Asymptomatic men without pain due to prostate cancer progressing with metastatic CRPC after treatment with combination or sequential ADT + Abi will be treated on a randomized, open label study to determine if sequential treatment with high dose T and Enza will improve primary and secondary objectives vs. continuous Enza as standard therapy.

Eligible patients are those who have progressive disease after treatment with Abi either in combination with ADT as initial therapy or as second-line therapy after development of resistance to primary ADT. Patients will continue on ADT with LHRH agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) or LHRH antagonist (Degarelix) if not surgically castrated throughout the duration of the study to inhibit endogenous testosterone production. Patients will be randomized 1:2:2 and stratified based on whether they received Abi in combination with ADT or in sequence after progression on ADT and based on duration of response to Abi (<6 or ≥ 6 months).

Patients randomized to Arm A will receive continuous therapy with standard dose Enza (160 mg po q day).

Patients randomized to Arm B will receive Sequential Testosterone and Enzalutamide (STE). Patients in Arm B will receive intramuscular injection with testosterone cypionate (T) at a dose of 400 mg every 28 days x 2 (i.e. cycle 1). This dose was selected based on data demonstrating that it produces an initial high dose serum level of T (i.e. > 1500 ng/dL or 3-10 times normal level) with eugonadal levels achieved at the end of two weeks and near castrate levels after 28 days. On Day 1 of cycle 2, patients will stop testosterone and begin enzalutamide 160 mg po q day for 56 days. Each cycle is 56 days. On Day 1 of cycle 3, patient will not take enzalutamide and will again receive injection of testosterone. Patients will continue to alternate one cycle of testosterone (2 injections) with one cycle of 56 days of enzalutamide.

Patients randomized to Arm C will receive Variable Sequential Testosterone and Enzalutamide (VSTE). Patients in Arm C will receive intramuscular injection with testosterone cypionate (T) at an FDA-approved dose of 400 mg every 28 days x 2 injections per cycle. Patients will remain on high dose T for at least one cycle. Each cycle is 56 days. Patients with PSA progression (≥25% increase in PSA from baseline PSA on BAT cycle) will stop T injection and begin Enzalutamide. Patients on T with initial with declining PSA decline PSA will remain on high dose T for additional cycles of 2 injections until PSA progression occurs (≥25% increase in PSA from PSA nadir on current BAT cycle)based on PCWG3 criteria. Patients with PSA progression (≥25% increase in PSA from baseline) will stop T injection. These patients will then be started on Enzalutamide. Patients with PSA progression (≥25% increase in PSA from baseline on enzalutamide cycle) will stop Enzalutamide and will restart injections of T with 2 injections/cycle. Patients on enzalutamide with initial PSA decline after one 56- day cycle will continue on Enzalutamide until PSA progression occurs (≥25% increase in PSA from PSA nadir on current Enzalutamide cycle). . Patients with PSA progression (≥25% increase in PSA from baseline) will stop Enzalutamide and will restart injections of T with 2 injections/cycle. These cycles of switching between T and Enza with onset of PSA progression will continue until clinical and/or radiographic progression occurs.

Patients will have prostate-specific antigen (PSA) level and symptoms assessment checked every cycle. Every 2 cycles (~4 months) patients will have repeat bone/CT scans to evaluate treatment response status. On CT scan, radiographic progression will be defined by RECIST criteria (i.e. >20% increase in the sum of target lesions). On bone scan, radiographic progression will be defined by PCWG3 criteria as ≥ 2 new bone lesions.

Patients with PSA progression but with disease response or stable disease on imaging studies will remain on study until clinical or radiographic progression criteria are met. Patients with radiographic disease progression will stop treatment and come off study. Patients with clinical progression due to pain flare after first two injection of testosterone can remain on study. If pain persists after first cycle of enzalutamide, patients will stop treatment and come off study. If pain resolves on enzalutamide, but returns with next or subsequent cycles of testosterone, patients will stop treatment and come off study.

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.