Importance: Magnetic resonance imaging (MRI) guidance offers multiple theoretical advantages in the context of stereotactic body radiotherapy (SBRT) for prostate cancer. However, to our knowledge, these advantages have yet to be demonstrated in a randomized clinical trial.Objective: To determine whether aggressive margin reduction with MRI guidance significantly reduces acute grade 2 or greater genitourinary (GU) toxic effects after prostate SBRT compared with computed tomography (CT) guidance.Design, Setting, and Participants: This phase 3 randomized clinical trial (MRI-Guided Stereotactic Body Radiotherapy for Prostate Cancer [MIRAGE]) enrolled men aged 18 years or older who were receiving SBRT for clinically localized prostate adenocarcinoma at a single center between May 5, 2020, and October 1, 2021. Data were analyzed from January 15, 2021, through May 15, 2022. All patients had 3 months or more of follow-up.Interventions: Patients were randomized 1:1 to SBRT with CT guidance (control arm) or MRI guidance. Planning margins of 4 mm (CT arm) and 2 mm (MRI arm) were used to deliver 40 Gy in 5 fractions.Main Outcomes and Measures: The primary end point was the incidence of acute (≤90 days after SBRT) grade 2 or greater GU toxic effects (using Common Terminology Criteria for Adverse Events, version 4.03 [CTCAE v4.03]). Secondary outcomes included CTCAE v4.03–based gastrointestinal toxic effects and International Prostate Symptom Score (IPSS)–based and Expanded Prostate Cancer Index Composite-26 (EPIC-26)–based outcomes.Results: Between May 2020 and October 2021, 156 patients were randomized: 77 to CT (median age, 71 years [IQR, 67-77 years]) and 79 to MRI (median age, 71 years [IQR, 68-75 years]). A prespecified interim futility analysis conducted after 100 patients reached 90 or more days after SBRT was performed October 1, 2021, with the sample size reestimated to 154 patients. Thus, the trial was closed to accrual early. The incidence of acute grade 2 or greater GU toxic effects was significantly lower with MRI vs CT guidance (24.4% [95% CI, 15.4%-35.4%] vs 43.4% [95% CI, 32.1%-55.3%]; P = .01), as was the incidence of acute grade 2 or greater gastrointestinal toxic effects (0.0% [95% CI, 0.0%-4.6%] vs 10.5% [95% CI, 4.7%-19.7%]; P = .003). Magnetic resonance imaging guidance was associated with a significantly smaller percentage of patients with a 15-point or greater increase in IPSS at 1 month (6.8% [5 of 72] vs 19.4% [14 of 74]; P = .01) and a significantly reduced percentage of patients with a clinically significant (≥12-point) decrease in EPIC-26 bowel scores (25.0% [17 of 68] vs 50.0% [34 of 68]; P = .001) at 1 month.Conclusions and Relevance: In this randomized clinical trial, compared with CT-guidance, MRI-guided SBRT significantly reduced both moderate acute physician-scored toxic effects and decrements in patient-reported quality of life. Longer-term follow-up will confirm whether these notable benefits persist.Trial Registration: ClinicalTrials.gov Identifier: NCT04384770

Prostate cancer (PCa) is the leading cause of cancer treatment–related years lived with disability worldwide, reflecting the confluence of its high incidence, high cure rate, and treatment-associated morbidity.¹ Most patients with PCa in the developed world receive a diagnosis of clinically localized disease, and the majority have low-risk or intermediate-risk disease as defined by the National Comprehensive Cancer Network (NCCN).² Multiple management options are available, including definitive external beam radiotherapy (EBRT), radical prostatectomy, brachytherapy, and (for patients with low-risk and favorable intermediate-risk disease) active surveillance.

Definitive radiotherapy with androgen deprivation therapy and radical prostatectomy are standard treatment options for patients with high-risk prostate cancer, characterized by initial prostate-specific antigen levels greater than 20 ng/mL, biopsy Gleason score 8-10 disease, or lesions with clinical T stage greater than or equal to 3.¹ Radiotherapy options include external beam radiotherapy (EBRT) alone and EBRT with a brachytherapy boost (EBRT+BT), with the latter constituting extreme dose escalation. Although randomized trials suggest a biochemical control benefit to EBRT+BT over EBRT, no differences in clinical outcomes have been established.^2-4 Whether radical prostatectomy and radiotherapy (either EBRT or EBRT+BT) offer equivalent outcomes for high-risk prostate cancer remains controversial, with no clear evidence from randomized trials.^5-7 Previous comparative retrospective series included patients treated during multiple decades to obtain enough person-years of follow-up to identify sufficient clinical events for valid statistical comparison. Thus, these studies have generally included patients treated with lower doses of radiotherapy⁸ or insufficient androgen deprivation therapy.^9,10 As a result, the relevance of such studies to the contemporary setting is unclear.