Randomized Phase II Study of Salvage XRT + ADT +/- Abiraterone Acetate and Apalutamide (ARN-509) for Rising PSA after Radical Prostatectomy with Adverse Features. Facilitating Optimal Radiation Management Using Leuprolide, Abiraterone Acetate, and Apalutamide (FORMULA-509 Trial)

This research study is comparing two different combinations of androgen deprivation therapy
(ADT) used together with radiation as a treatment for rising PSA after radical prostatectomy
(prostate cancer).

Inclusion Criteria:

- Histologically confirmed prostate cancer

- PSA ≥ 0.1 after radical prostatectomy (value w/in 3 months of registration) AND at
least 1 unfavorable risk factor listed below.

- Gleason 8-10

- PSA > 0.5

- Pathologically positive lymph nodes

- pT3 or pT4

- PSA doubling time (DT) < 10 months

- Negative margins

- Persistent PSA after RP (PSA never dropped below 0.1 after RP)

- Local/regional recurrence on imaging

- Decipher "High risk" (a Medicare-reimbursed test for risk of metastases after
prostatectomy)

- Candidate for salvage radiation and ADT treatment

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

- 18 ≤ Age ≤ 95 at the time of consent

- ECOG Performance Status ≤ 2 (Appendix A)

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

- System Laboratory Value

- Hematological:

- Platelet count (plt) ≥ 100,000/ µL

- Hemoglobin (Hgb) ≥ 9 g/dL

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

- Renal:

--GFR1 ≥ 45 mL/min

- Hepatic and Other:

- Bilirubin2 ≤ 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
molecular weight heparin)

- Cockcroft-Gault formula will be used to calculate creatinine clearance (see study
procedure manual SPM)

- In subjects with Gilbert's syndrome, if total bilirubin is >1.5 × ULN, measure
direct and indirect bilirubin; if direct bilirubin is ≤1.5 × ULN, subject may be
eligible

- 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.

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

- Medications known to lower the seizure threshold (see list under prohibited meds) must
be discontinued or substituted at least 4 weeks prior to study entry (Section 5.5)

- Use of CYP3A4 inhibitors or inducers and CYP2D6 substrates must be discontinued prior
to study entry

- Able to swallow pills

Exclusion Criteria:

- Use of post-prostatectomy ADT for > 30 continuous days prior to registration (ADT
defined as use of GnRH agonist, with or without an anti-androgen). However, patients
with testosterone recovery after post-prostatectomy ADT are eligible (testosterone
recovery defined as total testosterone > 190 ng/dL) regardless of how long they have
been on ADT.

- Prior pelvic radiation unless additional radiation can be safely delivered according
to the treating physician

- PSA > 15 ng/mL in screening

- History of any of the following:

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

- Severe or unstable angina, myocardial infarction, symptomatic congestive heart
failure, arterial or venous thromboembolic events (e.g., pulmonary embolism,
cerebrovascular accident including transient ischemic attacks), or clinically
significant ventricular arrhythmias within 6 months prior to randomization

- Current evidence of any of the following:

- Uncontrolled hypertension

- Gastrointestinal disorder affecting absorption

- Active infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis)

- Any chronic medical condition requiring a dose of corticosteroid higher than 10
mg prednisone/prednisolone once daily

- Any condition that, in the opinion of the site investigator, would preclude
participation in this study

- Moderate or severe hepatic impairment (Child Pugh Class B or C)

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to study drugs

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

- Individuals with a history of another malignancy are not eligible if:

- the cancer is under active treatment or

- the cancer can be seen on radiology scans or

- if they are off cancer treatment but in the opinion of their oncologist have a
high risk of relapse within 5 years

- Confirmed bone metastases on imaging