To determine if dexamethasone or dexamethasone plus metronidazole restore sensitivity to abiraterone for the treatment of metastatic prostate cancer.

To test whether giving dexamethasone with or without metronidazole in combination with abiraterone could help reverse resistance to abiraterone for patients with metastatic castration-resistant prostate cancer (mCRPC). Abiraterone and prednisone (AA/P) is a second-line therapy for mCRPC given when first-line androgen deprivation therapy fails. However, resistance to AA/P can develop. The investigators do not know exactly how cancer becomes resistant, but there is evidence that suggests it could be due to androgen production by the bacteria in your gut (gut microbiome). This study is focused on the gut microbiome as a source of androgen production that could cause AA/P resistance in mCRPC.

Inclusion Criteria:

• Males aged 18 years of age and above.
• Prostate adenocarcinoma
• Absolute PSA ≥ 2.0 ng/mL at screening.
• PSA (+/- radiographic) progression after having been on abiraterone and prednisone for at least 12 weeks.
• Must be maintained on a GnRH analogue or have undergone orchiectomy.
• Participants must have a life expectancy ≥ 6 months
• Ability to swallow study medication tablets
• Willing to abstain from alcohol during and for 14 days after treatment with metronidazole
• Willing and able to collect urine and stool samples per protocol

Exclusion Criteria:

• Active infection or other medical condition that would make dexamethasone use contraindicated

• Any chronic medical condition requiring a higher systemic dose of corticosteroid

• Pathological finding consistent with small cell carcinoma of the prostate

• Has imminent or established spinal cord compression based on clinical findings and/or MRI.

• Chronic liver disease with Child-Pugh class C cirrhosis (see calculator in protocol)

• Bilirubin >3x ULN or AST and ALT >5x ULN

• Congenital prolonged QTc syndrome or QTc > 500 msec (non-paced rhythm)

• History of pituitary or adrenal dysfunction

• Uncontrolled diabetes (Hemoglobin A1c > 10%) or increasing doses of insulin within the past 4 weeks due to poorly controlled glucoses.

• Administration of an investigational therapeutic or invasive surgical procedure (not including surgical castration) within 30 days of Cycle 1 Day 1 or currently enrolled in an investigational drug study

• Any other serious illness or medical condition that would, in the opinion of the investigator, make this protocol unreasonably hazardous, including, but not limited to:

  • Any uncontrolled major infection.
  • Crohn's disease or ulcerative colitis.
  • Known or suspected toxic megacolon and/or known small bowel ileus.
  • Known allergy to any of the compounds under investigation.

• On antibacterial therapy within 30 days prior to administration of study treatment.

• Any condition or situation which, in the opinion of the investigator, would put the subject at risk, or interfere with the subject's participation in this study.