Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance

Inclusion Criteria:

* Eastern Cooperative Oncology Group Performance status ≤2
* Age ≥18 years
* Histologically-confirmed adenocarcinoma of the prostate
* Treated with continuous androgen ablative therapy (either surgical castration or luteinizing hormone-releasing hormone agonist/antagonist)
* Documented castrate level of serum testosterone (\<50 ng/dl)
* Metastatic disease radiographically documented by CT/MRI or bone scan.
* Must have had disease progression while on abiraterone acetate alone or abiraterone acetate in combination with other investigational agents based on:

  * Prostate-specific antigen progression defined as an increase in Prostate-specific antigen, 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 PCWG2 for patients with bone disease

  * Screening Prostate-specific antigen must be ≥ 1.0 ng/mL.
  * Prior treatment with additional second line hormone therapies is allowed.
  * No prior treatment with enzalutamide, Apalutamide (ARN-509), Darolutamide (ODM-201), galeterone or other investigational androgen receptor targeted treatment is allowed.
  * Prior docetaxel for hormone-sensitive prostate cancer is permitted if ≤ 6 doses were given in conjunction with first-line androgen deprivation therapy and \>12 months since last dose of docetaxel.
  * Prior treatment with Provenge vaccine and 223Radium (Xofigo) is allowed if \>4 weeks from last dose.
  * Patients must be withdrawn from abiraterone for ≥ 2 weeks.
  * Patients must be weaned off prednisone and be off therapy for ≥ 1 week prior to starting therapy.
  * Acceptable liver function:
* Bilirubin \< 2.5 times institutional upper limit of normal (ULN)
* aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) \< 2.5 times ULN

  \- Acceptable renal function:
* Serum creatinine \< 2.5 times ULN

  \- Acceptable hematologic status:
* Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 ×109/L)
* Platelet count ≥ 100,000 platelet/mm3 (100 ×109/L)
* Hemoglobin ≥ 9 g/dL.

  * At least 4 wks since prior radiation.
  * Ability to understand and willingness to sign a written informed consent document.
  * Patients on either treatment arm will be considered for crossover if they demonstrate evidence of radiographic disease progression.

Exclusion Criteria:

* Pain due to metastatic prostate cancer requiring treatment intervention.
* Eastern Cooperative Oncology Group Performance status ≥3
* Prior treatment with enzalutamide is prohibited
* Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant prostate cancer is prohibited.
* Requires urinary catheterization for voiding due to obstruction secondary to prostatic enlargement well documented to be due to prostate cancer or benign prostatic hyperplasia (BPH).
* 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)
* 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
* Active uncontrolled infection, including known history of HIV/AIDS or hepatitis B or C.
* Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule.
* Patients receiving anticoagulation therapy with Coumadin are not eligible for study. \[Patients on non-coumadin anticoagulants (Lovenox, Xarelto, etc.) are eligible for study. Patients on Coumadin who can be transitioned to lovenox prior to starting study treatments will be eligible\].
* Patients with prior history of a thromboembolic event within the last 12 months that is not being treated with systemic anticoagulation are excluded.
* Patients allergic to sesame seed oil or cottonseed oil are excluded.
* 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.