Through the conduct of a Phase III randomized controlled trial, investigators plan to: 1) determine if PSMA PET/CT guided intensification of radiotherapy or surgery improves cancer outcomes compared to conventional imaging-guided therapy in patients at risk of advanced disease, 2) evaluate its impact on toxicity and quality of life, and 3) measure the cost-effectiveness of the PSMA PET/CT guided approach.

Participants with high-risk prostate cancer planned for curative-intent standard-of-care radiotherapy or surgery, or with biochemical failure after radical prostatectomy planned for salvage radiotherapy will be enrolled over 3 years (n=776). Those randomized to the investigational arm will have PSMA PET/CT prior to therapy. Based on the imaging results, treating physicians will intensify radiotherapy or surgery unless widely metastatic disease is found, in which case systemic therapy will be intensified.

PSMA PET/CT, particularly with the new generation [18F]DCFPyL radiotracer, has substantially improved our ability to detect sites of prostate cancer compared with conventional imaging alone. When combined with innovative radiotherapeutic and surgical techniques that can now safely target and ablate such disease sites, next generation imaging is now poised to transform the therapeutic paradigm for patients at risk of advanced cancer.

Investigators postulate that intensification of radiotherapy or surgery based on the results of PSMA PET/CT will improve cancer control outcomes in a cost-effective manner, with minimal toxicity, and an overall improvement in quality of life in the longer term.

Investigators expect to show that PSMA PET/CT will have a direct and profound impact on radiotherapy and surgery practice, translating to improved failure-free survival outcomes in patients at risk of advanced prostate cancer. The subset of patients potentially impacted is broad, including patients recurring after prostatectomy and newly presenting patients with high-risk features. Although PSMA PET/CT is increasingly making its way into clinical practice around the world, Canadian provinces will need to make an informed decision of whether to fund this imaging for our patients. The high-level evidence gathered in this trial is desperately needed to assess the impact on patient outcomes and, in doing so, justify broad access and reimbursement for patients with prostate cancer.

Inclusion Criteria:

• Histological diagnosis of adenocarcinoma of the prostate planned for curative-intent standard-of-care radiotherapy (primary or salvage post prostatectomy) or radical prostatectomy with lymph node dissection.
• Age ≥ 18
• High risk of regional or distant metastases as defined by any of:
• Newly diagnosed and untreated prostate cancer with CAPRA score 6-10, or stage cN1.
• Prior history of radical prostatectomy and biochemical failure (PSA>0.1ng/mL).
• Patients must provide study-specific informed consent prior to study entry.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

Exclusion Criteria:

• Active or prior androgen deprivation therapy (except 5-alpha reductase inhibitor) terminated < 12 months prior to enrollment.
• Prior or planned PSMA PET/CT scan outside of this clinical trial.
• Charlson Comorbidity Index > 5 (see Appendix 2).
• Prior curative intent treatment for prostate cancer with local therapy other than surgery (primary radiotherapy or ablative therapies)
• Evidence of extra-pelvic nodal disease (M1a) on conventional imaging (if performed)
• Evidence of metastatic disease (M1b bone, M1c viscera/soft tissue) on conventional imaging (if performed)