Using genetic information to assist treatment decision making for people on active surveillance following diagnosis with favourable intermediate-risk prostate cancer

Experimental Arm: Genomically Informed Risk Stratification Participants assigned to the experimental arm will undergo genomic testing of prospectively collected blood and archival tissue to determine their genomically informed risk stratification. Upon confirmation of eligibility, consent, and randomisation into the trial, tissue samples from the initial prostate biopsy conducted at the time of diagnosis with intermediate risk prostate cancer will be obtained from relevant pathology providers. Additionally, a 10mL blood sample (approximately 2 teaspoons) will be collected at local pathology providers. Hematoxylin and eosin (H&E) slides, along with 5µm thick serial sections of biopsy tumour cores on uncharged slides, will be prepared for testing. An optional tumour tissue sample may be collected and analysed at cancer progression. The following assessments will be performed on samples: • Germline screening for prostate cancer high risk variants, using a DNA Damage Response Gene+ assay • Somatic tumour panel using archival tissue using the Illumina TSO500 • Tissue based transcriptional gene signatures using the Decipher Prostate Cancer Test These assessments are commercially available, however, they are not offered as part of standard care in prostate cancer. It may take between 8-12 weeks for results to become available. Participants will be assigned as genomic ‘high-risk’ if a listed deleterious germline or somatic mutation is identified, or a Decipher ‘high-risk’ score is returned. Participants without any deleterious germline or somatic mutation, or with a Decipher ‘low- or intermediate-risk’ score will be categorised as genomic ‘low-risk’. This will be communicated both verbally and in writing to the participant as well as their referring clinician using a standard template to assist in treatment decision-making. At the time of providing results, no explicit treatment recommendation will be made – specifically, in patients who are labelled as ‘high-risk’, a recommendation to proceed with radical treatment will not be made. Rather the information will be provided to both the patient and the physician, and the treatment pathway arrived at through shared decision-making. Risk stratification assessments will remain identical in all stages of the trial. The difference between each stage is the follow-up time required to achieve each primary endpoint: 6 months for Stage 1, 3 years for Stage 2, and 10 years for Stage 3. The activities associated with follow-up remain consistent throughout all stages of the trial. Participants will be asked to complete questionnaires focusing on health-related quality of life at baseline and then every 6 months for the first 12 months after randomisation, then every 12 months until the end of follow-up. Participants will be followed-up for six months in stage 1, three years in stage 2 and ten years in stage 3. Each stage will be conducted in sequence. If the study progresses into the next stage, follow-up period will be extended to reflect the required duration of the next stage. Therefore, the maximum period of follow-up is approximately ten years.