This phase 2 randomised clinical trial will compare the effectiveness of Lu-PSMA therapy followed by docetaxel chemotherapy versus docetaxel chemotherapy on its own in patients with newly-diagnosed high-volume metastatic hormone-naive prostate cancer (mHNPC).

This is an open label, randomised, stratified, 2-Arm, multi-centre, phase 2 clinical trial recruiting 140 newly-diagnosed high-volume mHNPC patients at 11 Australian centres over a period of 18 months. Patients will be randomised to the experimental Arm (177Lu-PSMA followed by docetaxel) or standard-of-care Arm (docetaxel) in a 1:1 ratio. All patients will receive ADT continuously throughout the trial. Patients will be stratified according to disease volume by conventional imaging (low-volume vs. high-volume) and duration of ADT at time of registration (≤ 28 days vs. > 28 days).

Inclusion Criteria for study registration:

1. Patient has provided written informed consent

2. Male aged 18 years or older at screening

3. Prostate cancer diagnosed within 12 weeks of commencement of screening

4. Histologically or cytologically confirmed adenocarcinoma of the prostate without significant neuroendocrine differentiation or small cell histology OR metastatic disease typical of prostate cancer (i.e. involving bone or pelvic lymph nodes or para-aortic lymph nodes) with a rising serum PSA

5. Evidence of metastatic disease on CT and/or bone scan

6. PSA > 10ng/ml prior to commencement of medical ADT or surgical orchidectomy

7. Adequate haematological, renal and hepatic functions as defined by:

   • Absolute neutrophil count >1.5 x 109/L
   • Platelet count >100 x 109/L
   • Haemoglobin ≥ 90g/L (no red blood cell transfusion in 4 weeks prior to randomisation)
   • Creatinine Clearance ≥ 40mL/min (Cockcroft-Gault formula)
   • Total bilirubin < 1.5 x ULN (unless known or suspected Gilbert syndrome)
   • Aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.0 x ULN (or ≤ 5.0 x ULN in the presence of liver metastases)

8. Have a performance status of 0-2 on the ECOG Performance Scale (see Appendix 1)

9. Life expectancy greater than 6 months with treatment

10. Assessed by a medical oncologist as suitable for treatment with docetaxel

11. Patients must agree to use an adequate method of contraception

12. Willing and able to comply with all study requirements, including all treatments and required assessments including follow-up

Exclusion Criteria for Registration:

1. Any prior pharmacotherapy, radiation therapy, or surgery for metastatic prostate cancer. The following exceptions are permitted:

   • Up to 4 weeks of ADT with luteinising hormone releasing hormone agonists or antagonists or orchiectomy ± concurrent anti-androgens are permitted prior to commencement of screening. At investigator discretion, patients may start ADT at commencement of protocol therapy
   • Up to one course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 14 days prior to registration

2. Symptomatic cord compression, or clinical or imaging findings concerning for impending cord compression

3. Central nervous system metastases

4. Patients with Sjogren's syndrome

5. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator

6. Prior diagnosis of another cancer that was:

   • More than 3 years prior to current diagnosis with subsequent evidence of disease recurrence or clinical expectation of recurrence greater than 10%
   • Within 3 years of current diagnosis with the exception of successfully treated basal cell or squamous cell skin carcinoma or adequately treated non-muscle invasive bladder cancer (Tis, Ta and low grade T1 tumours)

Inclusion Criteria for Randomisation:

1. Significant PSMA avidity on 68Ga-PSMA PET/CT, defined after central review as a minimum uptake of SUVmax 15 at a site of disease
2. High-volume metastatic disease on 68Ga-PSMA PET/CT defined as visceral metastases or ≥ 4 bone metastases with ≥ 1 outside the vertebral column and pelvis (extra-axial skeleton)
3. Patient continues to meet all the inclusion criteria for registration

Exclusion Criteria for Randomisation:

1. Major FDG-PET discordance defined as presence of FDG positive disease with minimal PSMA expression in multiple sites (>5) or in more than 50% of total disease volume
2. All the exclusion criteria for registration continue to not apply

Men with a diagnosis of de novo high-volume mHNPC by PSMA-PET/CT criteria