311 - Germline Biomarker for Late Genitourinary Adverse Events after Radiotherapy for Prostate Cancer: Validation in Multiple Prospective Trials
Presenter(s)
A. U. Kishan1, D. Telesca2, E. Hall3, H. Lukka4, S. Pugh5, S. A. Seaward6, I. Dayes7, J. Helou8, J. M. Michalski9, S. N. Seyedin10, W. Shi11, J. P. Bahary12, M. L. Steinberg1, J. Patel13, A. Tree3, L. A. Kachnic14, P. Tran15, N. van As16, K. McGreevy17, and J. B. Weidhaas1; 1Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 2Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, 3The Institute of Cancer Research, London, United Kingdom, 4Juravinski Cancer Centre, Hamilton, ON, Canada, 5NRG Oncology Statistics and Data Management Center, Philadelphia, PA, 6Kaiser Permanente Oncology Clinical Trials, Vallejo, CA, 7McMaster University, Juravinski Cancer Centre, Hamilton, ON, Canada, 8Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON, Canada, 9Washington University School of Medicine, St. Louis, MO, 10Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, 11Department of Radiation Oncology, Sidney Kimmel Medical College & Cancer Center at Thomas Jefferson University, Philadelphia, PA, 12CHUM, Montreal, QC, Canada, 13The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, United Kingdom, 14Department of Radiation Oncology, Columbia University Irving Medical Center, New York, NY, 15MD Anderson, Houston, TX, 16The Royal Marsden NHS Foundation Trust, London, United Kingdom, 17MiraDx, Los Angeles, CA
Purpose/Objective(s):
Radiotherapy (RT)–related genitourinary (GU) adverse effects (AEs) after prostate cancer treatment affect survivorship. PROSTOX Ultra (PROSTOXu), a biomarker based on germline microRNA binding site variants, identifies patients at higher risk of late GU AEs specifically after stereotactic body RT (SBRT). We sought to determine whether (a) prospective PROSTOXu testing reduced late GU AEs and (b) high-risk PROSTOXu predicted late GU AEs in a cohort of patients receiving SBRT on phase II-III trials.Materials/Methods:
GARUDA (NCT04624256), a phase II trial, was powered to detect a reduction (vs. historical 32%) in two-year cumulative incidence of grade =2 GU AEs by providing PROSTOXu results prospectively and offering moderately hypofractionated RT (MHFRT) for high-risk patients. A mediation analysis was performed to quantify the effect of prospective testing on AEs. A meta-analysis was performed to validate PROSTOXu across GARUDA, MIRAGE, NRG 0938, and PACE-B. In each cohort, associations between high-risk PROSTOXu status and late grade =2 GU toxicity were estimated using odds ratios. Log odds ratios were pooled via inverse-variance weighted random-effects meta-analysis with restricted maximum likelihood estimation.Results:
GARUDA enrolled 208 patients (2020–2021). Among low-risk patients, 177/180 (98.3%) received SBRT; among high-risk, 18/31 (58.1%) received SBRT and the remainder received MHFRT. Two-year cumulative late grade =2 GU rates were 18.5% (95% CI 12.8–24.2%; p=0.0002). Mediation analysis showed prospective PROSTOXu testing reduced late GU AEs by 17.2% (average ACME, p<2e-16), likely by the reduced AEs for high-risk PROSTOXu patients who received MHFRT (n=0/13, 0%) versus SBRT (n=13/17 included in the analysis, 76.5%). The meta-analysis to validate PROSTOXu included 457 SBRT patients; 78 (17.1%) who were high-risk by PROSTOXu. Over a median follow-up of 4.9 years, 121 patients developed late grade =2 GU AEs. The risk of late grade =2 GU AEs was significantly higher in high-risk versus low-risk PROSTOXu patients (80.8% vs 15.3%, p<2.2e-16), OR 22.1 (95% CI 11.7–41.6, p<0.0001), with PROSTOXu having a pooled AUC of 0.754. Trial-specific results are shown in Table 1.Conclusion:
PROSTOX Ultra is validated for predicting late grade =2 GU AEs in a phase II trial, with prospective determination reducing AEs. Meta-analysis in patients treated with SBRT on phase II/III trials confirmed robust predictive performance, highlighting the importance of germline risk stratification in counseling and survivorship planning. Abstract 311 - Table 1: PROSTOX Ultra Performance Metrics| Trial | Number of G=2 Late GU AE | Odds Ratio for G=2 Late GU AE in High-Risk PROSTOXu [95% CI] | AUC |
| GARUDA | 37 (22.3%) | 16.9 [5.1, 56.4] | 0.70 |
| MIRAGE | 13 (25.5%) | 60.8 [6.2, 593] | 0.80 |
| NRG/RTOG 0938 | 18 (26.9%) | 29.25 [6.9, 125.0] | 0.82 |
| PACE-B | 53 (30.6%) | 19.51 [7.7, 49.7] | 0.74 |
| Pooled Cohort | 84 (28.9%) | 22.1 [11.7, 41.6] | 0.75 |