Using Multiparametric MRI to Evaluate Intraprostatic Tumor Responses and Androgen Resistance Patterns in Newly Diagnosed Prostate Cancer

Background:

- Most men diagnosed with prostate cancer will present with intermediate or high-risk
disease

- Many develop castrate resistant prostate cancer (CRPC) as curative strategies are often

unsuccessful

- Treatment options typically involve radical prostatectomy (RP) or radiation therapy (RT)
in combination with androgen deprivation therapy (ADT)

- Even when cancers are initially sensitive to ADT, resistance ultimately emerges either
through clonal selection or through a variety of adaptive mechanisms (secondary
resistance).

- The recent introduction of novel androgen pathway inhibitors offers an opportunity to
potentially improve the cure rate of men with intermediate and high risk localized
prostate cancer

- There remains a great need for improved techniques to determine mechanisms of treatment
response and resistance.

Objectives:

-To test the feasibility of multi parametric magnetic resonance imaging (mpMRI) for the
localization and detection of focal prostate cancer both before and after pre-operative
treatment with ADT and enzalutamide.

Eligibility:

- Patients with nonmetastatic castration sensitive prostate cancer with intermediate or
high-risk features

- Patients with testosterone levels greater than or equal to 100 ng/dL.

- ECOG 0-1.

Design:

- Patients will be treated with ADT and enzalutamide for 6 months

- Two 3T mpMRI endorectal examinations (One at screening and after 6 month of treatment)

- Screening biopsy (MR/US guided) samples

- Standard of care prostatectomy(RP) following post treatment mpMRI

- All tumor specimens will undergo genomic analysis

- INCLUSION CRITERIA:

- Patients must have histologically or cytologically confirmed prostate cancer confirmed
by the Laboratory of Pathology, NCI or Pathology Department at Walter Reed Bethesda

- Must have previously untreated (with definitive therapy) prostate cancer with
intermediate or high risk features defined as:

- Intermediate risk:

- PSA level is between 10 and 20 ng/ml or

- Gleason score is 7 or

- Stage T2b or T2c

- High Risk:

- Gleason 8 and higher OR

- PSA greater than 20 at the time of diagnosis OR

- Seminal vesicle involvement OR

- Possible (on MRI) Extra-capsular extension (T3 disease)

- Patients must be eligible for and must be planning to undergo radical prostatectomy

- Patients must have testosterone levels greater than or equal to 100 ng/dL

- Men age greater than or equal to 18 years.

- Children are excluded because prostate cancer is not common in pediatric
populations.

- Women are not eligible because this disease occurs only in men.

- ECOG performance status less than or equal to 1

- Patients must have normal organ and marrow function as defined below:

- Hemoglobin greater than or equal to 9 g/dL

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 150,000/mcL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional upper limit of normal

- creatinine within normal institutional limits

OR

- creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with
creatinine levels above institutional normal.

- The effects of enzalutamide on the developing human fetus are unknown. For this reason
and because androgen receptor antagonists as well as other therapeutic agents used in
this trial are known to be teratogenic, male participants and their female partners of
child bearing potential must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence). Male participants should use a condom if having
intercourse with a pregnant woman. Additionally, a condom plus another effective
method of birth control is recommended during therapy and for 3 months after treatment
for male participants having intercourse with a woman of reproductive potential.
Should a woman become pregnant or suspect she is pregnant while her partner is
participating in this study, she should inform her treating physician immediately.

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

- Willingness to undergo biopsy.

- Ability to detect lesions within prostate on MRI for biopsy

- Willingness to travel to NIH for follow-up visits.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents (in the past 28 days) or
herbal medications (within 1 day).

- Patients with distant metastatic disease beyond N1(regional) lymph nodes on
conventional imaging studies (CT, MRI or Bone Scan).

- Patients who have received any prior therapy for prostate cancer with surgery,
radiation, and/or chemotherapy

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to enzalutamide or other agents used in study.

- Clinically significant cardiac disease, e.g. New York Heart Association (NYHA) classes
III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension,
myocardial infarction in the previous 6 months as confirmed by an electrocardiogram
(ECG).

- Contraindication to biopsy:

- Bleeding disorders

- PT/PTT greater than or equal to 1.5 times the upper limit of normal

- Artificial heart valve

- Contraindication to MRI:

- Patients weighing more than weight limit for the scanner tables

- Allergy to MR contrast agent

- Patients with pacemakers, cerebral aneurysm clips, shrapnel injury or implantable
electronic device

- 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 that would limit compliance with
study requirements.

- Patients with known HIV are eligible. These patients are at increased risk of lethal
infections when treated with marrow-suppressive therapy. In addition, if patients are
receiving combination antiretroviral therapy, there is potential for pharmacokinetic
interactions with enzalutamide. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.

- Patients with known active treatment for Hepatitis B and C infections.

- Patients who are taking medications that are strong inhibitors of CYP3A4 or PgP and
need to remain on these medications. For a current table of Substrates, Inhibitors and
Inducers please access the following website:

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLa
beling/ucm093664.htm

- History of seizure, including any febrile seizure, loss of consciousness, or transient
ischemic attack, or any condition that may pre-dispose to seizure (e.g., prior stroke,
brain arteriovenous malformation, head trauma with loss of consciousness requiring
hospitalization).

- Other medications used for urinary symptoms including 5-alpha reductase inhibitors
(finasteride and dutasteride) and alternative medications known to alter PSA (eg
phytoestrogens and saw palmetto) cannot be taken while patients are receiving
enzalutamide

- Patients with a malignancy within the past 3 years for which study drugs or a
prostatectomy is a contraindication.