ENZA-p: This phase II trial is trying to understand the safety and potential impact of adding radiotherapy to standard hormone therapy in patients with castration resistant prostate cancer that has not previously been treated using chemotherapy and has spread to other parts of the bodyA Randomised Phase II Trial Using PSMA as a Therapeutic Agent and Prognostic Indicator in Men With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide

Inclusion

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