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

Open to males ages 18-95

• 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

• 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