab 1 mg/kg every three weeks for a maximum of 4 doses
• 3 week gap after last combination dose
• 480 mg flat dose of nivolumab every 4 weeks for up to one year, or until progression, unacceptable toxicity or withdrawal of consent.

Patients must have ongoing androgen deprivation to maintain serum testosterone < 1.73 nmol/L.

Inclusion Criteria:

• Metastatic castrate resistant prostate cancer.
• Histologically confirmed prostate adenocarcinoma.
• Patient has archival prostate cancer tissue available or is willing to undergo a new biopsy.
• Immunogenic biomarker positive disease - see Appendix 1 NB patients will be included in the trial if they meet all other eligibility criteria. Analysis of the ImS will take place after registration. Patients who do not have ImS positive disease will be withdrawn from the trial.
• WHO performance status of 0-1.
• Adequate haematological status.
• Adequate liver and renal function.
• Has had 1 or more lines of systemic treatment for mCRPC.
• Documented prostate cancer progression within 6 months prior to screening
• Ongoing androgen deprivation with serum testosterone <1.73 nmol/L.

Exclusion Criteria:

• Any history of autoimmune disease, with the exception of patients with a history of autoimmune-related hyperthyroidism or hypothyroidism who are in remission or on a stable dose of thyroid-replacement hormone.
• Patients with prior allogeneic stem cell or solid organ transplantation.
• Active invasive malignancy in the previous 2 years excluding non-melanoma skin cancer.
• History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.

(History of radiation pneumonitis in the radiation field is permitted).

• Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
• Patients with risk factors for bowel perforation.
• History of grade ≥2 peripheral neuropathy.
• Received therapeutic oral or intravenous (IV) antibiotics within 14 days prior to enrolment (Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or COPD) are eligible).
• Patients must not have had systemic corticosteroid therapy (>10mg daily prednisone equivalent) for 14 days prior to study entry, or concomitant use of other immunosuppressive medications. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone) is allowed.
• Prior treatment with Sipuleucel-T, immune checkpoint targeting agents or other novel immune-oncology agents.
• Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study.
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias, or unstable angina.
• Patients with uncontrolled Type 1 diabetes mellitus. Patients controlled on a stable insulin regimen are eligible.
• Patients with uncontrolled adrenal insufficiency.
• Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C.
• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.