Testing the Addition of the Drug Apalutamide to the Usual Hormone Therapy and Radiation Therapy After Surgery for Prostate Cancer, INNOVATE Trial

Inclusion Criteria:

• Pathologically (histologically) proven diagnosis of prostate adenocarcinoma. Anytype of radical prostatectomy is permitted, including retropubic, perineal,laparoscopic or robotically assisted

• Any T-stage is eligible (American Joint Committee on Cancer [AJCC] 8th edition [ed])

• Appropriate stage for study entry based on fluciclovine F-18 PET scan (FACBC,Axumin) F-18 prostate-specific membrane antigen (PSMA) PET (PyLarify) scan,Gallium-68 PSMA PET scan, flotufolastat F-18 PSMA PET scan (Posluma), or C-11 orF-18 Choline PET within 90 days prior to registration that is negative for distantmetastatic (M1a, M1b, M1c) disease. For patients with PSA < 0.20 ng/mL at time ofregistration, PET scan is recommended but not required

• Pathologically node positive disease with nodal involvement only in the pelvis inthe prostatectomy specimen or nodal disease on imaging at time of recurrence (including external iliacs, internal iliacs, and/or obturator nodes); peri-prostaticand peri-rectal nodes can also be considered regional lymphadenopathy and areallowed

• History/physical examination within 90 days prior to registration

• Age >= 18

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 90 daysprior to registration

• Detectable PSA after radical prostatectomy. Detectable PSA is defined as serum PSA > 0 ng/mL at least 30 days after prostatectomy

• Patients who have already started on post-prostatectomy GnRH agonist/antagonist for =< 180 days prior to registration are eligible (Note: patients who started on anoral antiandrogen are eligible if started =< 180 days and stopped prior toregistration)

• Hemoglobin >= 9.0 g/dL, independent of transfusion and/or growth factors (within 90days prior to registration)

• Platelet count >= 100,000 x 10^9/uL independent of transfusion and/or growth factors (within 90 days prior to registration)

• Serum potassium >= 3.5 mmol/L within 90 days prior to registration

• Creatinine clearance (CrCl) >= 30 mL/min estimated by Cockcroft-Gault (please useactual weight for calculation unless greater than 30% above ideal body weight thenuse the adjusted body weight) (within 90 days prior to registration)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (Note: Insubjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure directand indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject is eligible) (within 90 days prior to registration)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) oralanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5x institutional ULN (within 90 days prior to registration)

• Serum albumin >= 3.0 g/dL (within 90 days prior to registration)

• Discontinue or substitute concomitant medications known to lower the seizurethreshold at least 30 days prior to registration

• The patient must agree to use a condom (even men with vasectomies) and anothereffective method of birth control if he is having sex with a woman of childbearingpotential or agree to use a condom if he is having sex with a woman who is pregnantwhile on study drug and for 3 months following the last dose of study drug

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial andhave a CD4 count >= 200 cells/microliter within 30 days prior to registration. Note:HIV testing is not required for eligibility for this protocol

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy within 30 days prior toregistration, if indicated. Note: HBV viral testing is not required for eligibilityfor this protocol

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load within 30 days prior toregistration

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial. Note: Any patient with acancer (other than keratinocyte carcinoma or carcinoma in situ) who has no evidenceof disease for < 3 years must contact the principal investigator, Ronald Chen,Doctor of Medicine (MD)

• The patient or a legally authorized representative must provide study-specificinformed consent prior to study entry

Exclusion Criteria:

• Definitive radiologic evidence of metastatic disease (M1a, M1b or M1c) on molecularimaging (e.g. Fluciclovine F-18 PET, [FACBC, Axumin], F-18 PSMA PET [Pylarify],flotufolastat F-18 PSMA PET scan [Posluma], Gallium-68 PSMA PET scan or C-11 cholinePET)

• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for adifferent cancer is allowed (completed > 3 years prior to registration)

• Prior radiotherapy to the region of the study cancer that would result in overlap ofradiation therapy fields

• Androgen deprivation therapy (ADT) prior to radical prostatectomy

• Prior treatment with androgen receptor signaling inhibitor (including but notexclusive to a growing list of: abiraterone acetate, enzalutamide, apalutamide,darolutamide), unless started =< 180 days and stopped prior to registration, whichis allowed

• Current use of 5-alpha reductase inhibitor. NOTE: if the alpha reductase inhibitoris stopped prior to randomization the patient is eligible

• History of any of the following:

• Seizure or known condition that may pre-dispose to seizure (e.g. prior strokewithin 1 year prior to registration, brain arteriovenous malformation,Schwannoma, meningioma, or other benign central nervous system [CNS] ormeningeal disease which may require treatment with surgery or radiationtherapy)

• Severe or unstable angina, myocardial infarction, arterial or venousthromboembolic events (e.g., pulmonary embolism, cerebrovascular accidentincluding transient ischemic attacks), or clinically significant ventriculararrhythmias within 12 months prior to registration

• New York Heart Association functional classification III/IV (Note: Patientswith known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment ofcardiac function using the New York Heart Association functionalclassification.)

• History of any condition that in the opinion of the investigator, wouldpreclude participation in this study

• Current evidence of any of the following:

• Known gastrointestinal disorder affecting absorption of oral medications

• Active uncontrolled infection

• Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] >= 160 mmHg or diastolic BP >= 100 mmHg). Subjects with a history ofhypertension are allowed, provided that BP is controlled to within these limitsby anti-hypertensive treatment

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

• Baseline moderate and severe hepatic impairment (Child-Pugh Class B & C)

• Inability to swallow oral pills

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

• Patients must not plan to participate in any other therapeutic clinical trials whilereceiving treatment on this study

• Patients with inflammatory bowel disease