Ipilimumab With Nivolumab for Molecular-selected Patients With Castration-resistant Prostate Cancer

Inclusion Criteria: In order to be eligible to participate in this study, a subject must meet all of the following criteria: 1. Written informed consent. 2. Histological diagnosis of adenocarcinoma of the prostate. Patients who have no histological diagnosis must be willing to undergo a biopsy to prove prostate adenocarcinoma. 3. Metastatic Castration-Resistant Prostate Cancer (mCRPC), metastatic disease defined either as measurable disease by RECIST1.1 criteria or presence of bone-metastatic disease evaluable per PCWG3 criteria. For cohort 1, measurable disease is compulsory. 4. An immunogenic phenotype, consisting of one of the next criteria: 1, mismatch repair deficiency and/or a high mutational burden of \>7 mutations per Mb (cluster A); 2, BRCA2 inactivation or BRCAness signature (cluster B); 3, a tandem duplication signature and/or CDK12 biallelic inactivation (cluster C) 5. Age ≥18 years. 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. 7. PSA ≥ 2 ng/ml. 8. Documented willingness to use an effective means of contraception while participating in the study and for 7 months post last dose of treatment 9. Documented ongoing castrate serum testosterone \<50 ng/dL (\<2.0 nM). 10. Received prior castration by orchiectomy and/or ongoing Luteinizing Hormone-Releasing Hormone (LH-RH) agonist treatment. 11. Progression of disease by: 1. PSA utilizing PCWG3 criteria 2. Bone scan: disease progression as defined by at least 2 new lesions on bone scan. 3. Soft tissue disease progression defined by modified RECIST 1.1. 4. Clinical progression with worsening pain and the need for palliative radiotherapy for bone metastases. 12. Having a biopsiable metastatic lesion and willingness to undergo a baseline\* and on treatment tumour biopsy for next-generation sequencing and biomarker analyses. * When sufficient FFPE material is available from a biopsy in castrate-state, one may apply for a waiver for a new baseline biopsy. Exclusion Criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: 1. Prior treatment with checkpoint immunotherapy (CTLA-4, or PD-1 and PD-L1 antagonists) for cohort 1. For cohort 2, patients may have prior treatment with monotherapy CTLA-4 or PD-1 or PD-L1. 2. Surgery or chemotherapy within 4 weeks prior to trial entry / randomisation into the study. Any other therapies for prostate cancer, other than GnRH analogue therapy and osteoporosis preventing agents, are not allowed. 3. Radiotherapy within 2 weeks prior to trial entry. Radiation-related side effects higher than grade 1, or above baseline. 4. Participation in another interventional clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry/randomisation. 5. History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumours, brain metastases, or alcoholism. 6. Untreated or symptomatic brain or leptomeningeal involvement. 7. Inadequate organ and bone marrow function as evidenced by: 1. hemoglobin \<6.2 mmol/L 2. Absolute neutrophil count \<1.0 x 109/L 3. Platelet count \< 75 x 109/L 4. Albumin \<30 g/dL. 5. AST / SGOT and/or ALT / SGPT ≥ 2.5 x ULN (≥ 5 x ULN if liver metastases present) 6. Total bilirubin ≥ 1.5 x ULN (except for patient with documented Gilbert's disease) 7. Serum Creatinine \> 1.5 x ULN 8. Any of the following cardiac criteria; a. Any clinically significant abnormalities in rhythm conduction, or morphology of a resting ECG (e.g., complete left bundle branch block, third degree heart block) c. Experience of any of the following procedures or conditions in the preceding six months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, congestive heart failure NYHA ≥ Grade2 d. Uncontrolled hypotension defined as systolic blood pressure (BP) \<90mmHg and/or diastolic BP \<50mmHg 9. Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis. 10. History of clinically relevant auto-immune disease (including Crohn's disease or ulcerative colitis). Any other finding giving reasonable suspicion of a disease or condition that contraindicates the use of nivolumab or ipilimumab or that may affect the interpretation of the results or renders the patients at high risk from treatment complications. 11. Need for chronic corticosteroid therapy of \>10 mg of prednisolone or \>0.5mg of dexamethasone per day or an equivalent dose of other anti-inflammatory corticosteroid. Patients in which corticosteroids cannot be stopped prior to entering the trial are allowed a maximum of 10mg of prednisolone per day or equivalent. In the case of corticosteroid discontinuation, a 2-week (14 days) washout is required with a mandatory PSA check prior to starting the trial. If the PSA has declined compared to the value obtained prior to stopping corticosteroids, patients will not be eligible for study. Patients can only enter the study with a confirmed PSA increase. 12. Malignancies other than prostate cancer within 3 years prior to trial entry / randomization, except for adequately treated basal or squamous cell skin cancer and non-muscle invasive bladder cancer. 13. Active second malignancy, except basal or squamous cell skin cancer and non-muscle invasive bladder cancer. Other treated malignancies with curative intent, including colorectal cancer, may be included following PI consent. 14. Unresolved clinically significant toxicity from prior therapy except for alopecia and Grade 1 peripheral neuropathy. 15. Inability to comply with study and follow-up procedures. 16. Patients with predominant small cell or neuroendocrine prostate cancer are not eligible. 17. Patients without measurable lesion per RECIST1.1, and with a superscan on bone scintigraphy not evaluable per PCWG3 criteria, are not eligible