PROstate Cancer TReatment Optimization Via Analysis of Circulating Tumour DNA

INCLUSION CRITERIA Patients must meet ALL of the following criteria: 1. Willing and able to provide informed consent 2. Adult males ≥ 18 years age 3. History of histologically confirmed adenocarcinoma of the prostate without evidence of neuroendocrine or small cell differentiation. If histology is not available, patients must have metastatic disease typical of prostate cancer (i.e., involving bone or pelvic lymph nodes or para-aortic lymph nodes) AND a serum concentration of PSA that is rising and \>20ng/mL at the time prostate cancer was diagnosed clinically 4. Consent to analysis of archival tissue collected at diagnosis is mandatory 5. Prior surgical orchiectomy or if on LHRH agonist/antagonist then testosterone \< 1.7 nmol/L at screening visit (patients must maintain LHRH agonist/antagonist therapy for duration of study treatment if not surgically castrated) 6. Evidence of metastatic disease on bone scan or CT scan 7. Evidence of biochemical or imaging progression in the setting of surgical or medical castration while on abiraterone. Progressive disease for study entry is defined by one of the following three criteria as per PCWG317: 1. PSA progression: minimum of two rising PSA values from a baseline measurement of one week interval. Minimum PSA at screening visit is 1.0 ng/mL 2. Soft tissue or visceral disease progression: an increase ≥20% in the sum of the diameter (short axis for nodal lesions and long axis for non-nodal lesions) from the smallest sum of the diameter since treatment started, or appearance of any new lesions (see Appendix B for definition of measurable disease as per RECIST 1.1 criteria). 3. Bone progression: ≥ 2 new lesions on bone scan confirmed on subsequent bone scan at least 8 weeks apart (2+2 rule as per PCWG317) 8. ECOG performance status 0-2 (see Appendix C) 9. Prior treatment with abiraterone, in either castration-sensitive or castration-resistant setting. 10. Eligible for treatment with either enzalutamide or docetaxel as per standard of care guidelines 11. Adequate organ function defined as: 1. Absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L and hemoglobin ≥ 90 g/L 2. Creatinine clearance ≥ 30 ml/min (calculated by Cockcroft-Gault formula, see Appendix D) 3. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) except for patients with known Gilbert's syndrome (direct bilirubin ≤ 1.5 x ULN) 4. Alanine aminotransferase (ALT) ≤ 5 x ULN 12. Able to swallow study drug and comply with study requirements including provision of peripheral blood samples at specified time points for correlative studies 13. Recovery from all prior treatment-related toxicity to grade ≤ 2 (as per CTCAE 5.0) EXCLUSION CRITERIA Patients must NOT meet any of the following criteria: 1. Severe concurrent illness or co-morbid disease that would make the subject unsuitable for enrolment 2. Prior therapy with enzalutamide or other experimental anti-androgens (e.g. ARN-509, TOK-001) 3. Prior systemic chemotherapy with docetaxel or cabazitaxel (with the exception of: patients who were treated with docetaxel for castration sensitive disease and did not progress for at least 12 months after completion of docetaxel) 4. Active concurrent malignancy (with the exception of non-melanomatous skin cancer, or other solid tumours curatively treated with no evidence of disease for ≥3 years) 5. Wide-field radiotherapy or radioisotopes such as Strontium-89, or Radium-223 ≤ 28 days prior to starting study drug (limited-field palliative radiotherapy for up to 5 fractions prior to starting study drug is permitted) 6. Brain metastases or active epidural disease (treated epidural disease is permitted) 7. Contraindication to prednisone therapy including poorly controlled diabetes mellitus 8. History of seizure or seizure disorder, or history of any cerebrovascular event within 6 months of study entry. 9. Uncontrolled hypertension Grade ≥3 (i.e. systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) 10. Gastrointestinal disorder affecting absorption 11. Major surgery within 4 weeks of starting study treatment