Randomized Phase II Study of Salvage XRT + ADT +/- Abiraterone and Apalutamide for Rising PSA After RP (FORMULA-509)

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that an intervention is being
studied. In this study, the investigational agents are apalutamide and abiraterone acetate.

Currently, the best standard treatment for men with this type of prostate cancer includes
radiation therapy combined with androgen deprivation therapy (ADT). ADT blocks the function
of hormones including testosterone which prostate cancer uses to grow and spread. All
participants in this study will receive the main standard form of ADT called a luteinizing
hormone-releasing hormone agonist (LHRHA). Physicians often also use another drug called
bicalutamide to help the LHRHA block hormone function. The investigators are testing whether
using two newer anti-hormonal drugs called abiraterone acetate and apalutamide with LHRHA can
improve cure rates compared to using bicalutamide plus LHRHA. These two drugs work together
to suppress both testosterone and the receptor where testosterone binds thereby providing
more potent hormone suppression.

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:

- Post-prostatectomy use of ADT for > 30 days prior to study entry

- Prior pelvic radiation

- PSA > 10 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