Testosterone Therapy in Castration Resistant Prostate Cancer

The primary endpoint of this trial is to determine the feasibility of the administration of
transdermal testosterone alternating with enzalutamide. High dose testosterone has shown
activity in phase II studies of patients with castration resistant metastatic prostate
cancer; however, these studies have generally employed the intramuscular formulation. It has
been hypothesized that the transdermal formulation will show activity but will have less
potential for toxicity due to extremely high levels of circulating testosterone (i.e.
thrombotic events). In addition, this will allow for a steady state of elevated testosterone,
rather than the peaks and troughs seen with the IM approach.

Inclusion Criteria:

1. Provision to sign and date the consent form

2. Male and age > or = 18 years old

3. Stated willingness to comply with all study procedures and be available for the
duration of the study

4. Histologically or cytologically proven adenocarcinoma of the prostate

5. Ongoing ADT for prostate cancer with a GnRH analogue/antagonist or bilateral
orchiectomy for at least 6 months prior to day 1

6. Patients on a first generation anti-androgen (e.g. bicalutamide, flutamide,
nilutamide) must have at least a 6-week washout prior to randomization and must show
continued PSA progression

7. Serum testosterone level <50ng/dL at the screening visit

8. Progressive disease at screening as defined by one or more of the following criteria:

- PSA progression: minimum of 2 rising values within an interval of >1 week between
values. And a value at screening of >1ng/mL

- Soft tissue progression on CT or MRI based on RECIST 1.1 criteria or progression
of bone disease according to PCWG3 criteria

9. Patients worst pain in the last 24 hours must rank less than 4 on a 0-10 scale and
patients cannot be on daily narcotic medications to treat cancer-related pain. This
assessment must occur within the screening window and be documented in the patient's
medical record.

10. Acceptable Clinical laboratory values at Screening Visit which include:

- Absolute neutrophil count ≥ 1000/uL; platelet count ≥ 100,000/uL, hemoglobin ≥
8g/dL

- Total bilirubin ≤ 1.5xULN (unless documented Gilbert's); alanine aminotransferase
or aspartate aminotransferase ≤ 2.5xULN

- Creatinine ≤ 2mg/dL

- Hemoglobin ≤ 17.5 g/dL

11. Evidence of metastatic disease at any time point on axial imaging or bone scan, or
previous biopsy. Stage IV pelvic lymph node involvement is acceptable

12. Must use a condom if having sex with a pregnant woman

13. A male patient and his female partner who is of childbearing potential must use 2
acceptable methods of birth control (one of which must include a condom as a barrier
method of contraception) starting at screening and continuing throughout the study
period and for 3 months after final study drug administration

14. Patients may have received any number of lines of therapy for castration resistant
disease

Exclusion Criteria:

1. Requires urinary catheterization for voiding due to obstruction secondary to prostatic
enlargement that is well documented to be due to prostate cancer or benign prostatic
hyperplasia

2. Evidence of disease in sites or extent that, in the opinion of the investigator, would
put the patient at risk from therapy with testosterone due to a potential tumor flare
(e.g. high-risk bone lesions which may result in fracture or spinal cord compression

3. Clinically significant cardiovascular disease as evidenced by any of the following:

- Myocardial infarction with 6 months of screening

- uncontrolled angina within 3 months of screening

- NYHA class 3 or 4 congestive heart failure

- clinically significant ventricular arrhythmia

- Mobitz II/Second degree/or 3rd degree heart block without a pacemaker in place;
uncontrolled HTN (systolic >180mmHg or diastolic >105mmHg at screening

4. Previous exposure to a second-generation anti-androgen i.e enzalutamide or apalutamide

5. Received investigational agent within 2 weeks of screening

6. Therapy with antineoplastic systemic chemotherapy or biological therapy within 2 weeks
of screening

7. Radiation therapy within 2 weeks of screening

8. History of a prior malignancy (excluding an adequately treated basal or squamous cell
skin cancer, superficial bladder cancer, or a cancer in situ) within 5 years prior to
study enrollment

9. History of gastrointestinal disorders (medical disorders or extensive surgery) that
may interfere with the absorption of the study agent

10. Known or suspected brain metastasis or active leptomeningeal disease

11. History of seizure at any time in the past. Also, history of loss of consciousness or
transient ischemic attack within 12 months of Day 1 visit

12. Have any condition that, in the opinion of the investigator, would compromise the
well-being of the subject or the study or prevent the subject from meeting or
performing study requirements