Germline DNA-Based Radiosensitivity Biomarker Influence on Toxicity Following Prostate Radiotherapy, GARUDA Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the impact on the 5-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. IV. To determine the 5-year cumulative incidence 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. V. 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. VI. 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. 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.

Official Title
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Germline DNA-Based Radiosensitivity Biomarker Influence on Toxicity Following Prostate Radiotherapy

Conditions
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Prostate Adenocarcinoma, Stage I Prostate Cancer American Joint Committee on Cancer (AJCC) v8, Stage II Prostate Cancer AJCC v8, Stage IIA Prostate Cancer AJCC v8, Stage IIB Prostate Cancer AJCC v8, Stage IIC Prostate Cancer AJCC v8

Intervention / Treatment
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* Procedure: Discussion
* Radiation: Hypofractionated Radiation Therapy
* Radiation: Hypofractionated Radiation Therapy
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Radiation: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (radiotherapy, genomic DNA testing)<br>Patients undergo SBRT per standard of care, then 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. | Procedure: Discussion<br>* Patients and physicians engage in discussion<br>* Other names: Discuss;Radiation: Hypofractionated Radiation Therapy<br>* Undergo conventional hypofractionated radiation therapy<br>* Other names: hypofractionation;Radiation: Hypofractionated Radiation Therapy<br>* Undergo moderate hypofractionated radiation therapy<br>* Other names: hypofractionation;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SBRT<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year cumulative incidence of late grade >= 2 physician-scored genitourinary toxicity | Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 scale, stratified by positive or negative status for the biomarker thought to predict for late grade >= 2 genitourinary (GU) toxicity. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year biochemical recurrence-free survival | Will be estimated by the Kaplan-Meier method, with biochemical recurrence (BCR) defined as serum prostate specific antigen (PSA) levels that are 2 ng/mL higher than the nadir PSA achieved after magnetic resonance imaging-guided stereotactic body radiation therapy (SBRT). | Up to 5 years | 
| Rate of acute grade >= 2 genitourinary and gastrointestinal physician-scored toxicity | Assessed by the CTCAE version 4.03 scale, based on being positive or negative for the biomarker thought to predict for late grade >= 2 GU toxicity. The timeframe will be restricted to the first 90 days after radiotherapy. | Up to the first 90 days after radiotherapy | 
| Rate of acute grade >= 2 gastrointestinal physician-scored toxicity | Assessed by the CTCAE version 4.03 scale, based on being positive or negative for the biomarker thought to predict for late grade >= 2 GU toxicity. | Up to the first 90 days after radiotherapy (acute). | 
| 5-year cumulative incidence of Late grade >= 2 GU physician-scored toxicity | Assessed by the CTCAE version 4.03 scale, in patients who test positive or negative for the biomarker. | Up to 5 years | 
| Proportions of patients who choose to receive radiation treatment | Will analyze 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. | Up to 5 years | 
| Change in patient-reported urinary quality of life | Will be obtained depending on the instrument used. For the Expanded Prostate Cancer Index-26 instrument, these will be represented by changes from baseline in the urinary symptom domain. The scores will range from 0-100, with a higher number indicating a better quality of life. Changes will be analyzed with respect to whether they represent minimally important differences, based on approved thresholds in the literature. | Baseline up to 5 years | 
| Change in patient-reported bowel quality of life | Will be obtained depending on the instrument used. For the Expanded Prostate Cancer Index-26 instrument, these will be represented by changes from baseline in the bowel domain. The scores will range from 0-100, with a higher number indicating a better quality of life. Changes will be analyzed with respect to whether they represent minimally important differences. | Baseline up to 5 years | 
| Change in patient-reported sexual quality of life outcome | will be assessed by the International Prostate Symptom Scores (I-PSS) instrument by five years. Scoring is from 1 - 35, a higher number is worse outcome. | Baseline up to 5 years | 
| Change in patient-reported sexual quality of life by the Sexual Health Inventory for Men instrument by five years | Will be represented by changes from baseline in the urinary incontinence and urinary obstruction domains on the Sexual Health Inventory for Men instrument (SHIM). coring from 1-25, higher number is better outcome. | Baseline up to 5 years |