Apalutamide With or Without Stereotactic Body Radiation Therapy in Treating Participants With Castration-Resistant Prostate Cancer

PRIMARY OBJECTIVES:

I. To demonstrate whether the proportion of patients with an undetectable serum prostate
specific antigen (PSA) at 6 months following cessation of apalutamide is higher with addition
of stereotactic body radiation therapy (SBRT) to prostate specific membrane antigen
(PSMA)-avid oligometastatic sites of disease compared to the group of patients receiving
apalutamide monotherapy.

SECONDARY OBJECTIVES:

I. To compare the time to PSA progression by Prostate Cancer Working Group (PCWG) criteria
between treatment arms.

II. To compare radiologic progression free survival (rPFS) between treatment arms.

III. To evaluate the safety and tolerability of apalutamide in combination with SBRT.

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM I: Participants receive apalutamide orally (PO) once daily (QD) on days 1-28. Courses
repeat every 28 days for up to 52 weeks in the absence of disease progression or unacceptable
toxicity. Beginning 60 days after first dose of apalutamide, participants also undergo
stereotactic body radiation therapy for 1-5 fractions.

ARM II: Participants receive apalutamide PO QD on days 1-28. Courses repeat every 28 days for
up to 52 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed at for 30 days.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the prostate

- Prior radical prostatectomy

- Progressive, castration-resistant prostate cancer demonstrated during continuous
antiandrogen therapy (ADT), defined as 3 PSA rises at least 1 week apart, with the
last PSA > 2 ng/mL

- 5 metastases on conventional imaging with computed tomography (CT)/magnetic
resonance imaging (MRI) of the abdomen/pelvis and whole body bone scan

- At least one but no more than 5 discrete PSMA-avid metastases on baseline PSMA-PET
scan; all PSMA-avid lesions must be amenable to SBRT in judgment of treating radiation
oncologist; there are no restrictions on site of metastasis (e.g. bone, lymph node,
visceral); equivocal lesions on PSMA PET scan that are not definitive for metastasis
will not count towards the limit of metastases and will not undergo SBRT

- Surgically or medically castrated, with testosterone levels of < 50 ng/dL; if the
patient is medically castrated, continuous dosing with luteinizing hormone-releasing
hormone (LHRH) analogue must have been initiated at least 4 weeks prior to
randomization and must be continued throughout the study to maintain castrate levels
of testosterone including post-treatment follow up period

- No prior abiraterone acetate, enzalutamide or apalutamide or other novel AR or CYP17
antagonist, or docetaxel for castration resistant prostate cancer; if used for hormone
naïve disease, last dose was at least 12 months prior to randomization

- Patients receiving bone loss prevention treatment with bone-modifying agents (e.g.
denosumab, zoledronic acid) must be on stable doses for at least 4 weeks prior to
randomization

- Patients who received a first generation anti-androgen (e.g., bicalutamide, flutamide,
nilutamide) as most recent treatment must have at least a 6-week washout prior to
randomization and must show continuing disease (PSA) progression (an increase in PSA)
after washout

- At least 4 weeks or 5 half-lives, whichever is shorter, must have elapsed from the use
of any anti-cancer therapy prior to randomization

- At least 4 weeks must have elapsed from major surgery or radiation therapy prior to
randomization

- Eastern Cooperative Oncology Group (ECOG) performance status grade 0 or 1

- Resolution of all acute toxic effects of prior therapy or surgical procedure to grade
1 or baseline prior to randomization

- Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and
serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x
upper limit of normal (ULN)

- Total serum bilirubin ≤ 1.5 x ULN; in subjects with known or suspected Gilbert's
syndrome, if total bilirubin is > 1.5 x ULN, direct bilirubin is ≤ 1.5 x ULN

- Glomerular filtration rate ≥ 45 ml/min based on Cockcroft-Gault equation

- Absolute neutrophil count (ANC) ≥ 1500/microliter

- Platelets ≥ 100,000/microliter without transfusion and/or growth factors in the 3
months prior to randomization

- Hemoglobin ≥ 9.0 g/dL without transfusion and/or growth factors in the 3 months prior
to randomization

- Serum albumin ≥ 3.0 g/dL

- Signed and dated informed consent document indicating that the patient has been
informed of all pertinent aspects of the trial prior to randomization

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
and radiographic assessments, and other study procedures, including ability to swallow
study drug tablets and long-term follow-up

- 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

Exclusion Criteria:

- Presence of visceral metastases (e.g. lung, liver) detectable on cross-sectional
imaging or bone metastases requiring the use of opioid analgesic or focal radiation
treatment at the time of study entry

- History of seizure or condition that may pre-dispose to seizure (e.g., prior stroke
within 1 year prior to randomization, brain arteriovenous malformation, Schwannoma,
meningioma, or other benign central nervous system (CNS) or meningeal disease which
may require treatment with surgery or radiation therapy

- Concurrent therapy with any of the following (all must have been discontinued or
substituted for at least 1 week prior to randomization, except for medications known
to lower seizure threshold which must be discontinued or substituted at least 4 weeks
prior to randomization)

- Medications known to lower the seizure threshold

- Herbal (e.g., saw palmetto) and non-herbal (e.g., pomegranate) products that may
decrease PSA levels

- Systemic (oral/intravenous [IV]/intramuscular [IM]) corticosteroids; patients on
chronic stable dose of steroids at an equivalent dose of prednisone ≤ 10 mg daily may
be permitted to enroll at the discretion of principal investigator

- Any other experimental treatment on another clinical trial

- Any of the following within 6 months prior to randomization: Severe/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

- Uncontrolled hypertension at study entry; patients with a history of uncontrolled
hypertension are allowed provided blood pressure is controlled by antihypertensive
treatment

- Gastrointestinal disorder affecting absorption

- Secondary malignancy requiring active treatment except for non-melanoma skin cancer
and superficial bladder cancer

- Any medical condition that would be a contra-indication to radiation therapy, such as
inflammatory bowel disease

- Spinal cord compression or impending spinal cord compression

- Any other condition that, in the opinion of the Investigator, would impair the
patient's ability to comply with study procedures