Effects of Apalutamide Plus LHRH Agonist or Apalutamide Plus Abiraterone Acetate Plus LHRH Agonist for Six Months for Prostate Cancer Patients at High Risk for Recurrence

Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (as
in the flip of a coin) to 1 of 2 study groups. This is done because no one knows if one study
group is better, the same, or worse than the other group. You will have an equal chance of
being assigned to either group:

- If you are assigned to Group A, you will receive an LHRH agonist and apalutamide.

- If you are assigned to Group B, you will receive an LHRH agonist, apalutamide,
abiraterone acetate, and prednisone.

Study Drug Administration:

Each study cycle is 28 days.

You will take 4 apalutamide tablets by mouth 1 time each day with or without food.

The type of LHRH agonist you receive will depend on what the study doctor thinks is in your
best interest and may be either leuprolide, goserelin, or triptorelin. These drugs are given
as injections, but the schedule for each is different. The study doctor will explain how and
when the drug is given, as well as its risks.

If you are in Group B, you will take 1 prednisone tablet by mouth 1 time each day. It is
recommended that prednisone be taken with food, but this is not required.

If you are in Group B, you will take 4 abiraterone acetate tablets by mouth 1 time each day
on an empty stomach (no food for at least 2 hours before and at least 1 hour after each
dose). Do not crush or chew the tablets.

You may take your tablets at the same time, if needed.

Length of Treatment:

You may take the study drugs for up to 6 cycles. You will no longer be able to take the study
drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to
follow study directions.

All participants on this study will be scheduled to have surgery. You will receive a separate
consent form that details the surgical procedure in more detail. Your participation on the
study will be over after the follow-up visit after surgery (described below).

Study Visits:

On Day 1 of Cycle 1:

- You will have a physical exam.

- Blood (about 2-3 tablespoons) will be drawn for routine tests. This blood will also be
used to check your prostate specific antigen (PSA) and testosterone levels. You must
fast for up to 12 hours before this blood draw.

- Urine will be collected for routine tests.

On Day 1 of Cycles 2, 3, 5, and 6:

- You will have a physical exam.

- Blood (about 2-3 tablespoons) will be drawn for routine testing. This blood will also be
used to check your PSA level. You must fast for up to 12 hours before this blood draw.

On Day 15 of Cycle 1, 2, and 3, blood (about 3 teaspoons) will be drawn for routine testing.

On Day 1 of Cycle 4:

°Blood (about 2-3 tablespoons) will be drawn for routine testing. You must fast for up to 12
hours before this blood draw.

After you stop taking the study drugs (End-of-Treatment Visit):

- You will have a physical exam.

- Blood (about 3-4 teaspoons) will be drawn for routine testing and to test your PSA
level. °You must fast for up to 12 hours before this blood draw.

- Urine will be collected for routine tests.

- You will have a chest x-ray to check the status of the disease.

- You will have an EKG to check your heart function.

For the purposes of this study, tissue samples that are removed on the day of surgery will be
collected for biomarker testing (including genetic biomarkers).

About 4 Weeks after surgery:

- You will have a physical exam.

- Blood (about 3-4 teaspoons) will be drawn for routine testing and to test your PSA
level. °You must fast for up to 12 hours before this blood draw. hours before blood
draw.

- You will have a chest x-ray to check the status of the disease.

- You will have an EKG to check your heart function.

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed adenocarcinoma of the
prostate with no histological variants (such as small cell, sarcomatoid, pure ductal
cancer, transitional cell carcinoma).

2. Patients may have received one prior depot injection of LHRH agonist or LHRH
antagonist (degarelix) within 30 days prior to study entry. Patients who have received
any other prior hormonal therapy or any chemotherapy for prostate cancer will be
excluded. (Patients who have discontinued finasteride or dutasteride or testosterone
supplement for at least 2 weeks will be allowed to enroll).

3. Be willing/able to adhere to the prohibitions and restrictions specified in this
protocol.

4. Have signed an informed consent document indicating that the subject understands the
purpose of and procedures required for the study and is willing to participate in the
study.

