PSMA-Guided Ablation of the Prostate

1. Background \& Rationale

Focal therapy is emerging as a new treatment strategy for appropriately selected men with localized prostate cancer. Focal therapy (also called partial gland ablation) is the concept of treating only where the tumor is believed to be located within the prostate, leaving normal healthy regions of the prostate untreated. Thus, focal therapy minimizes treatment side effects such as erectile dysfunction and incontinence, while providing good cancer control.

The foundation of performing oncologically sound partial gland ablation is possessing a high degree of diagnostic certainty that the tumor is limited to the region that is being treated and is not unknowingly present elsewhere in the gland. However, this is currently a major diagnostic challenge. The current diagnostic strategy for work-up of a patient for focal therapy is based on a pre-operative multiparametric MRI and combined targeted and systematic prostate biopsy showing intermediate risk prostate cancer localized to only one side of the prostate gland. This combination has been shown to accurately diagnose the final tumor grade in 96.5% of men. However, whole mount pathology data after radical prostatectomy shows that over 50% of cases that would pre-operatively have been deemed appropriate for focal therapy, which is a unilateral treatment, in fact harbour bilateral disease, which would mean that contralateral tumor would be inadvertently left untreated. Similarly, our group has shown that of the 35% of men who were found to have residual tumor after hemigland ablation of their prostate for unilateral disease, two-thirds of residual tumors were identified on the side contralateral to the ablative treatment. Therefore, our current gold standard pre-operative imaging and biopsy techniques are under staging many men who are undergoing focal therapy and a new paradigm is required to advance focal ablative treatments.

PSMA PET is a new imaging technique that uses a radioligand that binds to prostate specific membrane antigen (PSMA). PSMA is expressed at high levels in prostate cancer and the degree of expression correlates proportionately with tumor grade. A second generation PSMA PET radioligand, called 18F-PSMA-1007, has been used extensively at our site and possesses the key attributes of minimal urinary excretion, high resolution, and a half-life that as Gallium based radioligands. This makes 18F-PSMA-1007 an excellent candidate for improving the intraprostatic diagnostic accuracy of prostate cancer localization in patients considering focal therapy as a treatment option. 2. Research Question \& Objectives

Primary outcome:

The primary outcome is the detection of any clinically significant prostate cancer (defined as greater than or equal to Gleason Grade Group 2) at MRI-guided combined targeted and systematic biopsy 12 months after hemigland ablation.

Secondary outcomes: * the number of men found to have bilateral disease on PSMA PET prior to hemi-gland ablation * the number of men found to have bilateral disease on PSMA PET after hemi-gland ablation * the rate of contralateral Gleason Grade Group 2 or greater prostate cancer at 12-month biopsy * the rate of contralateral Gleason Grade Group 2 or greater prostate cancer at final pathology in men undergoing radical prostatectomy after PSMA PET detected bilateral disease * 5-year failure free survival defined as freedom from radical or systematic therapies, metastasis, prostate cancer specific and overall survivals. * side effects of PSMA PET imaging * health economics analysis of PSMA PET prior to hemigland ablation * Quality of life outcomes will be assessed with validated questionnaires 3. Methods The investigators propose a multi-centre phase II randomized-controlled trial of 138 patients deemed appropriate for focal therapy based on current standard-of-care (SOC) diagnostic work-up to be randomized to receive 18F-PSMA-1007 imaging or no further imaging. Patients found to have bilateral disease by PSMA PET will be ineligible for focal therapy and will proceed with SOC treatments (radical prostatectomy or radiation therapy). Men with unilateral disease on PSMA PET as well as all men receiving no further imaging will undergo hemigland ablation followed by PSMA PET, MRI, and combined targeted and systematic biopsy 12 months after ablation. The primary outcome will be the detection of Gleason Grade Group 2 or higher prostate cancer in men 12 months after hemigland ablation.

• Tumor Staging - bilateral disease on PSMA PET prior to hemi-gland ablation [Time frame: Prior to hemigland ablation - at study enrollment]
• Tumor Staging - bilateral disease on PSMA PET after hemi-gland ablation [Time frame: 12 months after hemigland ablation.]
• Tumor Staging- rate of contralateral Gleason Grade Group 2 or greater prostate cancer at biopsy [Time frame: 12 months after hemigland ablation.]
• Tumor Staging - rate of contralateral Gleason Grade Group 2 or greater prostate cancer at final pathology [Time frame: Through study completion, expected within 1 year of randomization]
• Tumor Staging - 5-year failure free survival [Time frame: 5 years after hemigland ablation]
• Side Effects of Intervention [Time frame: Immediately after the imaging]
• Early Economic analysis [Time frame: 12 months after hemigland ablation]
• Post Trial Economic analysis [Time frame: Through Study Completion, completion by end of study at 5 year mark]
• Quality of Life Outcomes - EPIC-26 [Time frame: Through Study Completion, completion by end of study at 5 year mark. Every 3 months for first year and every 6months-1 year after]
• Quality of Life Outcomes - AUA Symptom Score [Time frame: Through Study Completion, completion by end of study at 5 year mark. Every 3 months for first year and every 6months-1 year after]
• Quality of Life Outcomes - IIEF 5 [Time frame: Through Study Completion, completion by end of study at 5 year mark. Every 3 months for first year and every 6months-1 year after]
• Quality of Life Outcomes - EQ-5D-5L [Time frame: Through Study Completion, completion by end of study at 5 year mark. Every 3 months for first year and every 6months-1 year after]