Enzalutamide With Lu PSMA-617 Versus Enzalutamide Alone in Men With Metastatic Castration-resistant Prostate Cancer

Inclusion Criteria: 1. Males aged 18 or older with metastatic adenocarcinoma of the prostate defined by: * Documented histopathology of prostate adenocarcinoma (no features of neuroendocrine carcinoma) OR * Metastatic disease typical of prostate cancer 2. Castration-resistant prostate cancer (defined as disease progressing despite castration by orchiectomy or ongoing luteinising hormone-releasing hormone agonist or antagonist). 3. Progressive disease with rising PSA defined by PCWG3 criteria (sequence of 2 rising values at a minimum of 1-week intervals) AND PSA ≥ 5 ng/mL. 4. At least 2 of the following risk factors for early treatment failure with enzalutamide: * LDH ≥ ULN * ALP ≥ ULN * Albumin \<35 g/L * De novo metastatic disease (M1) at initial diagnosis \* * \<3 years since initial diagnosis * \>5 bone metastases \* * Visceral metastases \* * PSA doubling time \<84 days * Pain requiring opiates for \>14 days * Prior treatment with abiraterone \* Based on conventional imaging (CT and/or bone scan) 5. Target or non-target lesions according to RECIST 1.1 6. Significant PSMA avidity on 68Ga-PSMA PET/CT, defined as SUVmax \>15 at a single site (regardless of lesion size) and SUV max \>10 at sites of disease ≥10mm (unless subject to factors explaining a lower uptake, e.g. respiratory motion, reconstruction artefact) 7. ECOG performance status 0-2 8. Adequate renal function: \- Creatinine clearance ≥ 40mL/ min 9. Adequate liver function: * Bilirubin \< 1.5 x upper limit of normal (ULN) (or if bilirubin is between 1.5 - 2x ULN, must have a normal conjugated bilirubin) * AST or ALT ≤ 2.0 x ULN (or ≤ 5.0 x ULN in the presence of liver metastases) 10. Adequate bone marrow function: * Platelets ≥ 100 x109/L * Haemoglobin ≥ 90g/L (no red blood cell transfusion in last 4 weeks) * Neutrophils \> 1.5 x109/L 11. Estimated life expectancy \> 12 weeks 12. Study treatment both planned and able to start within 21 days of randomisation 13. Willing and able to comply with all study requirements (including both treatments: enzalutamide and Lu-PSMA), and all required study assessments 14. Signed, written, informed consent Exclusion Criteria: 1. Prostate cancer with known significant sarcomatoid, or spindle cell, or neuroendocrine small cell components, or metastasis of other cancer to the prostate 2. 68Ga-PSMA PET/CT SUVmax \< 10 at a site of measurable disease \> 10mm 3. Prior treatment with enzalutamide, darolutamide, or apalutamide. Prior treatment with abiraterone is allowed. 4. Prior treatment with any PSMA-targeted radiotherapy 5. Prior chemotherapy for mCRPC. Prior docetaxel in castration-sensitive setting is permitted 6. History of another malignancy within 5 years prior to randomisation except for non-melanomatous carcinoma of the skin; or, adequately treated, non-muscle-invasive urothelial carcinoma of the bladder (i.e. Tis, Ta and low grade T1 tumours) 7. Concurrent illness, including severe infection that may jeopardise the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety 8. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse 9. Men in sexual relationships with women of reproductive potential who are not willing/able to use medically acceptable forms of barrier contraception 10. History of: 1. seizure or any condition that may predispose to seizure (e.g. prior cortical stroke or significant brain trauma) 2. loss of consciousness or transient ischemic attack within 12 months of randomization 3. significant cardiovascular disease within the last 3 months: including myocardial infarction, unstable angina, congestive heart failure (NYHA grade II or greater, see Appendix 4), ongoing arrhythmias of Grade \> 2, thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism). Chronic stable atrial fibrillation on stable anticoagulant therapy is allowed