Study of Apalutamide and Abiraterone Acetate in Castration-Resistant Bone Metastatic Prostate Cancer Patients

Study Drug Administration:

Each study cycle is 28 days.

If you are found to be eligible to take part in this study, you will take 4 apalutamide
tablets by mouth 1 time at about the same time each day with or without food.

You will take 4 abiraterone acetate tablets by mouth 1 time at about the same time every day.
Do not eat for at least 2 hours before your dose and for at least 1 hour after the dose of
abiraterone acetate.

You will take prednisone by mouth 1 time every day. You can take the dose with or without
food, but it is recommended that you take prednisone with a meal.

You may take these tablets together, when possible. All tablets should be swallowed whole and
not crushed or chewed.

If you overdose (take 2 days of study drugs or more in 24 hours), contact the study doctor
right away.

Length of Study:

You may continue taking the study drugs for as long for as long as the doctor thinks it is in
your best interest. You will no longer be able to take the study drug if the disease gets
worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visit.

Study Visits:

On Day 1 of Week 1:

- You will have a physical exam.

- You will have an EKG.

- Blood (about 3-4 teaspoons) will be drawn for routine testing and to check for genetic
mutations (changes).

On Day 1 of Week 4 and then every 4 weeks starting at Week 9 (Weeks 13, 17, 21, and so on):

- You will have a physical exam

- You will have an EKG (Weeks 5 and 9).

- Blood (about 3-4 teaspoons) will be drawn for routine testing and to check your PSA
levels. During Week 9, this sample will also be used to check your testosterone levels.

On Day 1 of Week 13 and every 12 weeks after that (Weeks 25, 37, 49, and so):

- You will have an EKG.

- Blood (about 3 teaspoons) will be drawn for routine testing.

- At Week 13 only, you will have a chest x-ray, MRI, and a bone scan to check the status
of the disease. If the chest x-ray shows signs of disease, you will also have a chest CT
scan.

End-of-Treatment Visit:

As soon as possible after your last dose of study drugs:

- You will have a physical exam.

- You will have an EKG.

- Blood (about 3-4 teaspoons) will be drawn for routine testing and to check your PSA and
testosterone levels.

- You will have a CT scan or MRI.

Follow-Up Visit:

Within 30 days after your last dose of study drug:

- You will have a physical exam.

- You will have an EKG.

- Blood (about 3 teaspoons) will be drawn for routine tests.

Inclusion Criteria:

1. Histologically or cytologically confirmed adenocarcinoma of the prostate without
neuroendocrine differentiation or small cell features;

2. Presence of metastatic disease that can be biopsied by any methodology applicable

3. Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH)
analogue or orchiectomy (i.e., surgical or medical castration);

4. Serum testosterone level
5. Patients receiving bisphosphonate or denosumab therapy must have been on stable doses
for at least 4 weeks prior to screening

6. Progressive disease defined as one or more of the following three criteria (NOTE:
Patients who received an antiandrogen must demonstrate disease progression following
discontinuation of antiandrogen): - PSA progression defined by a minimum of two rising
PSA levels with an interval of >/= 1 weeks between each determination. The PSA value
at the Screening visit should be >/= 2 ng/mL - Soft tissue disease progression as
defined by the Response Evaluation Criteria in Solid Tumors (RECIST) - Bone disease
progression defined by two or more new lesions on bone scan.

7. Patients previously treated with chemotherapy must have no more than two prior
chemotherapy regimens for the treatment of metastatic prostate cancer;

8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;

9. Serum Albumin >/= 3.0 g/dL

10. Serum potassium >/= 3.5 mmol/L

11. Estimated life expectancy of >/= 6 months;

12. Able to swallow the study drug and comply with study requirements;

13. Willing and able to give informed consent.

14. Tumor specimen obtained prior to treatment initiation by interventional radiology
guided biopsy will be interrogated per IHC and features should be as follows for a
patient to be eligible. - overexpression of AR-C terminal and AR-N terminal and PTEN
with lack of ARV7 expression along with and ki67 <=10%, no RB loss or p53 mutation and
no expression of neuroendocrine markers CD56 and chromogranin (all markers assessed by
standardized IHC protocols)

15. 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.