5. Written Authorization for Use and Release of Health and Research Study Information has
been obtained.

6. Age >/=18 years. Because no dosing or adverse event data are currently available on
the use of Abiraterone in combination with apalutamide (in patients <18 years of age,
children are excluded from this study.

7. Pathology review at MD Anderson (Note: if patient's prostate biopsy was not read at MD
Anderson, it must be reviewed at the study site to confirm eligibility).

8. Prostate Biopsy. If previous biopsy has been performed within 3 months of screening,
second biopsy procedure will not be required, if archival biopsies and at least one
formalin fixed paraffin embedded biopsy tissue block containing tumor is available.

9. The following tumor stage and Gleason scores: a) Clinical >/= stage T1c/T2 tumor with
Gleason score >/=8 b) Clinical stage >/=T2b tumor with Gleason score >/=7 and PSA >10
ng/ml

10. Serum testosterone >150 ng/dL. For patients treated up to 1 month of LHRH agonist, a
testosterone measurement prior to the LHRH treatment will be used to determine
eligibility, and must have been > 150 ng/dL. If no testosterone level is available
from before LHRHa injection up to 30 days prior to study entry, the patient will be
ineligible.

11. Patient is suitable for prostatectomy.

12. No evidence of metastatic disease as determined by imaging procedures.

13. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

14. Hemoglobin >/= 9.0 g/dL independent of transfusion; b) Platelet count >/=100,000/µL.
c) Patients should have adequate bone marrow function defined as an absolute
peripheral neutrophil count (ANC) >1,000; d) Creatinine clearance >/= 50 mL/min; e)
Serum potassium >/= 3.5 mmol/L; f) Serum bilirubin 2.5x ULN; g) Serum Albumin >/= 3 g/dl

15. Able to swallow the study drug whole as a tablet.

16. Patients must have normal coagulation profile and no history of substantial non-
iatrogenic bleeding diathesis.

17. Agrees to use a condom (even men with vasectomies) and another effective method of
birth control if he is having sex with a woman of childbearing potential or agrees to
use a condom if he is having sex with a woman who is pregnant while on study drug and
for 3 months following the last dose of study drug. Must also agree not to donate
sperm during the study and for 3 months after receiving the last dose of study drug.

18. Willing to take abiraterone acetate on an empty stomach; no food should be consumed at
least two hours before and for at least one hour after the dose of abiraterone acetate
is taken.

19. Life expectancy of greater than 12 months.

Exclusion Criteria:

1. Patients who have had any prior chemotherapy or radiotherapy for prostate cancer.

2. Patients who have had >1 LHRH agonist or antagonist depot injection or received depot
injection > 30 days before study entry.

3. Patients may not be receiving any other investigational agents.

4. Patients may not be receiving the concomitant administration of any systemic therapy,
biologic therapy, or other agents with anti-tumor activity against prostate cancer
while the patients are on study.

5. Patients with known metastatic prostate cancer.

6. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to leuprolide acetate, abiraterone acetate, prednisone or apalutamide or
other agents used in the study.

7. 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.

8. HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with Apalutamide and Abiraterone.
Appropriate studies will be undertaken in patients receiving combination
antiretroviral therapy when indicated.

9. Avoid concomitant strong CYP3A4 inducers during abiraterone acetate treatment. If a
strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate dosing
frequency.

10. Avoid co-administration of abiraterone acetate with CYP2D6 substrates that have a
narrow therapeutic index. If an alternative treatment cannot be used, exercise caution
and consider a dose reduction of the concomitant CYP2D6 substrate.

11. Patients receiving medications known to lower the seizure threshold are ineligible
unless discontinued or substituted at least 4 weeks prior to study entry. These
include: 1) Aminophylline/theophylline; 2) Atypical antipsychotics (e.g., clozapine,
olanzapine, risperidone, ziprasidone); 3) Bupropion; 4) Lithium; 5) Pethidine; 6)
Phenothiazine antipsychotics (e.g., prochlorperazine (compazine), chlorpromazine,
mesoridazine, thioridazine); 7) Tricyclic and tetracyclic antidepressants (e.g.,
amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine).

