• Histologically or cytologically proven metastatic castration-resistant prostate cancer or adenocarcinoma refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient.

• Documented prostate cancer progression as assessed by the investigator with RECIST (v1.1) and PCWG3 criteria with at least one 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 and/or

‣ Clinical progression with worsening pain and need for palliative radiotherapy for bone metastases.

• Phase I: Patients that have progressed after at least 12 weeks of treatment with a NAAT within the previous 6 months Phase II: Patients that have progressed after at least 12 weeks of treatment with a NAAT within the previous 6 months (for combination treatment) or more than 6 months prior to trial entry (for enzalutamide alone resistance run-in).

• Previously progressed on at least one line of taxane chemotherapy (or not fit or not willing to receive a taxane).

• Ongoing androgen deprivation maintaining serum testosterone of less than 50 ng/dL (less than 2.0 nM) is mandatory.

• Life expectancy of at least 12-weeks.

• Able to swallow tablets.

• Archival tumour tissue must be available for analyses.

• Willing to have pre- and post-treatment biopsies if biopsy is feasible.

⁃ World Health Organisation (WHO) performance status of 0-2 (Appendix 1).

⁃ Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) prior to the patient's first dose of IMP.

⁃ Haemoglobin (Hb): ≥ 9.0 g/dL

⁃ Absolute neutrophil count: ≥ 1.5 x 109/L

⁃ Platelet count: ≥ 75 x 109/L

⁃ Serum bilirubin: ≤ 1.5 x upper limit of normal (ULN)

⁃ Alanine aminotransferase (ALT): ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 x ULN is permissible

⁃ Aspartate aminotransferase (AST): ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 x ULN is permissible

⁃ Serum creatinine / calculated creatinine clearance: ≤ 1.5 x upper limit of normal (ULN) / GFR ≥ 50 mL/min (uncorrected value)

⁃ Serum albumin: \>25 g/L

⁃ 18 years or over

⁃ Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up

⁃ Willing and able to comply with the study requirement including the collection of blood, fresh tumour biopsy, urine, rectal swab and stool samples.