Neoadjuvant Androgen Deprivation Therapy Combined With Enzalutamide and Abiraterone Using Multiparametric MRI and 18FDCFPyL PET/CT in Newly Diagnosed Prostate Cancer

Background:

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

- PET imaging based on prostate specific membrane antigen (PSMA), including use of the
radiotracer DCFPyL, which binds PSMA, has emerged as a sensitive modality to detect
localized and metastatic prostate cancer

- It is unknown how androgen-targeted therapy affects expression of the androgen-
regulated PSMA gene, FOLH1, and 18F -DCFPyL-PET/CT sensitivity; and, the correlation
between response on 18F -DCFPyL-PET/CT imaging and clinical response needs further
evaluation

- The use of highly effective androgen pathway inhibitors enzalutamide and abiraterone
offers an opportunity to understand the characteristics of 18F -DCFPyL-PET imaging
during treatment while potentially improving the cure rate of men with potentially
lethal 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 18F -DCFPyL-PET/CT for the localization of prostate cancer
before, during, and after pre-operative treatment with ADT, enzalutamide, and
abiraterone/prednisone in patients negative for metastatic disease

Eligibility:

- Pathologic diagnosis of castration-sensitive prostate cancer with intermediate- or high-
risk features and no evidence of metastases beyond N1 on conventional imaging

- Candidates for radical prostatectomy

- Testosterone levels greater than or equal to 100 ng/dL

- ECOG PS 0-1

- Men age greater than or equal to 18 years

Design:

- Patients will be treated with ADT, enzalutamide, and abiraterone/prednisone for 6
months, followed by standard of care radical prostatectomy (RP)

- 18F-DCFPyL-PET/CT and mpMRI scans prior to treatment, and after 2 and 6 months of
treatment

- Prostate tumor biopsy (MR/US-guided) samples for research analyses at baseline and after
mid-treatment imaging (post-month 2)

- It is anticipated that approximately 1.5 to 2 years may be required for accrual of up to
25 evaluable subjects.

-INCLUSION CRITERIA:

1. Patients must have histologically or cytologically confirmed prostate cancer confirmed
by the Laboratory of Pathology, NCI, OR documented histopathological confirmation of
prostate cancer from a CLIA-certified laboratory.

2. Must have previously untreated (with definitive therapy ie: surgery, systemic
treatment or radiation therapy) prostate cancer with intermediate or high risk
features defined as:

- Intermediate risk:

-- PSA level is between 10 and 20 ng/ml, AND/OR

- Gleason score is 7, AND/OR

- Stage T2b or T2c, AND/OR

- No high risk feature(s)

- High risk:

- PSA > 20 at the time of diagnosis, AND/OR

- Gleason 8 or higher, AND/OR

- Seminal vesicle involvement, AND/OR

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

3. Patients must be eligible for and must be planning to undergo radical prostatectomy

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

5. Men age greater than or equal to18 years.

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

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

6. ECOG performance status 0-1.

7. Patients must have adequate organ and marrow function, and other laboratory parameters
as defined below:

-- hemoglobin greater than or equal to 9 g/dL

-- 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 less than or equal to 60 mL/min/1.73 m2 for patients with
creatinine levels above institutional normal (calculated via EGFR)

8. Lesions within prostate must be detectable on MRI for biopsy.

9. No other active malignancies within the past 3 years (with the exception of
nonmelanoma skin cancers or non-muscle invasive bladder cancer).

10. The effects of enzalutamide and abiraterone 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.

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

12. Willingness to adhere to protocol requirements (e.g., required biopsies).

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

EXCLUSION CRITERIA:

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

2. Patients taking anti-seizure medicines (e.g. bupropion, clozapine, and other deemed
clinically significant in the opinion of investigator) will be excluded from the
study.

3. Patients with evidence of distant metastatic disease beyond N1 (regional) lymph nodes
on conventional imaging studies (e.g., CT, MRI or Bone Scan).

4. Patients who have received any prior definitive therapy (ie: surgery, systemic
treatment or radiation therapy) for prostate cancer.

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

6. Clinically significant cardiac disease, e.g., New York Heart Association (NYHA)
classes III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled
hypertension (greater than or equal to 160/100 mmHg on two consecutive readings),
myocardial infarction in the previous 6 months as confirmed by an electrocardiogram
(ECG).

7. Contraindication to biopsy:

- Bleeding disorders

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

- Artificial heart valve

8. Contraindication to MRI:

-- Patients weighing more than the weight limit or unable to fit the scanner

- Allergy to MR contrast agent

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

9. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, or psychiatric illness/social situations that would limit compliance with
study requirements.

10. Patients with known history of HIV are ineligible. 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 and/or abiraterone. Appropriate studies
will be undertaken in patients receiving combination antiretroviral therapy when
indicated.

11. Patients undergoing active treatment for Hepatitis B or C infections.

12 Patients who have taken medications that are strong inhibitors or inducers of CYP3A4 or
PgP within 14 days prior to enrollment and need to remain on these medications.

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

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

15. Contraindication to steroid use.