This trial studies the changes in long-term physician-scored genitourinary toxicity achieved in prostate cancer patients eligible for stereotactic radiation therapy when both patients and physicians have access to convincing but non-validated germline signature that can characterize patients as having a low or high risk of developing toxicity after radiation therapy. The information learned from this study may guide patients' and physicians' decisions on radiotherapy fractionation.

PRIMARY OBJECTIVE:

I. To determine the impact on the 2-year cumulative incidence of late grade ≥2 genitourinary (GU) physician-scored toxicity, as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 scale, caused by presenting both the physicians and patients with the results of a non-prospectively validated biomarker panel that dichotomizes any given patient into having a high versus a low risk of late grade ≥2 GU physician-scored toxicity following stereotactic body radiotherapy (SBRT).

SECONDARY OBJECTIVES:

I. To determine the late grade ≥2 genitourinary (GU) physician-scored toxicity, as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 scale, in patients who test positive for the biomarker.

II. To determine the late grade ≥2 genitourinary (GU) physician-scored toxicity, as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 scale, in patients who test negative for the biomarker.

III. To observe the proportions of patients who choose to receive conventionally fractionated radiotherapy, moderately hypofractionated radiotherapy, and SBRT, based on being positive or negative for the biomarker thought to predict for late grade ≥2 GU toxicity.

To determine the 2- and 5-year cumulative incidences of late grade ≥2 gastrointestinal (GI) physician-reported toxicity, as assessed by the CTCAE version 4.03 scale, following the same intervention as for the primary objective.

IV. To determine the incidence of acute grade ≥2 GU and GI toxicity as assessed by the CTCAE version 4.03 scale, following the same intervention as for the primary objective.

V. To quantify the temporal changes in patient-reported quality of life (QOL) outcomes, as assessed by the Expanded Prostate Cancer Index-26 (EPIC-26), International Prostate Symptom Scores (IPSS), and Sexual Health Inventory for Men (SHIM) QOL indices, following the same intervention as for the primary objective.

VI. To determine the 5-year cumulative incidence of late grade ≥2 GU physician-reported toxicity, as assessed by the CTCAE version 4.03 scale.

OUTLINE:

Patients planning to undergo SBRT per standard of care undergo collection of cheek swab and blood samples for the analysis of germline biomarkers. Afterwards, patients and their physicians engage in discussion about which form of radiotherapy to proceed with. Based on the decision, patients predicted to be at low risk of toxicity with SBRT continue to receive SBRT over 14 days while patients predicted to be at high risk of toxicity with SBRT will be counseled to undergo either conventionally fractionated radiotherapy over 63-70 days, moderate hypofractionated radiotherapy over 28-35 days, or may opt to still receive SBRT over 14 days per standard of care.

After completion of radiotherapy treatment, patients are followed up at 1 ,3, 6, 9, 12, 18, and 24 months, and then every 6 months for 4 years.

Inclusion Criteria:

• Histologically confirmed, clinical localized adenocarcinoma of the prostate

• No evidence of disease beyond the prostate and/or seminal vesicles (i.e., no suspicious pelvic lymph nodes or presence of metastatic disease outside the pelvis)

• Staging workup as recommended by the National Comprehensive Cancer Network (NCCN) on the basis of risk grouping:

  • Low risk: No staging workup required
  • Favorable intermediate-risk: computed tomography (CT) abdomen/pelvis only if Memorial Sloan Kettering Cancer Center (MSKCC) nomogram predicts > 10% probability of lymph node involvement (note: CT simulation scan will count as a CT abdomen/pelvis)
  • Unfavorable intermediate-risk: technetium bone scan, CT abdomen/pelvis if MSKCC nomogram predicts > 10% probability of lymph node involvement (note: CT simulation scan will count as a CT abdomen/pelvis)
  • High-risk: technetium bone scan, CT abdomen/pelvis if MSKCC nomogram predicts > 10% probability of lymph node involvement (note: CT simulation scan will count as a CT abdomen/pelvis) =
  • Advanced imaging studies (i.e. prostate specific membrane antigen [PSMA] positron emission tomography [PET] and Axumin scan) can supplant a bone scan if performed first

• Ability to understand, and willingness to sign, the written informed consent

Exclusion Criteria:

• Patients with neuroendocrine or small cell carcinoma of the prostate
• Patients with any evidence of distant metastases. Note, evidence of lymphadenopathy below the level of the renal arteries can be deemed loco regional per the discretion of the investigator
• Prior whole-gland cryosurgery, high-intensity focused ultrasound (HIFU) or brachytherapy of the prostate
• Prior pelvic radiotherapy
• History of Crohn's disease, ulcerative colitis, or ataxia telangiectasia