Sequential Testosterone and Enzalutamide Prevents Unfavorable Progression

Inclusion Criteria:

1. ECOG Performance status ≤2.
2. Age ≥18 years.
3. Histologically-confirmed adenocarcinoma of the prostate.
4. Treated with continuous androgen ablative therapy (either surgical castration or LHRH agonist/antagonist).
5. Documented castrate level of serum testosterone (\<50 ng/dl).
6. Metastatic disease radiographically documented by CT or bone scan.
7. Must have had disease progression while on combination of abiraterone acetate plus ADT either given concurrently or sequentially 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 PCWG3 for patients with bone disease
8. Screening PSA must be ≥ 1.0 ng/mL.
9. 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.
10. No prior treatment with enzalutamide, apalutamide, darolutamide, or other investigational AR targeted treatment is allowed.
11. Prior treatment with testosterone is allowed.
12. Prior treatment with one chemotherapy regimen with docetaxel (≤ 6 doses) for hormonesensitive prostate cancer is allowed.
13. Prior treatment with Provenge vaccine and 223Radium (Xofigo) is allowed if \>4 weeks from last dose.
14. Patients must be withdrawn from abiraterone for ≥ 2 weeks.
15. 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.
16. Acceptable liver function:

    1. Bilirubin \< 2.5 times institutional upper limit of normal (ULN)
    2. AST (SGOT) and ALT (SGPT) \< 2.5 times ULN
17. Acceptable renal function:

    a. Serum creatinine \< 2.5 times ULN
18. Acceptable hematologic status:

    1. Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 ×109/L)
    2. Platelet count ≥ 100,000 platelet/mm3 (100 ×109/L)
    3. Hemoglobin ≥ 8 g/dL.
19. At least 4 weeks since prior radiation or chemotherapy.
20. Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

1. Pain due to metastatic prostate cancer requiring treatment intervention with pain medication.
2. ECOG Performance status ≥3
3. Prior treatment with enzalutamide is prohibited.
4. Prior chemotherapy with docetaxel or cabazitaxel for castration resistant prostate cancer is prohibited.
5. Requires urinary self-catheterization for voiding due to obstruction secondary to prostatic enlargement well documented to be due to prostate cancer or benign prostatic hyperplasia (BPH). Patients with indwelling Foley or suprapubic catheter for obstructive symptoms are eligible.
6. Evidence of disease in sites or extent that, in the opinion of the investigator, would put the patient at risk from therapy with testosterone (e.g. femoral metastases with concern over fracture risk, severe and extensive spinal metastases with concern over spinal cord compression, extensive liver metastases).
7. Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study.
8. Active uncontrolled infection, including known history of HIV/AIDS or hepatitis B or C.
9. Any condition or mental impairment that may compromise the ability to give informed consent, patient's safety or compliance with study requirements as determined by the investigator.
10. Patients receiving anticoagulation therapy with warfarin, rivaroxaban, or apixaban are not eligible for study. \[Patients on enoxaparin eligible for study. Patients on warfarin, rivaroxaban,or apixaban, who can be transitioned to enoxaparin prior to starting study treatments will be eligible\].
11. Patients are excluded with prior history of a thromboembolic event within the last 12 months that are not being treated with systemic anticoagulation.
12. Hematocrit \>51%, untreated severe obstructive sleep apnea, uncontrolled or poorly controlled heart failure \[per Endocrine Society Clinical Practice Guidelines (34)\]
13. Patients allergic to sesame seed oil or cottonseed oil are excluded.
14. Major surgery (eg, requiring general anesthesia) within 3 weeks before screening, or has not fully recovered from prior surgery (ie, unhealed wound). Note: subjects with planned surgical procedures to be conducted under local anesthesia may participate.