This study is a prospective Phase I/II protocol enrolling men with either high intermediate-risk or high-risk or very high-risk prostate cancer. All men will have PSMA Targeted PET (using the PSMA targeting ligand PSMA 1007) and multiparametric magnetic resonance imaging (mpMRI) for delineation of intra-prostatic foci of cancer and any involved regional lymph nodes based on high SUV uptake on PET or mpMRI (T2W, DWI/ADC, DCE) appearance suspicious for cancer. Tumour delineation will be performed by fusing the PSMA PET and mpMRI with planning CT simulation images. Fiducial marker implantation for treatment guidance will be mandatory but use of other organs at risk protection strategies (i.e. GU Loc, Space-OAR) will be allowed but not mandatory. Patients will be treated with image-guided SBRT using the fiducial markers for intra-fraction motion management. Dose escalation to imaging defined targets (intra-prostatic and involved nodes on PSMA PET + MRI) will be accomplished through a simultaneous boost technique. Maintaining dose to organs at risk will take precedence over boost dose targets (targeted maximum dose of 50Gy/5 fractions to imaging defined prostatic lesion; 35Gy/5 fractions to imaging defined involved nodes).

Cohort extension: We hypothesize that integration of neoadjuvant androgen deprivation therapy will provide for pretreatment cancer downstaging and will allow us to achieve higher target doses to the imaging defined DILs than currently achieve. Additionally, we plan to include a novel sodium MRI protocol into the baseline imaging to compare DIL volumes delineated by this modality to those by mpMRI and PSMA PET and to characterize changes in sodium MRI in response to ADT alone and subsequent radiotherapy

Inclusion Criteria:

• Age > 18 years of age
• Histologically confirmed carcinoma of the prostate
• High-intermediate risk or high risk as defined by NCCN criteria:
• High intermediate: 2 or 4 intermediate risk factors (T2B-T2C, Gleason GG 2 or 3, PSA 10-20) or GG 3 or intermediate risk with equal or >50% biopsy core involvement
• High-risk: one of T3a, Gleason GG 4 or 5, or PSA >20 ng/ml
• Very-high risk: one of primary Gleason Pattern 5, >4 cores Grade Group 4 or 5, clinical T3b, or more than 1 high-risk feature
• Conventional imaging (bone scan and abdominal pelvic computed tomography) negative for extra-pelvic nodal, skeletal or visceral metastases
• Willing to give informed consent to participate in this clinical trial
• Able and willing to complete EPIC questionnaires

Exclusion Criteria:

• Prior prostate cancer treatment (apart from prior 5-alpha reductase inhibitor treatment); androgen deprivation therapy prior to enrollment or treatment planning not permitted
• Men with clinical T4 disease are excluded
• Contraindication to radical prostate radiotherapy e.g. connective tissue disease or inflammatory bowel disease
• Contraindication to prostate MRI (i.e. non0compatible stent, pacemaker, prosthesis, etc.)
• Contraindication to use of PSMA PET agent PSMA 1007 due to intolerance or allergy
• Anticoagulation medication (if unsafe to discontinue for gold seed insertion)
• Diagnosis of bleeding diathesis
• Poor baseline urinary function defined as a score of 5 ("big problem") on question 5 of the EPIC 26 (Overall, how big a problem has your urinary function been for you during the last 4 weeks?)
• Definitive extra-pelvic nodal or distant metastatic disease on conventional staging investigations