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.