• Written informed consent and be capable of cooperating with treatment.

• Age ≥ 18 years.

• Histologically or biochemically confirmed adenocarcinoma of the prostate and with tumour tissue accessible for research analysis for this trial. Patients who have no histological diagnosis must be willing to undergo a biopsy to prove prostate adenocarcinoma.

• Patients recruited to phase 1 dose escalation cohorts must have biopsiable disease and consent to mandatory pre- and post-treatment biopsies (baseline and on Cycle 2 Day 1).

• Metastatic castration-resistant prostate cancer.

• All patients must have documented resistance to 1 prior next generation antiandrogen therapy (NAAT) defined as:

• For phase 1 and phase 2 Cohorts:

• Patients who have progressed after either enzalutamide, Apalutamide or darolutamide (having received a minimum of 12-weeks of enzalutamide, Apalutamide or darolutamide) will enter phase 1 or phase 2 cohorts directly. Patients that have previously received abiraterone but not an AR antagonist should receive a lead-in with Apalutamide on trial and receive the combination on progression through the lead-in.

• Documented prostate cancer progression as assessed by the investigator with RECIST v1.1 and PCWG3 criteria (Section 3.5) with at least two of the following criteria:

∙ Progression of soft tissue/visceral disease by RECIST v1.1 and/or,

‣ Progression of bone disease by PCWG3 bone scan criteria and/or,

‣ Progression of PSA by PCWG3 PSA criteria.

• PSA ≥ 10ng/ml.

• Received prior castration by orchiectomy and/or ongoing luteinizing hormone releasing hormone agonist treatment.

⁃ Ongoing androgen deprivation with serum testosterone \< 50 ng/dL (\< 1.7 nM).

⁃ Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2.

⁃ Documented willingness to use an effective means of contraception while participating in the study and for 6 months post last treatment dose.

⁃ Able to swallow the study drug.

⁃ All efforts should be made to discontinue steroid usage but up-to 5mg BD prednisolone (or equivalent) will be allowed.

⁃ Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes on trial.

• Haemoglobin (Hb) ≥ 9.0 g/dL Absolute neutrophil count ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L WBC ≥ 3.0 x 109/L Calculated creatinine clearance ≥ 50 mL/min (uncorrected value) Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) unless documented Gilbert's disease., in which case ≤ 3 x ULN is permissible Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x (ULN) unless raised due to known metastatic liver disease in which case ≤ 5 x ULN is permissible