Exclusion Criteria:

1. Known allergy to the study drugs or any of its components.

2. Severe, concurrent disease, infection, or co-morbidity that, in the judgment of the
investigator, would make the patient inappropriate for enrollment or other medical
condition that would make prednisone/prednisolone (corticosteroid) use
contraindicated.

3. Metastases in the brain;

4. Absolute neutrophil count < 1000/µL, platelet count hemoglobin < 9 g/dL at the Screening visit; (NOTE: patients may not have received any
growth factors or blood transfusions within seven days of the hematologic laboratory
values obtained at the Screening visit);

5. Total bilirubin (Tbili), >1.5 times the upper limit of normal alanine aminotransferase
(ALT) or aspartate aminotransferase (AST) > 2.5 times the upper limit of normal at the
Screening visit;

6. Creatinine (Cr) > 2 mg/dL at the Screening visit;

7. History of another malignancy within the previous 2 years with >30 % probability of
relapse other than curatively treated non-melanomatous skin cancer;

8. Treatment with androgen receptor antagonists (bicalutamide, flutamide, nilutamide),
5-alpha reductase inhibitors (finasteride, dutasteride), estrogens, chemotherapy, or
biologic therapy within 4 weeks of enrollment (Day 1 visit)

9. Radiation therapy within 3 weeks (if single fraction of radiotherapy within 2 weeks)
of enrollment (Day 1 visit);

10. Planned palliative procedures for alleviation of bone pain such as radiation therapy
or surgery;

11. Structurally unstable bone lesions suggesting impending fracture;

12. History of seizure or any condition that may increase the patient's seizure risk.
Also, history of loss of consciousness or transient ischemic attack within 12 months
of Day 1;

13. Clinically significant cardiovascular disease including: - Myocardial infarction
within 6 months - Uncontrolled angina within 6 months; - Congestive heart failure New
York Heart Association (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 results in a left
ventricular ejection fraction that is >/= 45%; - History of clinically significant
ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation,
torsades de pointes);

14. Continued from 13) Prolonged corrected QT interval by the Fridericia correction
formula (QTcF) on the screening Electrocardiogram (ECG) > 470 msec; - History of
Mobitz II second degree or third degree heart block without a permanent pacemaker in
place; - Hypotension (systolic blood pressure <86 millimeters of mercury or
bradycardia with a heart rate of <50 beats per minute on any ECG taken at the
Screening visit; - Bradycardia with a heat rate of <50 beats per minutes in the
Screening ECG, unless pharmaceutically induced and reversible; - Uncontrolled
hypertension as indicated by a resting systolic blood pressure >170 mmHg or diastolic
blood pressure >105 mmHg at the Screening visit.

15. Have used or plan to use from 30 days prior to enrollment (Day 1 visit) through the
end of the study the following medications known to lower the seizure threshold: -
Aminophylline/theophylline; - Atypical antipsychotics (e.g., clozapine, olanzapine,
risperidone, ziprasidone); - Bupropion; - Insulin; - Lithium; - Pethidine; -
Phenothiazine antipsychotics (e.g., prochlorperazine (compazine), chlorpromazine, -
mesoridazine, thioridazine); - Tricyclic and tetracyclic antidepressants (e.g.,
amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine).

16. Prior use of ketoconazole, enzalutamide, abiraterone or apalutamide or participation
in a previous clinical trial of ketoconazole, enzalutamide, abiraterone or
apalutamide.

17. Use of an investigational agent within 4 weeks of enrollment (Day 1)

18. Gastrointestinal disorder affecting absorption (e.g., gastrectomy)

19. Major surgery within 4 weeks prior to enrollment (Day 1);

20. History of significant bleeding disorder unrelated to cancer, including: - Diagnosed
congenital bleeding disorders (e.g., von Willebrand's' disease) - Diagnosed acquired
bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) -
History of GI bleeding within one year.

21. Active or symptomatic viral hepatitis or chronic liver disease

22. Known history of pituitary or adrenal dysfunction

23. Baseline moderate and severe hepatic impairment (Child Pugh Class B & C)

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

25. 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.