Germline radiosensitivity biomarker for radiation-induced GU toxicity following radiation therapy in localized prostate cancer (GARUDA): Two-year outcomes of a phase II clinical trial.

359 Background: Stereotactic body radiation therapy (SBRT) is increasingly used for localized prostate cancer, yet treatment-related genitourinary (GU) toxicity remains a concern, with grade ≥2 GU toxicity after SBRT impacting nearly one-third of patients two-years after treatment. PROSTOX, a biomarker based on germline genetic variants, may identify patients who are more likely to experience late grade ≥2 GU toxicity after SBRT. The GARUDA trial prospectively evaluated whether pre-treatment determination of PROSTOX status followed by shared decision-making on treatment choice would lead to lower rates of late grade ≥2 GU toxicity in a cohort of patients that would otherwise receive SBRT. Methods: GARUDA (NCT04624256) was a single-arm, prospective Phase II trial that enrolled patients with localized prostate cancer considering SBRT. Participants underwent PROSTOX testing prior to treatment and were offered SBRT (40 Gy in 5 fractions) or moderately hypofractionated radiotherapy (MHFRT, 60 Gy in 20 fractions). Co-primary endpoints were physician-scored acute and late GI and GU toxicity by CTCAE 4.03 and PROs assessed by the Expanded Prostate Cancer Index-26 (EPIC-26) and International Prostate Symptom Scores (IPSS). Statistical comparisons of stratified proportions are based on Gaussian approximations to Binomial probabilities. This is a secondary endpoint analysis of 2-year toxicity outcomes. Results: Between November 2020 and May 2022, 208 patients were enrolled. Median follow-up was 25 months (IQR: 24–30). Based on PROSTOX, 180 patients (86.5%) were classified as low-risk and 28 (13.5%) as high-risk for late grade ≥2 GU toxicity. Among low-risk patients, 98.6% elected SBRT and 1.4% chose MHFRT; among high-risk patients, 57.1% chose SBRT and 42.9% MHFRT Of those treated with SBRT, 66% received MRI-guided SBRT. The 2-year cumulative incidences of late grade ≥2 GU toxicity for the whole cohort was 18%. At 24 months, 18.1% (26/144) of patients reported a >2-fold minimal clinically important difference in urinary incontinence scores, and 22.9% (33/144) in urinary irritation scores. Mean 24-month changes from baseline were +0.47 for IPSS, -3.1 for EPIC urinary incontinence, -2.53 for urinary irritation, and -3.5 for overall urinary scores. Conclusions: Two-year data from the GARUDA trial support the clinical utility of a germline biomarker in predicting radiation-related GU toxicity. Despite high-dose SBRT being delivered in 93% of patients, the incidence of grade ≥2 GU toxicity at two years was lower than expected. These findings highlight the potential of integrating germline biomarkers into radiation planning for men with localized prostate cancer. Clinical trial information: NCT04624256 .