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

This is an open label, randomised, stratified, 2-arm, multicentre phase 2 clinical trial recruiting 160 participants over 12 months and followed until 150 events occurred (approximately another 18 months). Participants will be randomised to enzalutamide or enzalutamide and Lu-PSMA in a 1:1 ratio. A minimisation approach will be used to minimise chance imbalances across the following stratification factors: study site, volume of disease (>20 versus ≤20 sites of disease measured on 68Ga-PSMA PET/CT), prior treatment with early docetaxel for castration- sensitive disease (yes vs no), and prior treatment with early abiraterone for castration-sensitive disease (yes vs no).

Inclusion criteria

• 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
• Castration-resistant prostate cancer (defined as disease progressing despite castration by orchiectomy or ongoing luteinising hormone-releasing hormone agonist or antagonist).
• 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.
• 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)
• Target or non-target lesions according to RECIST 1.1
• 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)
• ECOG performance status 0-2
• Adequate renal function:

• Creatinine clearance ≥ 40mL/ min
• 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)
• 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
• Estimated life expectancy > 12 weeks
• Study treatment both planned and able to start within 21 days of randomisation
• Willing and able to comply with all study requirements (including both treatments: enzalutamide and Lu-PSMA), and all required study assessments
• Signed, written, informed consent

Exclusion criteria

• Prostate cancer with known significant sarcomatoid, or spindle cell, or neuroendocrine small cell components, or metastasis of other cancer to the prostate
• 68Ga-PSMA PET/CT SUVmax < 10 at a site of measurable disease > 10mm
• Prior treatment with enzalutamide, darolutamide, or apalutamide. Prior treatment with abiraterone is allowed.
• Prior treatment with any PSMA-targeted radiotherapy
• Prior chemotherapy for mCRPC. Prior docetaxel in castration-sensitive setting is permitted
• 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)
• Concurrent illness, including severe infection that may jeopardise the ability of the participant to undergo the procedures outlined in this protocol with reasonable safety
• 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
• Men in sexual relationships with women of reproductive potential who are not willing/able to use medically acceptable forms of barrier contraception
• History of:

• seizure or any condition that may predispose to seizure (e.g. prior cortical stroke or significant brain trauma)
• loss of consciousness or transient ischemic attack within 12 months of randomization
• 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