NRG-GU008, Randomized Phase III Trial Incorporating Apalutamide and Advanced Imaging into Salvage Treatment for Patients with Node-Positive Prostate Cancer after Radical Prostatectomy (INNOVATE*)

This phase III trial studies whether adding apalutamide to the usual treatment improves
outcome in patients with lymph node positive prostate cancer after surgery. Radiation therapy
uses high energy x-ray to kill tumor cells and shrink tumors. Androgens, or male sex
hormones, can cause the growth of prostate cancer cells. Drugs, such as apalutamide, may help
stop or reduce the growth of prostate cancer cell growth by blocking the attachment of
androgen to its receptors on cancer cells, a mechanism similar to stopping the entrance of a
key into its lock. Adding apalutamide to the usual hormone therapy and radiation therapy
after surgery may stabilize prostate cancer and prevent it from spreading and extend time
without disease spreading compared to the usual approach.

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