• Eastern Cooperative Oncology Group (ECOG) Performance status ≤2.

• Age ≥18 years.

• Histologically-confirmed adenocarcinoma of the prostate.

• Treated with continuous androgen ablative therapy (either surgical castration or LHRH agonist/antagonist).

• Documented castrate level of serum testosterone (\<50 ng/dl).

• Metastatic disease radiographically documented by CT or bone scan.

• Must have had disease progression while on abiraterone acetate based on:

‣ PSA progression defined as an increase in PSA, as determined by 2 separate measurements taken at least 1 week apart And/ Or

⁃ Radiographic disease progression, based on RECIST 1.1 in patients with measurable soft tissue lesions or Prostate Cancer Working Group 3 (PCWG3) for patients with bone disease

• Screening PSA must be ≥ 1.0 ng/mL.

• Patients with soft tissue lesion amenable to biopsy must agree to biopsy collection pre-treatment and at a defined point on treatment to perform tumor tissue analysis.

⁃ Prior treatment with Provenge vaccine, 223Radium (Xofigo), Poly (ADP-ribose) polymerase (PARP) inhibitors, taxane chemotherapy, Lutetium prostate-specific membrane antigen (LuPSMA), antiandrogens (including enzalutamide, darolutamide, and apalutamide), and radiation is allowed if \>4 weeks from last dose.

⁃ Prior treatment with bipolar androgen therapy (BAT) is allowed if the patient has progressed on an AR-axis inhibitor (i.e. abiraterone or antiandrogen) since BAT treatment.

⁃ Patients must be withdrawn from abiraterone for ≥ 2 weeks.

⁃ Attempts must be made to wean patients off prednisone prior to starting therapy. Patients who cannot be weaned due to symptoms may continue on lowest dose of prednisone achieved during weaning period.

⁃ Acceptable liver function:

• Bilirubin \< 2.5 times institutional upper limit of normal (ULN)

∙ Aspartate transaminase (AST) (SGOT) and alanine transaminase (AST) (SGPT) \< 2.5 times ULN

⁃ Acceptable renal function:

⁃ Glomerular filtration rate (GFR) of 50 mL/min/1.73 m2 or higher. GFR will be estimated by the 2021 chronic kidney disease epidemiology (CKD-EPI) creatinine equation (REF: Inker LA, Eneanya ND, Coresh J, et al. Chronic Kidney Disease Epidemiology Collaboration. New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. N Engl J Med 2021; 385:1737) using the online calculator found on UpToDate (https://www.uptodate.com/contents/calculator-glomerular-filtration-rate-gfr-by-ckd-epiequation-in-adults-conventional-and-si-units search=gfr\&topicRef=2359\&source=see\_link).

⁃ Acceptable hematologic status:

• Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 ×109/L)

∙ Platelet count ≥ 100,000 platelet/mm3 (100 ×109/L)

∙ Hemoglobin ≥ 8 g/dL.

⁃ Ability to understand and willingness to sign a written informed consent document.

⁃ Sexually active participants with female partners of childbearing potential are eligible to participate if they agree to follow 1 of the following methods of contraception consistently, starting from screening, during the study and for at least 3 months after the last dose of DFMO and/or enzalutamide:

∙ Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a longterm and persistent basis) and agree to remain abstinent.

‣ Are sterilized (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate);

‣ Agree to use a male condom and have their partner use a contraceptive method with a failure rate of \<1% per year as described below when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant, and who agrees to the use of a condom by her partner.

⁃ In addition, participants must refrain from donating sperm starting from Screening, during the study and for at least 3 months after the last dose of DFMO and/or enzalutamide.

⁃ Sexually active participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse; or use a male condom during each episode of penile penetration during the study

⁃ Patients with soft-tissue disease amenable to biopsy as determined by Interventional Radiology must agree to serial biopsies as per the study schedule to be eligible.