The researchers hope to learn if Trimethoprim, 150mg taken daily for 3 months, is a safe and effective way to reduce folate levels at time of Androgen Deprivation Therapy (ADT) in men with advanced prostate cancer.

This study will help find out what effects, good and/or bad, this drug has on people who take it and on its effect on the disease. The safety of this drug in humans has been tested in prior research studies; however, some side effects may not yet be known.

While taking part in this study, participants will be asked to attend approximately 4 to 7 visits - depending on what randomized arm they are in - with the researchers or study staff.

It may be necessary for participants to return to the hospital/clinic every 1-3 months as part of their regular care. Research procedures will be completed at the same time as these routine standard of care visits. Participants will be asked to stop taking any supplements or medications containing folic acid or potassium prior to enrolling in the study.

INCLUSION CRITERIA

1. Provision of signed and dated informed consent form.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Age ≥ 18 years.
4. Proven diagnosis of prostate cancer (intermediate unfavorable risk, high risk, very high risk localized per the 2025 NCCN guidelines), or metastatic hormone-sensitive prostate cancer with confirmation by pathology report and most recent prostate biopsy procedure note.
5. Prostate cancer treatment naïve.
6. Commencing androgen deprivation therapy for prostate cancer within 4 weeks of enrollment in the study. Note that radiotherapy and androgen receptor pathway inhibitors, apart from abiraterone, are allowed in both arms.
7. Hemoglobin ≥ 11 g/dL.
8. Red blood cell folate > 750 nmol/L.
9. Homocysteine < 15 micromol/L.
10. Creatine clearance within the normal range.
11. Eastern Cooperative Oncology Group performance status 0-1
12. Stated willingness to abstain from consumption of any supplements or medications containing folic acid or potassium.
13. Ability to take oral medications and be willing to adhere to trimethoprim and androgen deprivation therapy regimens.
14. For participants able to cause a pregnancy: use of condoms or other methods to ensure effective contraception with partner.
15. Agreement to adhere to lifestyle considerations described in the protocol throughout study duration.

EXCLUSION CRITERIA

1. Current use of memantine, phenytoin, and any medications that may significantly interact with TMP, including prohibited concomitant medications listed in the protocol.
2. Current use of medications that would interfere with folate metabolism (for example, methotrexate).
3. Treatment with another investigational drug while on this study.
4. Treatment with hormone therapy, immunotherapy, chemotherapy and/or radiation therapy for any malignancies within the past 2 years. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
5. History of renal or hepatic disease, including history of hepatitis B and C.
6. Recurrent urinary tract infections, urinary retention, or neurological conditions affecting bladder function.
7. Known hypersensitivity or allergy to trimethoprim.
8. Hematological disorders (including megaloblastic anemia).
9. Commencing chemotherapy for metastatic prostate cancer.