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

Eligible patients will have metastatic CRPC with no disease related symptoms and progression
on Androgen deprivation therapy and will have progressed post-treatment with abiraterone.
Patients will continue on Androgen deprivation therapy with Luteinising Hormone Releasing
Hormone agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) or Luteinising Hormone Releasing
Hormone antagonist (Degarelix) if not surgically castrated throughout the duration of the
study to inhibit endogenous testosterone production. Patients will be randomized 1:1 and
stratified based on duration of prior abiraterone acetate therapy (6 months or less or
greater than 6 months). Patients randomized to BAT (Arm A) will receive intramuscular
injections with either testosterone cypionate or testosterone enanthate at a dose of 400 mg
every 28 days. This dose was selected based on data demonstrating that it produces an initial
supraphysiologic 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.
Patients randomized to enzalutamide (Arm B) will receive daily oral dose of 160 mg. Each
cycle is defined as 28 days.

Patients will have Prostate-specific antigen level and symptoms assessment checked every
cycle. Every 3 cycles 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 PCWG2 criteria as ≥ 2 new bone lesions. However, for the first reassessment scan
only, patients should remain on study and have a confirmatory scan performed 12 weeks (3
cycles) later. If this confirmatory scan shows 2 or more additional new lesions, this defines
progression. The date of progression is the date of the first reassessment bone scan. If the
confirmatory scan does not show any additional new lesions, patient remains on study. If
progression is observed on subsequent bone scans, a confirmatory scan is not required; the
date of this bone scan is the date of progression.

Patients with Prostate-specific antigen progression but with disease response or stable
disease on imaging studies will remain on study until radiographic or other clinical
progression criteria are met. Patients with radiographic disease progression will not receive
continued BAT (arm A) or enzalutamide (arm B) and will be eligible for crossover to the
opposite therapy. Patients on the BAT arm A can cross over to receive enzalutamide at time of
progression or can choose to go off study and be treated with other standard of care
treatments. Patients on the enzalutamide arm B will be allowed to cross-over to receive BAT
or can choose to go off study and be treated with other standard of care treatments.

Patients with clinical progression due to prostate cancer must meet study exclusion criteria
to be permitted to cross-over to the opposite treatment. Patients with clinical progression
due to pain from prostate cancer are not permitted to cross-over.

Inclusion Criteria:

1. Eastern Cooperative Oncology Group 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
luteinizing hormone-releasing hormone agonist/antagonist)

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

6. Metastatic disease radiographically documented by CT/MRI or bone scan.

7. 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

8. Screening Prostate-specific antigen must be ≥ 1.0 ng/mL.

9. Prior treatment with additional second line hormone therapies is allowed.

10. No prior treatment with enzalutamide, Apalutamide (ARN-509), Darolutamide (ODM-201),
galeterone or other investigational androgen receptor targeted treatment is allowed.

11. 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.

12. Prior treatment with Provenge vaccine and 223Radium (Xofigo) is allowed if >4 weeks
from last dose.

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

14. Patients must be weaned off prednisone and be off therapy for ≥ 1 week prior to
starting therapy.

15. Acceptable liver function:

1. Bilirubin < 2.5 times institutional upper limit of normal (ULN)

2. aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) < 2.5 times
ULN

16. Acceptable renal function:

a. Serum creatinine < 2.5 times ULN

17. 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 ≥ 9 g/dL.

18. At least 4 wks since prior radiation.

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

20. Patients on either treatment arm will be considered for crossover if they demonstrate
evidence of radiographic disease progression.

Exclusion Criteria:

1. Pain due to metastatic prostate cancer requiring treatment intervention.

2. Eastern Cooperative Oncology Group Performance status ≥3

3. Prior treatment with enzalutamide is prohibited

4. Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant
prostate cancer is prohibited.

5. 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).

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 psychological, familial, sociological, or geographical condition that could
potentially interfere with compliance with the study protocol and follow-up schedule.

10. 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].

11. Patients with prior history of a thromboembolic event within the last 12 months that
is not being treated with systemic anticoagulation are excluded.

12. Patients allergic to sesame seed oil or cottonseed oil are excluded.

13. 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.