Conventional Androgen Deprivation Therapy (ADT) With or Without Abiraterone Acetate + Prednisone and Apalutamide Following a Detectable PSA After Radiation and ADT

Inclusion Criteria:

• In order to ensure a homogenous population at study entry, a bone scan and not a PETwill be used to ensure M0 high risk prostate cancer. A bone scan is to be done up to 6 months prior to the start of initial ADT therapy or up to one month afterinitiation of ADT to rule out bony metastatic disease.

• Histologically confirmed prostate cancer

• PSA> undetectable (any value at or above the lower limit of detection for the assayused) after radiation and at least 6, but not more than 12 months of conventionalADT (LHRH agonist or antagonist with or without oral anti androgens, excludingabiraterone acetate and apalutamide) in patients with non-metastatic high risk or N1prostate cancer

• High risk is defined per the NCCN guidelines - clinical, radiographic, orpathological (biopsy proven) T3 or higher, Gleason 8-10, PSA > 20 ng/mL, thepresence of intraductal, ductal, or cribriform features with any Gleason score,and can be N0 or N1

• A month is defined as 28 days

• Written informed consent and HIPAA authorization for release of personal healthinformation prior to registration. NOTE: HIPAA authorization may be included in theinformed consent or obtained separately. Subject must have the ability to understandand willingness to sign the written informed consent document.

• Age ≥18 at the time of consent

• ECOG Performance Status ≤ 2 (Appendix A)

• Demonstrate adequate organ function as defined in the table below. All screeninglabs to be obtained within 3 months of registration.

• System Laboratory Value

• Hematological:

• Platelet count (plt)1 ≥ 100,000/ µL

• Hemoglobin (Hgb)1 ≥ 9 g/dL

• Absolute neutrophil count (ANC) ≥ 1000 cells/µL

• Renal:

--CrCl2 ≥ 45 mL/min

• Hepatic and Other:

• Bilirubin3 ≤ 1.5 × upper limit of normal (ULN)

• Aspartate aminotransferase (AST) < 2.5 × ULN

• Alanine aminotransferase (ALT) < 2.5 × ULN

• Serum Albumin > 3.0 g/dL

• Serum potassium ≥ 3.5 mmol/L

• Coagulation:

--International Normalized Ratio (INR) or Prothrombin Time (PT)

• Activated Partial Thromboplastin Time

• (aPTT) ≤ 1.5 × ULN (unless on prophylactic or therapeutic dosing with low molecularweight heparin)

• Independent of transfusion and/or growth factors within 3 months prior torandomization

• Cockcroft-Gault formula will be used to calculate creatinine clearance

• In subjects with Gilbert's syndrome, if total bilirubin is >1.5 × ULN, measuredirect and indirect bilirubin; if direct bilirubin is ≤1.5 × ULN, subject maybe eligible

• Agrees to use a condom (even men with vasectomies) and another effective method ofbirth control if he is having sex with a woman of childbearing potential OR agreesto use a condom if he is having sex with a woman who is pregnant while on study drugand for 3 months following the last dose of study drug. Must also agree not todonate sperm during the study and for 3 months after receiving the last dose ofstudy drug.

• Ability to understand and comply with study procedures for the entire length of thestudy as determined by the site investigator or protocol designee

• Medications known to lower the seizure threshold (section 5.4.4) must bediscontinued or substituted prior to C1D1 of study treatment for patients on Arm 2

• Able to swallow pills

Exclusion Criteria:

• Prior radical prostatectomy (excluding TURP and simple prostatectomy)

• History of any of the following:

• Seizure or known condition that may predispose to seizure (e.g., prior strokewithin 1 year of randomization, brain arteriovenous malformation, Schwannoma,meningioma, or other benign CNS or meningeal disease which may requiretreatment with surgery or radiation therapy)

• Severe or unstable angina, myocardial infarction, symptomatic congestive heartfailure, arterial or venous thromboembolic events (eg, pulmonary embolism,cerebrovascular accident including transient ischemic attacks), or clinicallysignificant ventricular arrhythmias within 6 months prior to randomization

• Known current evidence of any of the following:

• Uncontrolled hypertension. Participants with a history of hypertension areallowed provided blood pressure is controlled by anti-hypertensive therapy

• Gastrointestinal disorder affecting absorption

• Known history of testing positive for human immunodeficiency virus (HIV) orknown acquired immunodeficiency syndrome.

• Known active or chronic hepatitis B infection (defined as having a positivehepatitis B surface antigen (HBsAg) test at screening). Subject with past orresolved hepatitis B infection (defined as having a negative HBsAg test andpositive antibody to hepatitis B core antigen test) are eligible. Hepatitis Bviral DNA must be obtained in subjects with positive hepatitis B core antibodyprior to first treatment start.

• Active hepatitis C infection. Subjects positive hepatitis C antibody test areeligible if PCR is negative for hepatitis C viral DNA.

• Pre-existing condition that warrants long-term corticosteroid use greater thanthe equivalent of 10 mg prednisone daily. Physiologic replacement is permitted.Topical, intra-articular steroids or inhaled corticosteroids are permitted.

• Any condition that, in the opinion of the site investigator, would precludeparticipation in this study

• Baseline moderate or severe hepatic impairment (ChildPugh Class B or C)

• Patients who are currently receiving treatment with a prohibited medicationaccording to Section 5.4 (Tables 2 and 3), must discontinue that medication prior tostarting treatment and must not restart for the duration of the study if randomizedto ARM 2.

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

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to study drugs

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, psychiatric illness or social situations that would limit compliance withstudy requirements

• Individuals with a history of another malignancy are not eligible if the cancer isunder active treatment or the cancer can be seen on radiology scans or if they areoff cancer treatment but in the opinion of their oncologist have a high risk ofrelapse within 5 years.