RE-sensitizing With Supraphysiologic Testosterone to Overcome REsistance (The RESTORE Study)

The trial will enroll up to 90 patients, 30 for each cohort. Eligible patients will continue
on androgen ablative therapy with LHRH agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) if
not surgically castrated to suppress endogenous testosterone production. Patients will also
receive intramuscular injection with either testosterone cypionate or testosterone enanthate
at a dose of 400 mg every 28 days. This dosing scheme was designed to produce rapidly
fluctuating serum testosterone levels from the supraphysiologic to the near-castrate range
(i.e. Bipolar Androgen Therapy [BAT]). Assessments for response to testosterone will be made
approximately every 3 months. Upon displaying evidence of progression, patients will then go
on to receive either abiraterone or enzalutamide (whichever agent they had previously
progressed on prior to study enrollment) or remain on LHRH agonist therapy and receive no
additional androgen ablative hormonal therapy.

Inclusion Criteria:

1. Performance status ≤2

2. Age ≥18 years

3. Histologically-confirmed adenocarcinoma of the prostate

4. Progressing on continuous androgen ablative therapy (either surgical castration or
LHRH agonist).

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

6. For Cohorts A and B, patients must have progressed on prior treatment with
enzalutamide or abiraterone acetate + prednisone (by PSA criteria or
radiographically).

7. For castration-only Cohort C, patients must have developed castrate resistant prostate
cancer after progressing on first line hormone therapy with either surgical castration
or LHRH agonist or LHRH agonist plus an anti-androgen.

8. Patients progressing on LHRH agonist plus an anti-androgen as first line therapy must
be off anti-androgen for 4 weeks prior to first treatment with testosterone.

9. Patients with rising PSA on two successive measurements at least two weeks apart.

10. For Cohort A (enzalutamide) and Cohort B (abiraterone acetate):

1. Prior treatment with up to 2 additional second line hormone therapies, including
ketoconazole is allowed.

2. Patients who have progressed on both enzalutamide and abiraterone acetate are
eligible and post-BAT will be retreated with the last second line agent they had
received (e.g. patient receiving abiraterone then enzalutamide would receive
retreatment with enzalutamide post-BAT).

3. Patients must be withdrawn from enzalutamide or abiraterone acetate for ≥ 4 weeks
and have documented PSA increase after the withdrawal period.

4. Patients receiving prednisone in conjunction with abiraterone acetate must be
weaned off prednisone prior to starting BAT.

11. For Cohort C (castration-only):

1. Patients must continue on castrating therapy throughout BAT treatment.

2. No prior second line hormone treatment with flutamide, bicalutamide, nilutamide,
enzalutamide, abiraterone, ketoconazole, ARN-509 or other investigational
androgen ablative therapies is permitted for Cohort C.

12. 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.

13. Acceptable liver function:

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

2. AST (SGOT) and ALT (SGPT) < 2.5 times ULN

14. Acceptable renal function:

a. Serum creatinine < 2.5 times ULN, OR

15. 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.

16. At least 4 weeks since prior surgery with full recovery (no persistent toxicity ≥
Grade 1).

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

Exclusion Criteria:

1. Pain due to metastatic prostate cancer requiring opioid analgesics.

2. >5 sites of visceral disease in lung or liver (nonspecific lung nodules ≤1 cm in
diameter are permitted).

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

4. Requires urinary catheterization for voiding due to obstruction secondary to prostatic
enlargement thought to be due to prostate cancer or benign prostatic hyperplasia.

5. 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, spinal metastases with concern over spinal cord
compression, lymph node disease with concern for ureteral obstruction).

6. 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.

7. Active uncontrolled infection, including known history of AIDS or hepatitis B or C.

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

9. Prior history of a thromboembolic event within the last two years and not currently on
systemic anticoagulation.

10. Hematocrit >50%, untreated severe obstructive sleep apnea, uncontrolled or poorly
controlled heart failure [per Endocrine Society Clinical Practice Guidelines (67)].