Dexamethasone Prior to Re-treatment With Enzalutamide in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer Previously Treated With Enzalutamide and Docetaxel

PRIMARY OBJECTIVES:

I. To determine the prostate-specific antigen (PSA) response rate to enzalutamide (Enza)
after treatment with dexamethasone (Dex) therapy.

SECONDARY OBJECTIVES:

I. Objective response rate to Enza in patients with measurable disease on computed tomography
(CT) scan using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

II. Time to PSA progression (based upon Prostate Cancer Working Group 2 [PCWG2] criteria) for
treatment with Dex.

III. Effect of each treatment on quality of life as assessed by patient completion of
validated instruments (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue
Scale, RAND Short Form-36 [RANDSF-36]).

IV. PSA response rates to Dex for patients who are androgen receptor splice variant 7 (AR-V7)
positive and AR-V7 negative, respectively, at study entry.

V. Response rates to Enza for patients who are AR-V7 positive and AR-V7 negative,
respectively, at study entry.

VI. Percentage of patients who are AR-V7 positive at study entry who are AR-V7 negative at
time of initiation of Enza, or vice-versa.

OUTLINE:

Patients receive dexamethasone orally (PO) once daily on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity until there is evidence
of PSA progression, clinical disease progression, or radiographic disease progression. At
time of progression, dexamethasone will be stopped via a rapid taper over one week if
patients were treated for over 30 days. Patients then receive enzalutamide PO once daily on
days 1-28. Treatment repeats every 28 days for up to 3 courses in the absence of clinical
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed adenocarcinoma of the
prostate

- Patients must have metastatic disease radiographically documented by CT/magnetic
resonance imaging (MRI) or bone scan; measurable disease is not necessary for
inclusion

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 3 months in the opinion of the investigator

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 8; transfusion is allowed

- Total bilirubin =< 1.5 x institutional upper limit of normal

- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Creatinine clearance >= 30 by Cockcroft-Gault formula

- Patients must have progression after prior treatment with Enza at any point in the
disease course (pre- or post-chemotherapy)

- Patients must have progressed after prior treatment with docetaxel; docetaxel must
have specifically been given for castration-resistant metastatic disease

- Prior treatment with other second line hormone therapy is allowed (e.g. flutamide,
bicalutamide, nilutamide, ketoconazole, abiraterone, ARN-509); patients must be off
these therapies for at least 4 weeks prior to starting treatment

- Prior treatment with Xofigo (223Radium), Provenge, mitoxantrone and cabazitaxel is
allowed

- Patients must have rising PSA on two successive measurements, at least 2 weeks apart

- Patient must be treated with continuous androgen ablative therapy (e.g. goserelin,
leuprolide, triptorelin, or degarelix, if he has not had prior surgical castration)
and have castrate levels of testosterone (< 50 ng/dL or 1.7 nmol/L)

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier (persistent toxicity >= grade 1)

- Patients who have received any other investigational agents within the last 4 weeks

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Dex or Enza

- Any use of systemic corticosteroids in the prior 4 weeks

- Uncontrolled diabetes mellitus

- History of seizure, underlying brain injury with loss of consciousness, transient
ischemic attack within the past 12 months, cerebral vascular accident, brain
metastases, and brain arteriovenous malformations

- Patients receiving any medications or substances that are inhibitors or inducers of
cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible (e.g.
gemfibrozil, rifampin, trimethoprim, pioglitazone)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations or geographical condition that
would limit compliance with study requirements