Randomized Phase III Trial Incorporating Abiraterone Acetate With Prednisone and Apalutamide and Advanced Imaging Into Salvage Treatment for Patients With Node-Positive Prostate Cancer After Radical Prostatectomy.

Inclusion Criteria

- Pathologically (histologically) proven diagnosis of prostate adenocarcinoma. Any type

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 positron emission

tomography (PET) scan (FACBC, Axumin) within 90 days prior to registration that is

negative for distant metastatic (M1a, M1b, M1c) disease; Note that though every effort

should be made to obtain a fluciclovine F-18 PET (FACBC, Axumin) scan; however, if the

patient has already had a recent F-18 PSMA PET (PyLarify) scan or gallium Ga

68-labeled PSMA-11 (Ga-68 PSMA) PET scan or C-11 or F-18 choline PET scan within 90

days prior to registration (to include scan report) then repeat molecular imaging with

a fluciclovine F-18 PET (FACBC, Axumin) scan will not be required.

- Pathologically node positive disease with nodal involvement only in the pelvis in the

prostatectomy specimen (including external iliacs, internal iliacs, and/or obturator

nodes); peri-prostatic and peri-rectal nodes can also be considered regional

lymphadenopathy and are allowed

- History/physical examination within 90 days prior to registration

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 90 days

prior to registration

- Detectable PSA after radical prostatectomy. Detectable PSA is defined as serum PSA > 0

ng/mL at least 30 days after prostatectomy and within 180 days of registration and

before start of GnRH agonist/antagonist

- Patients who have already started on post-prostatectomy GnRH agonist/antagonist for =<

180 days prior to registration are eligible (Note: patients who started on an oral

antiandrogen are eligible if started =< 180 days and stopped prior to registration)

- Hemoglobin >= 9.0 g/dL, independent of transfusion and/or growth factors (within 90

days 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 use

actual weight for calculation unless greater than 30% above ideal body weight then use

the adjusted body weight) (within 90 days prior to registration)

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (Note: In subjects

with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and

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]) or

alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x

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 seizure threshold

at least 30 days prior to registration

- The patient must agree 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 agree 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

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral

therapy with undetectable viral load within 6 months are eligible for this trial and

have 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 HBV viral

load must be undetectable on suppressive therapy within 30 days prior to registration,

if indicated. Note: HBV viral testing is not required for eligibility for this

protocol

- Patients with a history of hepatitis C virus (HCV) infection must have been treated

and cured. For patients with HCV infection who are currently on treatment, they are

eligible if they have an undetectable HCV viral load within 30 days prior to

registration

- Patients with a prior or concurrent malignancy whose natural history or treatment does

not have the potential to interfere with the safety or efficacy assessment of the

investigational regimen are eligible for this trial. Note: Any patient with a cancer

(other than keratinocyte carcinoma or carcinoma in situ) who has no evidence of

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-specific

informed consent prior to study entry

Exclusion Criteria

- Definitive radiologic evidence of metastatic disease (M1a, M1b or M1c) on molecular

imaging (e.g. fluciclovine F-18 PET, F-18 PSMA, PSMA, F-18 choline 11)

- Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a

different cancer is allowed (completed > 3 years prior to registration)

- Prior radiotherapy to the region of the study cancer that would result in overlap of

radiation therapy fields

- Androgen deprivation therapy (ADT) prior to radical prostatectomy

- Prior treatment with androgen receptor signaling inhibitor (including but not

exclusive to a growing list of: abiraterone acetate, enzalutamide, apalutamide,

darolutamide), unless started =< 180 days and stopped prior to registration, which is

allowed

- Current use of 5-alpha reductase inhibitor. NOTE: if the alpha reductase inhibitor is

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 stroke

within 1 year prior to registration, brain arteriovenous malformation,

Schwannoma, meningioma, or other benign central nervous system [CNS] or meningeal

disease which may require treatment with surgery or radiation therapy)

- Severe or unstable angina, myocardial infarction, arterial or venous

thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident

including transient ischemic attacks), or clinically significant ventricular

arrhythmias within 12 months prior to registration

- New York Heart Association functional classification III/IV (Note: Patients with

known history or current symptoms of cardiac disease, or history of treatment

with cardiotoxic agents, should have a clinical risk assessment of cardiac

function using the New York Heart Association functional classification.)

- History of any condition that in the opinion of the investigator, would preclude

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 of hypertension

are allowed, provided that BP is controlled to within these limits by

anti-hypertensive treatment

- Any chronic medical condition requiring a higher dose of corticosteroid than 10

mg 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 preclude

participation in this study

- Patients must not plan to participate in any other therapeutic clinical trials while

receiving treatment on this study

- Patients with inflammatory bowel disease