Phase II Randomised Controlled Trial of Patient-specific Adaptive vs. Continuous Abiraterone or eNZalutamide in mCRPC

Inclusion Criteria:

1. Willing and able to provide informed consent;

2. Aged 18 or older;

3. Histologically or cytologically confirmed adenocarcinoma of the prostate;

4. Ongoing androgen deprivation therapy with a GnRH analogue or bilateral orchiectomy (i.e. surgical or medical castration with testosterone at screening ≤1.7 nmol/L (<0.5 ng/mL)); patients who have not had a bilateral orchiectomy, must have a planto maintain effective GnRH-analogue therapy for the duration of the trial;

5. Presence of metastatic disease on WBBS and/or CT-scan;

6. Progressive disease at study entry defined as per PCWG3 as one or more of thefollowing criteria that occurred while the patient was on ADT:

7. PSA progression defined by a minimum of 2 rising PSA levels with an interval of ≥1 week between each determination. Patients who received an anti-androgen musthave progression after withdrawal (≥4 weeks since last flutamide or ≥6 weekssince last bicalutamide or nilutamide); OR

8. Radiographic PD on bone scintigraphy and/or CT-scan;

9. A PSA concentration of ≥2 ng/mL.

10. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;

11. Controlled symptoms (opioids for cancer related pain stable for >4 weeks, no needfor urgent radiotherapy for symptomatic lesions);

12. Estimated life expectancy of ≥12 months;

13. Patient has archival prostate cancer tissue available and which he consents to shareor is willing to undergo a new tumour biopsy;

14. Adequate organ function: absolute neutrophil count > 1,500/μL (> 1.5109/L);platelet count > 100,000/μL (> 100109/L), haemoglobin > 90 g/L; total bilirubin < 1.5 times ULN, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 3 times ULN; creatinine < 175 μmol/L; albumin > 30 g/L;

15. Any other therapies for CRPC (excluding denosumab and bisphosphonates) have to bediscontinued 3 weeks prior to study randomisation;

16. Able to swallow the study drug and comply with study requirements.

Exclusion Criteria:

1. Life-threatening or serious medical or psychiatric illness that could, ininvestigator's opinion, potentially interfere with participation in this study;

2. Diagnosis or treatment for another systemic malignancy within 2 years before thefirst dose of study drugs. Potential participants with non-melanoma skin cancer,non-muscle invasive bladder cancer, or carcinoma in situ of any type are allowed ifthey have undergone complete resection;

3. Known or suspected brain metastasis or leptomeningeal disease;

4. Small-cell or neuroendocrine differentiation of prostate cancer;

5. Radiation therapy for treatment of the primary tumour within 3 weeks of screeningvisit;

6. Radiation or radionuclide therapy for treatment of metastasis within 3 weeks ofscreening visit, excluding radiation to reduce pain symptoms;

7. History of uncontrolled seizures (if patient and investigator wish to choosetreatment with enzalutamide)

8. Unstable symptomatic ischemic heart disease, ongoing arrhythmias or New York HeartAssociation (NYHA) Class III or IV heart failure;

9. Known HIV infection, active chronic hepatitis B or C;

10. Known gastrointestinal (GI) disease that could interfere with GIabsorption/tolerance of study drugs;

11. Prior treatments with CYP17 inhibitors (e.g. ketoconazole) or novel androgenreceptor inhibitors (e.g. abiraterone, apalutamide, darolutamide or enzalutamide).Bicalutamide and nilutamide should be stopped >6 weeks before screening visit. Priortreatment with docetaxel in the mHSPC setting is allowed.

12. Any condition or reason that, in the opinion of the Investigator, interferes withthe ability of the patient to participate in the trial, which places the patient atundue risk, or complicates the interpretation of safety data.