This phase II trial studies how well antiandrogen therapy (leuprolide, apalutamide, and abiraterone acetate) and stereotactic body radiation therapy (SBRT) works in treating patients with prostate cancer that has come back and has spread to other parts of the body. Drugs used in chemotherapy, such as leuprolide, apalutamide, and abiraterone acetate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. SBRT uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving antiandrogen therapy and SBRT may work better in treating patients with prostate cancer.

PRIMARY OBJECTIVES:

I. To assess the efficacy of combined systemic and tumor directed therapy for recurrent oligometastatic M1a,b prostate cancer patients with 1-5 metastases (exclusive of pelvic nodal N1 metastases) staged by prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-computed tomography (CT).

SECONDARY OBJECTIVES:

I. Time to biochemical progression. II. Time to additional antineoplastic therapy. III. Prostate cancer specific survival. IV. Safety and tolerability. V. Assessment of health related quality of life using the Functional Assessment of Cancer Therapy - Prostate (FACT-P) scale.

CORRELATIVE OBJECTIVES:

I. To determine genomic and transcriptomic features present in metastatic tumors in patients that respond to this multimodal therapy.

II. To evaluate biomarkers of response using circulating tumor cells (CTCs). III. To evaluate biomarkers of response using circulating tumor deoxyribonucleic acid (DNA) (ctDNA).

IV. To evaluate immunophenotypes of circulating immune cells.

OUTLINE:

Patients receive a single dose of leuprolide subcutaneously (SC) on day 1 and apalutamide orally (PO) once daily (QD) and abiraterone acetate PO QD for up to 6 months in the absence of disease progression or unacceptable toxicity. Beginning 2 months of initiation of antiandrogen therapy (ADT), patients also receive SBRT over 1, 3, or 5 fractions in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 2 -4 weeks, every 30 days for 6 months, and then every 3 months thereafter.

Inclusion Criteria:

• Confirmed diagnosis of prostate adenocarcinoma after radical prostatectomy (primary small cell carcinoma of the prostate is not allowed, however adenocarcinoma with neuroendocrine differentiation is allowed)

• Presence of 1-5 visible metastases (by PSMA PET-CT)

  • At least one metastasis must be M1a-b
  • Visceral metastases are not allowed
  • Patients may have any number of pelvic nodal metastases (but largest must be < 2 cm)
  • Metastases must be amenable to treatment with SBRT
  • Biopsy of one metastasis must be attempted, unless unsafe to perform

• Patient must be fit to undergo SBRT to all visible sites of metastases, ADT

• Total testosterone > 150 ng/dL prior to ADT (optimal time to measure total testosterone is between 8 and 9 am)

• 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

• Platelet count >= 100,000 x 10^9/uL independent of transfusion and/or growth factors within 3 months prior to randomization

• Serum albumin >= 3.0 g/dL

• Glomerular filtration rate (GFR) >= 45 mL/min

• Serum potassium >= 3.5 mmol/L

• Serum total bilirubin =< 1.5 x upper limits 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

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x ULN

• Medications known to lower the seizure threshold 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 aside from salvage prostate radiation

• Concurrent malignancy aside from superficial skin cancers or superficial bladder tumors

• Inability to undergo radiotherapy, or ADT

• 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
  • Active infection (eg, human immunodeficiency virus [HIV] or viral hepatitis)
  • Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily
  • Any condition that in the opinion of the investigator would preclude participation in this study
  • Concomitant strong CYP3A4 inducers. (If a strong CYP3A4 inducer must be co-administered, abiraterone acetate dose frequency will be adjusted). [SAFETY: Warning against use with CYP2C8 inhibitors with narrow therapeutic index is also pertinent to be included as it is also part of United States Prescribing Information (USPI): In a CYP2C8 drug-drug interaction trial in healthy subjects, the area under curve (AUC) of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA]
  • 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 (ChildPugh Class B & C)

• Presence of visceral metastases (i.e., stage M1c)