Hormone Therapy (Apalutamide) and Image-guided Stereotactic Body Radiation Therapy for the Treatment of Patients With Prostate Cancer, HEATWAVE Trial

Inclusion Criteria:

* Confirmed diagnosis of prostate adenocarcinoma
* Age ≥ 18
* Classified as having National Comprehensive Cancer Network unfavorable intermediate risk prostate cancer (i.e., \[a\] 2 of the following: PSA 10-20 ng/mL, clinical T category 2b-2c, or International Society of Urological Pathology \[ISUP\] grade group 2; \[b\] OR any 1 of \[a\] with ISUP grade group 3 disease; OR \[c\] any 1 of \[a\] with 50% or more cores on systematic biopsy showing prostate cancer)
* Have a Decipher genomic classifier score
* Have at least one dominant intraprostatic lesion visible on multiparametric MRI (Prostate Imaging-Reporting and Data System \[PI-RADS\] version 2.1 score 4 or 5)
* Have underwent a prostate specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)
* Have total testosterone \>= 150 ng/dL
* Adequate performance status (Eastern Cooperative Oncology Group \[ECOG\] 0-1)
* Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors within 3 months prior to randomization (at screening)
* Platelet count ≥ 100,000 x 10\^9/uL independent of transfusion and/or growth factors within 3 months prior to randomization (at screening)
* Serum albumin ≥ 3.0 g/dL (at screening)
* Glomerular filtration rate (GFR) ≥ 45 mL/min (at screening)
* Serum potassium ≥ 3.5 mmol/L (at screening)
* 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 may be eligible) (at screening)
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \< 2.5 x ULN (at screening)
* Medications known to lower the seizure threshold (see list under prohibited medications) must be discontinued or substituted at least 4 weeks prior to study entry

Exclusion Criteria:

* Any evidence of spinal cord compression (radiological or clinical)
* Prior pelvic malignancy
* Prior pelvic radiation
* Concurrent malignancy other than adequately treated basal cell or squamous cell skin cancer, non-muscle invasive bladder cancer (NMIBC), or any other cancer in situ currently without evidence of recurrence or progression
* Inability to undergo radiotherapy, or hormonal therapy
* Primary small cell carcinoma of the prostate (prostate adenocarcinoma with neuroendocrine differentiation is allowed)
* Inflammatory bowel disease or active collagen vascular disease
* History of any of the following:

  * Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1 year 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)
  * Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization
* Current evidence of any of the following:

  * Uncontrolled hypertension
  * Gastrointestinal disorder affecting absorption
  * Known active infection (eg, human immunodeficiency virus \[HIV\] or viral hepatitis)
  * Any condition that in the opinion of the investigator would preclude participation in this study
  * Treatment with CYP2D6 substrates that have a narrow therapeutic index. If an alternative treatment cannot be used, a dose reduction of the CYP2D6 substrate may be considered
  * Baseline moderate and severe hepatic impairment (Child Pugh class B \& C)