Testing Shorter Duration Radiation Therapy Versus the Usual Radiation Therapy in Patients With High Risk Prostate Cancer

Study Overview
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Brief Summary
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This phase III trial compares stereotactic body radiation therapy (SBRT), (five treatments over two weeks using a higher dose per treatment) to usual radiation therapy (20 to 45 treatments over 4 to 9 weeks) for the treatment of high-risk prostate cancer. SBRT uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period of time. This trial is evaluating if shorter duration radiation prevents cancer from coming back as well as the usual radiation treatment.

Detailed Description
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PRIMARY OBJECTIVE: I. To compare metastasis-free survival, determined using conventional imaging, between men with high-risk prostate cancer randomized to ultrahypofractionation (stereotactic body radiation therapy [SBRT]) to those randomized to moderate hypofractionation and conventional fractionation. SECONDARY OBJECTIVES: I. To compare physician-reported toxicity as measured by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5 between treatment arms. II. To determine if ultrahypofractionation is non-inferior to moderate hypofractionation and conventional fractionation with respect to patient-reported urinary function (assessed by Expanded Prostate Cancer Index Composite [EPIC]-26 urinary domains). III. To determine if ultrahypofractionation is non-inferior to moderate hypofractionation and conventional fractionation with respect to patient-reported bowel function (assessed by EPIC-26 bowel domain). IV. To compare patient-reported fatigue (assessed by Patient Reported Outcomes Measurement Information System [PROMIS]-Fatigue) between treatment arms. V. To compare patient-reported treatment burden (assessed by COmprehensive Score for financial Toxicity [COST]) between treatment arms. VI. To compare failure-free survival between treatment arms. VII. To compare metastasis-free survival based on molecular imaging between treatment arms. VIII. To compare overall survival between treatment arms. EXPLORATORY OBJECTIVES: I. To compare patient-reported sexual function (assessed by EPIC-26 sexual domain) between treatment arms. II. To compare patient-reported quality of life (assessed by European Quality of Life Five Dimension Five Level Scale Questionnaire [EQ-5D-5L]) between treatment arms. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo SBRT for a total of 5 treatments over 2 weeks. ARM II: Patients undergo external beam radiation treatment (EBRT) for 20-45 treatments over 4 to 9 weeks. Patients are followed up every 6 months for 5 years.

Official Title
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The Phase III 'High Five Trial' Five Fraction Radiation for High-Risk Prostate Cancer

Conditions
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Stage III Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8

Intervention / Treatment
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* Radiation: External Beam Radiation Therapy
* Radiation: Stereotactic Body Radiation Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically (histologically or cytologically) proven diagnosis of adenocarcinoma of prostate cancer High-risk disease defined as having at least one or more of the following: cT3a-T3b by digital exam or imaging (American Joint Committee on Cancer [AJCC] 8th edition [Ed.]) Note: cT4 by imaging or on digital rectal exam is not allowed The patient's prostate specific antigen (PSA) > 20 ng/mL prior to starting ADT Note: Patients taking a 5-alpha reductase inhibitor (ex finasteride or dutasteride) are eligible. The baseline PSA value should be doubled for PSAs taken while on 5-alpha reductase inhibitors Gleason Score of 8-10 Pelvic node positive by conventional imaging with a short axis of at least 1.0 cm Prostate gland volume less than 100 cc prior to initiation of ADT as reported at time of biopsy or by separate measure with ultrasound or other imaging modalities including MRI or computed tomography (CT) scan No definitive clinical or radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e. bone scan, CT scan, MRI); Negative prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is an acceptable substitute Age >= 18 Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 No prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields No prior radical prostatectomy Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both luteinizing hormone releasing hormone [LHRH] agonist and oral anti-androgen) is =< 185 days prior to registration Patients enrolled in NRG-GU009 must be enrolled in NRG-GU013 prior to radiation therapy treatment planning and start of radiation therapy

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (SBRT)<br>Patients undergo SBRT for a total of 5 treatments over 2 weeks. | Radiation: Stereotactic Body Radiation Therapy<br>* Undergo SBRT<br>* Other names: Stereotactic Ablative Body Radiation Therapy;|
| Active Comparator: Arm II (EBRT)<br>Patients undergo EBRT for 20 to 45 treatments over 4 to 9 weeks. | Radiation: External Beam Radiation Therapy<br>* Undergo EBRT<br>* Other names: Teletherapy Radiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastasis-Free Survival (MFS) | Based on conventional imaging. MFS will be estimated using the Kaplan-Meier method (Kaplan 1958). A confidence interval approach will be used adjusting for stratification factors. If the one sided 95% upper confidence limit of HR < 1.35, then the null hypothesis of inferiority will be rejected. If the 95% upper confidence limit excludes HR=1.35, then the null hypothesis of inferiority will be rejected. Cox proportional hazards models will be used to obtain unadjusted and adjusted HRs and 95% confidence intervals for the treatment effects. | From randomization to the date of distant metastasis, or death from any cause, assessed up to 15 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure-Free Survival | Will be estimated using the Kaplan-Meier method and treatment arms compared using the stratified log-rank test. Cox proportional hazards models will be used to determine hazard ratios and to assess the effects of stratification factors and other covariates of interest, such as age, race, antiandrogen therapy (ADT) adherence, T stage, Gleason score, and performance status on outcomes. | From randomization to the date of distant metastasis, or death from any cause, assessed up to 15 years | 
| Overall Survival | Will be estimated using the Kaplan-Meier method and treatment arms compared using the stratified log-rank test. Cox proportional hazards models will be used to determine hazard ratios and to assess the effects of stratification factors and other covariates of interest, such as age, race, ADT adherence, T stage, Gleason score, and performance status on outcomes. | From the date of randomization to the date of death or last known follow-up date, with patients alive at the last known follow-up time treated as censored, assessed up to 15 years | 
| MFS | Based on molecular imaging. Will be estimated using the Kaplan-Meier method and treatment arms compared using the stratified log-rank test. Cox proportional hazards models will be used to determine hazard ratios and to assess the effects of stratification factors and other covariates of interest, such as age, race, ADT adherence, T stage, Gleason score, and performance status on outcomes. | From randomization to the date of distant metastasis, or death from any cause, assessed up to 15 years | 
| Incidence of Adverse Events (AEs) | AEs will be graded using National Cancer Institute's (NCI's) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5. Counts of all AEs by grade will be provided by treatment arm. | Up to 15 years | 
| Urinary Incontinence domain of the Expanded Prostate Cancer Index Composite (EPIC-26) | Each response is standardized to a 0 to 100 scale, with higher scores indicating better health-related quality of life. | Up to 5 years | 
| Urinary Irritative/Obstructive domain of the Expanded Prostate Cancer Index Composite (EPIC-26) | Each response is standardized to a 0 to 100 scale, with higher scores indicating better health-related quality of life. | Up to 5 years | 
| Bowel domain of the Expanded Prostate Cancer Index Composite (EPIC-26) | Each response is standardized to a 0 to 100 scale, with higher scores indicating better health-related quality of life. | Up to 5 years | 
| Fatigue | Measured by the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue. Raw scores range from 7 to 35 and are standardized. A higher score indicates more fatigue. | Up to 5 years | 
| Cost | Measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-COST. | Up to 1 year |