This phase II trial studies the effects of stereotactic body radiation therapy (SBRT) and the timing of treatment with androgen receptor pathway inhibitor (ARPI) plus androgen deprivation therapy (ADT) in treating patients with hormone sensitive prostate cancer that has spread from where it first started to other places in the body (metastatic), and that has come back after a period of improvement (recurrent). It also studies the effects of salvage radiation therapy (sXRT) on prostate cancer and to see if radiation to the pelvis helps prevent prostate cancer from spreading elsewhere. SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. Androgen can cause the growth of prostate cells. ADT lowers the amount of androgen made by the body. This may help stop the growth of tumor cells that need androgen to grow. Androgen receptor pathway inhibitors work by blocking the effects of androgen to stop the growth and spread of tumor cells. sXRT is a targeted radiation treatment for the prostate, typically given when cancer possibly returns after surgery or radiation. Its goal is to destroy any tumor cells in the area. Giving SBRT alone with watchful waiting may be as effective in treating prostate cancer as giving SBRT together with ARPI and ADT and sXRT may be effective in treating prostate cancer and preventing it from spreading elsewhere.

PRIMARY OBJECTIVES:

I. To evaluate and compare modified radiographic progression-free survival (mrPFS) in patients with metachronous recurrent oligometastatic prostate cancer treated with SBRT and 6 months ADT/ARPI followed by watchful wait (Group A) versus SBRT followed by watchful waiting (Group B). (De-escalation stratified by Extracellular Vesicles--Irradiation with Antiandrogen Therapy Exclusion [DEVIATE]) II. To evaluate and compare distant progression-free survival (PFS), landmarked at 12 months, in patients with biochemically recurrent prostate cancer treated with sXRT followed by watchful waiting (Group C) versus initial observation and subsequent image-guided therapy (Group D). (Biochemical Recurrence Irradiation versus Observation [BRIO])

SECONDARY OBJECTIVES:

I. To evaluate and compare overall survival (OS) between treatment groups. II. To evaluate and compare biochemical progression-free survival (bPFS) between treatment groups.

III. To evaluate and compare distant progression-free survival (PFS) starting from study registration, in patients with biochemically recurrent prostate cancer treated with sXRT followed by watchful waiting (Group C) versus initial observation and subsequent image-guided therapy (Group D).

TERTIARY OBJECTIVES:

I. To estimate rates of salvage radiotherapy to the pelvis in patients with biochemically recurrent prostate cancer treated with initial observation and subsequent image-guided therapy (Group D).

II. To evaluate the adverse event profile of the study treatments as assessed per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).

III. To evaluate and compare castration-resistant prostate cancer (CRPC)-free survival between treatment groups NOTE: CRPC-free survival: radiographic progression-free survival with castrate-level testosterone (< 50ng/mL).

IV. Determine the efficacy of extracellular vesicles (EVs) as a minimal residual disease (MRD) marker.

V. Determine the efficacy of EVs as an early indicator of disease relapse. VI. Determine whether early ADT and ARPI hasten CRPC. VII. Determine how circulating tumor deoxyribonucleic acid (ctDNA) compares as a biomarker to EVs.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

DEVIATE COHORT: Patients are randomized to 1 of 2 groups.

GROUP A: Patients undergo SBRT and receive ARPI (abiraterone and prednisone, apalutamide, darolutamide, or enzalutamide) and ADT (leuprolide, triptorelin, histrelin, goserelin, degarelix, or relugolix). Cycles repeat every 4 months (16 weeks) for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients then undergo watchful waiting thereafter until disease progression.

GROUP B: Patients undergo SBRT with watchful waiting. Cycles repeat every 4 months (16 weeks) in the absence of disease progression or unacceptable toxicity.

BRIO COHORT: Patients are randomized to 1 of 2 groups.

GROUP C: Patients undergo sXRT with watchful waiting. Cycles repeat every 4 months (16 weeks) in the absence of disease progression or unacceptable toxicity.

GROUP D: Patients undergo initial observation with subsequent image-guided therapy based on visualized distant progression, which may consist of cross-over to groups A & B, other off-trial radiotherapy, systemic therapy, surgical intervention, or other intervention per clinician discretion. Cycles repeat every 4 months (16 weeks) in the absence of disease progression or unacceptable toxicity.

Additionally, all patients undergo blood sample collection and positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), or bone scan throughout the trial.

Upon completion of study interventions patients are followed up every 6 months for up to 5 years.

Inclusion Criteria:

• Age ≥ 18 years

• Disease characteristics:

  • DEVIATE (Groups A and B only):

    • Clinical confirmation of metachronous (metastatic) recurrent hormone-sensitive prostate cancer
    • Five (5) or fewer metastases with at least one metastasis beyond the pelvis on advanced molecular and/or conventional imaging
    • Serum testosterone > 100ng/dL

  • BRIO (Gropus C & D only):

    • Prostate-specific antigen (PSA) between 0.2 and 1.5 ng/mL with PSA above 0.2 on at least two consecutive measurements at least 5 days apart
    • No local or metastatic recurrence apparent on advanced molecular imaging
    • Serum testosterone > 100 ng/dL

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1 or 2

• Hemoglobin ≥ 8.0 g/dL (obtained ≤ 15 days prior to registration)

• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (obtained ≤ 15 days prior to registration)

• Platelet count ≥ 80,000/mm^3 (obtained ≤ 15 days prior to registration)

• Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 3 x upper limit of normal (ULN) ( ≤ 5 x ULN for patients with liver involvement) (obtained ≤ 15 days prior to registration)

• Calculated creatinine clearance ≥ 30 ml/min using the Cockcroft-Gault formula (obtained ≤ 15 days prior to registration)

• Provide written informed consent

• Ability to complete questionnaire(s) by themselves or with assistance

• Willingness to provide mandatory blood specimens for correlative research

• Willingness to provide tissue specimens for correlative research

• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)

Exclusion Criteria:

• Any of the following because this study involves an investigational agent, the genotoxic, mutagenic, and teratogenic effects of which on the developing fetus and newborn are unknown

  • Pregnant persons
  • Nursing persons
  • Persons of childbearing potential or able to father a child who are unwilling to employ adequate contraception

• Prior metastasis-directed therapy

• Any of the following prior therapies:

  • Surgery ≤ 3 weeks prior to registration
  • Chemotherapy for prostate cancer at any time
  • Androgen receptor pathway inhibitor such as abiraterone, apalutamide, darolutamide, or enzalutamide in the last 2 years

• Uncontrolled intercurrent non-cardiac illness including, but not limited to:

  • Ongoing or active infection
  • Psychiatric illness/social situations
  • Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy
  • Any other conditions that would limit compliance with study requirements

• Receiving any other investigational agent which would be considered as a treatment for prostate cancer.

• Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at least 3 months since completion of prior treatment

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• Uncontrolled intercurrent illness including, but not limited to:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Or psychiatric illness/social situations that would limit compliance with study requirements

• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm

• Other active malignancy ≤ 3 years prior to registration

  • EXCEPTIONS: Curatively treated non-melanotic skin cancer or papillary thyroid cancer
  • NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment such as chemotherapy or antihormonal therapy for their cancer

• History of myocardial infarction ≤ 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias