Radiation Therapy With or Without Apalutamide in Treating Patients With Stage III-IV Prostate Cancer

PRIMARY OBJECTIVES:

I. To determine whether, in men with post-prostatectomy PSA recurrences, salvage radiation
(SRT) with enhanced anti-androgen therapy with apalutamide will improve biochemical
progression-free survival (bPFS) compared to SRT alone.

SECONDARY OBJECTIVES:

I. To assess whether molecular stratification by the PAM50 gene expression clustering will
identify subsets of prostate cancer (luminal A or basal, luminal B) which derive the greatest
benefit from anti-androgen therapy.

II. To assess overall survival. III. To assess cancer-specific mortality. IV. To assess
metastasis-free survival. V. To assess distant metastasis. VI. To assess local-regional
progression. VII. To assess PSA nadir during first year of treatment and prior to initiation
of any hormonal salvage therapy.

VIII. To assess initiation of salvage hormonal therapy. IX. To assess PSA with a non-castrate
testosterone at 1 and 3 years post randomization: PSA < 0.1 ng/ml and testosterone >= 50
ng/dl.

X. To assess acute and late physician-reported morbidity (per the Common Terminology Criteria
for Adverse Events [CTCAE] version 5) after SRT +/- apalutamide.

XI. To assess acute and late patient-reported morbidity (per the patient reported outcomes
[PRO]-CTCAE) after SRT +/- apalutamide.

XII. To assess testosterone levels at 3, 6, 9, 12, and 36 months post randomization.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients undergo external beam radiation therapy on Day 1 for 7.5 weeks. Beginning on
Day 1 of radiation therapy, patients receive placebo orally (PO) once daily (QD) on days
1-30. Treatment repeats every 30 days for up to 6 courses (6 months) in the absence of
disease progression or unacceptable toxicity.

ARM 2: Patients undergo external beam radiation therapy on Day 1 for 7.5 weeks. Beginning on
Day 1 of radiation therapy, patients receive apalutamide PO QD on Days 1-30. Treatment
repeats every 30 days for up to 6 courses (6 months) in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years,
then every 6 months for 3 years, and then yearly thereafter.

Inclusion Criteria:

- Pathologically (histologically) proven diagnosis of prostate adenocarcinoma;
prostatectomy must have been performed within 10 years prior to Step 1 registration
and any type of radical prostatectomy is permitted, including retropubic, perineal,
laparoscopic or robotically assisted

- Post-prostatectomy patients with a detectable serum PSA (≥ 0.1, but ≤ 1.0 ng/mL) at
study entry (within 90 days of Step 1 registration) and at least one of the following:

- Gleason score 7-10 (International Society of Urological Pathology [ISUP] grade
group 2 to 5)

- ISUP grade group:

- Grade Group 1: Gleason score ≤ 6,

- Grade Group 2: Gleason score 3 + 4 = 7,

- Grade Group 3: Gleason score 4 + 3 = 7,

- Grade Group 4: Gleason score 8,

- Grade Group 5: Gleason scores 9 and 10

- >= T3a disease

- Persistent elevation of PSA after prostatectomy measured within 90 days after
surgery (PSA never became undetectable) of > 0.04 but < 0.2 ng/mL (PSA nadir)

- pN0 or pNx

- History/physical examination within 90 days prior to Step 1 registration

- Karnofsky performance status of 70-100 within 90 days prior to Step 1 registration

- Surgical formalin-fixed paraffin-embedded (FFPE) specimen must be available for
submission to GenomeDx for genomic analysis on Decipher GRID platform; Note: if
Decipher results have already been obtained, in lieu of tissue, results must be
submitted to GenomeDx for validation

- Prior androgen deprivation therapy (luteinizing hormone-releasing hormone [LHRH]
agonist and/or non-steroidal anti-androgen) is allowed if discontinued at least 90
days prior to Step 1 registration and given for ≤ 90 days duration

- For example: patients on prior LHRH analogs (post-prostatectomy), the
discontinuation date should be calculated based on the expected duration of the
sustained release injection, not simply the injection date of the drug; for
instance, if a 22.5 mg sustained release dose of leuprolide acetate is given (3
month duration), then the expected duration of such a dose would be 90 days after
the injection date; for a 7.5 mg leuprolide (1 month duration), the
discontinuation date would be 30 days after the injection date

- Please note: finasteride or dutasteride must be stopped before treatment starts
but prior usage will not affect eligibility

- Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors within 90 days
prior to Step 1 registration

- Platelet count ≥ 100,000 x 10^9/uL independent of transfusion and/or growth factors
within 90 days prior to step 1 registration

- Serum albumin ≥ 3.0 g/dL within 90 days prior to Step 1 registration

- Glomerular filtration rate (GFR) ≥ 35 mL/min estimated by Cockcroft-Gault or measured
directly by 24 hour urine creatinine within 90 days prior to Step 1 registration

- Serum total bilirubin ≤ 1.5 x 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 Step 1 registration

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x ULN within
90 days prior to Step 1 registration

- Testosterone > 50 ng/dL within 90 days prior to Step 1 registration

- Concomitant medications known to lower the seizure threshold discontinued or
substituted at least 4 weeks (30 days) prior to Step 1 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

- The patient must agree not to donate sperm during the study treatment and for 3 months
after receiving the last dose of study drug

- The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry

Exclusion Criteria:

- Definitive clinical, radiologic, or pathologic evidence of metastatic disease (M1) or
lymph node involvement (N1)

- Prior invasive malignancy (except non-melanomatous skin cancer, carcinoma in situ of
the male breast, penis, oral cavity, or stage Ta of the bladder, or stage I completely
resected melanoma) unless disease free for a minimum of 2 years

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

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

- 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 Step 1 registration)

- History of documented inflammatory bowel disease

- Transmural myocardial infarction within the last 4 months prior to Step 1
registration.

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months prior to Step 1 registration

- 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 (eg, human immunodeficiency virus [HIV] or viral
hepatitis)

- Uncontrolled hypertension

- Any current condition that in the opinion of the investigator, would preclude
participation in this study

- Prior whole gland ablative therapy (i.e. cryoablation or high intensity focused
ultrasound [HIFU]) for prostate cancer is not allowed

- HIV positive with CD4 count < 200 cells/microliter within 30 days prior to
registration

- HIV patients under treatment with highly active antiretroviral therapy (HAART) within
30 days prior to registration regardless of CD4 count. (Note: HIV testing is not
required for eligibility for this protocol as it is self-reported.)

- For patients who have not undergone prior Decipher analysis, submission of the
specimen to GenomeDx should be as soon as possible after study registration (Step 1)
as these results can take up 21 days after the specimen is received at GenomeDx; Step
2 registration must occur within 6 weeks (42 days) of Step 1 registration; if Decipher
results have already been obtained, in lieu of tissue, results must be submitted to
GenomeDx for validation