A Randomized Phase 3 Trial of Metformin in Patients Initiating Androgen Deprivation Therapy as Prevention and Intervention of Metabolic Syndrome: The Prime Study

⁃ Participants must fulfill all the following criteria to be eligible for admission to the study:

• Pathologically confirmed adenocarcinoma of the prostate

• Eligible for initiating androgen deprivation therapy with either:

‣ (Neo-)Adjuvant therapy for localized prostate cancer that is planned continuously for at least 9 months; or

⁃ Metastatic disease: or

⁃ Biochemical recurrence of prostate cancer as defined as EITHER:

• A rising PSA after prior curative intent surgical therapy (e.g., prostatectomy with or without adjuvant/ salvage radiotherapy). Since an absolute consensus for this value has not been established, if a rising PSA has been documented by at least two PSA values at least 2 weeks apart, the criteria for biochemical recurrence are deemed to have been met. Or,

∙ PSA ≥ 2ng/mL above their nadir if previously treated with definitive radiotherapy

• Serum testosterone \> 5nmol/L (except for participants who have already started androgen deprivation therapy (within no more than 45 days of commencing study treatment)).

• The choice of androgen deprivation therapy is at the investigators discretion but must include at minimum the use of luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy. The addition of other hormonal agents (e.g., non-steroidal antiandrogens, abiraterone, enzalutamide, apalutamide) is allowed.

• The androgen deprivation therapy undertaken can be intermittent or continuous, but the treatment intent must be declared prior to randomization.

• Participant is able (e.g., sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French. The baseline assessment must be completed within required timelines, prior to registration/randomization. Inability (lack of comprehension in English or French, or other equivalent reason such as cognitive issues or lack of competency) to complete the questionnaires will not make the participant ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the participant ineligible.

• Participant consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each participant must sign a consent form prior to enrolment in the trial to document their willingness to participate.

• Participant must be accessible for treatment and follow up. Participants registered on this trial must be treated and followed at the participating centre. Investigators must assure themselves that the participants registered on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.

• Protocol treatment is to begin within 7 working days of participant randomization.