Combination Study of Antibiotics With Enzalutamide (PROMIZE)

Inclusion Criteria: 1. Histologically or cytologically proven metastatic castration-resistant prostate cancer or adenocarcinoma refractory to conventional treatment, or for which no conventional therapy exists or is declined by the patient. 2. Documented prostate cancer progression as assessed by the investigator with RECIST (v1.1) and PCWG3 criteria with at least one of the following criteria: 1. Progression of soft tissue/visceral disease by RECIST (v1.1) and/or, 2. Progression of bone disease by PCWG3 bone scan criteria and/or, 3. Progression of PSA by PCWG3 PSA criteria and/or 4. Clinical progression with worsening pain and need for palliative radiotherapy for bone metastases. 3. Phase I: Patients that have progressed after at least 12 weeks of treatment with a NAAT within the previous 6 months Phase II: Patients that have progressed after at least 12 weeks of treatment with a NAAT within the previous 6 months (for combination treatment) or more than 6 months prior to trial entry (for enzalutamide alone resistance run-in). 4. Previously progressed on at least one line of taxane chemotherapy (or not fit or not willing to receive a taxane). 5. Ongoing androgen deprivation maintaining serum testosterone of less than 50 ng/dL (less than 2.0 nM) is mandatory. 6. Life expectancy of at least 12-weeks. 7. Able to swallow tablets. 8. Archival tumour tissue must be available for analyses. 9. Willing to have pre- and post-treatment biopsies if biopsy is feasible. 10. World Health Organisation (WHO) performance status of 0-2 (Appendix 1). 11. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week (Day -7 to Day 1) prior to the patient's first dose of IMP. Haemoglobin (Hb): ≥ 9.0 g/dL Absolute neutrophil count: ≥ 1.5 x 109/L Platelet count: ≥ 75 x 109/L Serum bilirubin: ≤ 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT): ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 x ULN is permissible Aspartate aminotransferase (AST): ≤ 2.5 x (ULN) unless raised due to tumour in which case up to 5 x ULN is permissible Serum creatinine / calculated creatinine clearance: ≤ 1.5 x upper limit of normal (ULN) / GFR ≥ 50 mL/min (uncorrected value) Serum albumin: \>25 g/L 12. 18 years or over 13. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up 14. Willing and able to comply with the study requirement including the collection of blood, fresh tumour biopsy, urine, rectal swab and stool samples. Exclusion criteria: 1. Surgery, radiotherapy, chemotherapy, or other anti-cancer therapy within 4-weeks prior to trial entry into the study (6 weeks for bicalutamide). The use of bisphosphonates or RANK ligand inhibitors in patients with known osteopenia or osteoporosis or bone metastases is permitted. Prior antiandrogenic treatment exclusions as follows: * Patients receiving enzalutamide immediately preceding the trial will be able to continue on enzalutamide without washout. * Prior flutamide treatment during previous 4-weeks. N.B. Patients whose PSA did not decline in response to antiandrogens given as a second line or later intervention will only require a 14-day washout; * Prior bicalutamide (Casodex) and nilutimide (Nilandron) treatment during previous 6-weeks; * Prior progesterone, medroxyprogesterone, progestins, cyproterone acetate, tamoxifen, and 5-alpha reductase inhibitors during previous 2-weeks (14-days). 2. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities, which in the opinion of the Investigator and the DDU should not exclude the patient. 3. Previous treatment with any systemic antibiotic within 12 weeks of study entry. 4. Known hypersensitivity reaction or intolerance to any penicillin, amoxicillin, metronidazole, vancomycin, ciprofloxacin or enzalutamide. 5. History of tendon disorder secondary to quinolones 6. Use of drugs that are listed in the prohibited concomitant medications section including strong inducers and inhibitors of CYP450 (please refer to http://medicine.iupui.edu/clinpharm/ddis/table.aspx). Seville orange or grapefruit products and any herbal medications should be avoided for 4 weeks prior to starting trial treatment. 7. Concurrent treatment with prohibited medications which include medications that causes ototoxicity, neurotoxicity, and nephrotoxicity. 8. Known or suspected leptomeningeal metastases or untreated brain metastasis. Patients with brain metastases that have been treated and have been shown to be radiologically stable for more than 6 months may be considered for the trial. 9. History of stroke, epilepsy or current excessive alcohol intake. History of clinically significant hearing loss including but not limited to congenital hearing loss, need for hearing aids, ongoing acute or chronic ear infection, history of tympanic membrane perforation, tinnitus, vertigo, Meniere disease, cerebrovascular ischemia. 10. History of clinically significant hearing loss including but not limited to congenital hearing loss, need for hearing aids, ongoing acute or chronic ear infection, history of tympanic membrane perforation, tinnitus, vertigo, Meniere disease, cerebrovascular ischemia. 11. Patients with partners of child-bearing potential (unless they agree to use a barrier method of contraception \[condom plus spermicide\] or to sexual abstinence effective from the first administration of any of the investigational agents, throughout the trial and for 6 months afterwards. Patients with partners of child-bearing potential must also be willing to ensure that their partner uses an effective method of contraception for the same duration for example, hormonal contraception, intrauterine device, diaphragm with spermicidal gel or sexual abstinence). Patients with pregnant or lactating partners must be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure of the foetus or neonate. NB. Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception 12. Any condition that would increase enteral absorption in the opinion of the investigator, including but not limited to malabsorption syndromes, impaired GI motility, chronic pancreatitis, partial or complete gastric and/or bowel resections, history of clinically significant gastrointestinal bleeding in the last 6 months, history of mesenteric ischemia or bowel obstruction, chronic diarrhoea (≥Grade 2), inflammatory bowel disease (Crohn's disease, ulcerative colitis). 13. At high medical risk because of non-malignant systemic disease including active uncontrolled infection. 14. Clinically significant history of liver disease consistent with Child-Pugh Class B or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis. 15. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV). 16. Any of the following cardiac criteria: * Clinically important abnormalities including rhythm, conduction or ECG changes (left bundle branch block, third degree heart block). * Factors predisposing to QT prolongation including congenital long QT syndrome; family history of prolonged QT syndrome, unexplained sudden death (under 40); concomitant medications known to prolong QT interval. * Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association \[NYHA\] - refer to Appendix 5), prior history of cardiac ischaemia or prior history of cardiac arrhythmia. * QTcF (corrected using Fredericia formula) of ≥460 ms. 17. Prior bone marrow transplant or have had extensive radiotherapy to greater than 25% of bone marrow within eight weeks. 18. Active or uncontrolled autoimmune disease requiring corticosteroid therapy or other forms of systemic immunosuppression. 19. Patient is a participant or plans to participate in another interventional clinical trial, whilst taking part in this study. Participation in an observational trial would be acceptable. 20. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial. 21. Malignancy other than prostate cancer within 3-years of trial entry with the exception of adequately treated basal cell carcinoma. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy must have no evidence of that disease for at least-3 years and be deemed at negligible risk for recurrence, are deemed eligible. 22. Symptoms of COVID-19 and/or current documented COVID-19 infection.