12. Chronically uncontrolled hypertension, defined conventionally as consistent systolic
pressures above 170 or diastolic pressures above 110 despite anti-hypertensive
therapy. Note that this is NOT a criterion related to particular BP results at the
time of assessment for eligibility, nor does it apply to acute BP excursions that are
related to iatrogenic causes, acute pain or other transient, reversible causes. (for
example doctor's visit related stress i.e. "white coat syndrome".

13. Requirement for corticosteroids greater than the equivalent of 10 mg of prednisone
daily for more than 2 weeks.

14. Poorly controlled diabetes defined by Hemoglobin A1C > 9.0 at screening

15. Active or symptomatic viral hepatitis or chronic liver disease.

16. Known history of pituitary or adrenal dysfunction.

17. Other malignancy, except non-melanoma skin cancer, that is active or has a >/= 30%
probability of recurrence within 12 months.

18. History of gastrointestinal disorders (medical disorders or extensive surgery) which
may interfere with the absorption of the study drug.

19. Prior hormone therapy for prostate cancer including orchiectomy, antiandrogens,
ketoconazole, or estrogens (5-alpha reductase inhibitors allowed), or LHRH
agonists/antagonists (*Note: LHRH allowed if begun within 1 month of Day 1).

20. Prior systemic treatment with an azole drug within four weeks of Cycle 1 Day 1.

21. Current enrollment in an investigational drug or device study or participation in such
a study within 30 days of Cycle 1 Day 1.

22. Allergies, hypersensitivity, or intolerance to prednisone, LHRH analog or excipients
of prednisone LHRH analog, abiraterone acetate and apalutamide.

23. Previous use of abiraterone acetate or other investigational CYP17 inhibitor (e.g.,
TAK-700).

24. Previous investigational antiandrogens (e.g., apalutamide, enzalutamide, BMS-641988).

25. Condition or situation which, in the investigator's opinion, may put the patient at
significant risk, may confound the study results, or may interfere significantly with
patient's participation in the study.

26. Patients unable to tolerate transrectal ultrasound.

27. Anti-androgens (steroidal or non-steroidal) such as cyproterone acetate, flutamide,
nilutamide, bicalutamide, etc. other than assigned study drug unless given for weeks.

28. Estrogens, progestational agents such as megestrol, medroxyprogesterone, DES,
cyproterone, spironolactone > 50 mg/kg, etc. unless discontinued at least two weeks
prior to randomization.

29. Androgens such as testosterone, dehydroepiandrosterone [DHEA], etc. unless
discontinued at least two weeks prior to randomization.

30. Herbal products that may decrease PSA levels (e.g., saw palmetto) unless discontinued
two weeks prior to randomization.

31. Active infection or other medical condition that would make prednisone/prednisolone
(corticosteroid) use contraindicated.

32. Severe hepatic impairment (Child-Pugh Class C).

33. History of significant bleeding disorder unrelated to cancer, including: 1) Diagnosed
congenital bleeding disorders (e.g., von Willebrand's disease); 2) Diagnosed acquired
bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) of
screening visit; 3) History of GI bleeding within 3 months of screening visit
requiring >/=2 units packed red blood cells.

34. Clinically significant cardiovascular disease including: 1) Myocardial infarction
within 6 months of Screening visit; 2) Uncontrolled angina within 3 months of
Screening visit; 3) Congestive heart failure New York Heart Association (NYHA) class 3
or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the
past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, unless
a screening echocardiogram or multi-gated acquisition scan (MUGA) performed within
three months of the Screening visit results in a left ventricular ejection fraction
that is >/= 50%.

35. 33. continued: 4) History of clinically significant ventricular arrhythmias (e.g.,
ventricular tachycardia, ventricular fibrillation, torsade de pointes). 5) Prolonged
corrected QT interval by the Fridericia correction formula (QTcF) on the screening
Electrocardiogram (ECG) > 470 msec. 6) History of Mobitz II second degree or third
degree heart block without a permanent pacemaker in place. 7) Hypotension (systolic
blood pressure < 86 mmHg or bradycardia with a heart rate of <50 beats per minute on
the Screening ECG., unless pharmaceutically induced and thus reversible (i.e. beta
blockers).