Background and Objective. Positive predictive value of PI-RADS for clinically significant prostate cancer (csPCa, grade group [GG]≥2) varies widely between institutions and radiologists. The Restriction Spectrum Imaging restriction score (RSIrs) is a metric derived from diffusion MRI that could be an objectively interpretable biomarker for csPCa. Methods. In patients scanned for suspected or known csPCa at 7 centers, we calculated patient-level csPCa probability based on maximum RSIrs in the prostate, without relying on subjectively defined lesions. We used area under the ROC curve (AUC) to compare patient-level csPCa detection for RSIrs, ADC, and PI-RADS. Finally, we combined RSIrs with clinical risk factors via multivariable regression, training in a single-center cohort and testing in an independent, multi-center dataset. Key Findings and Limitations. Among all patients (n=1892), probability of csPCa increased with higher RSIrs. GG≥4 csPCa was most common in patients with very high RSIrs. Among biopsy-naive patients (n=877), AUCs for GG≥2 vs. non-csPCa were 0.73 (0.69-0.76), 0.54 (0.50-0.57), and 0.75 (0.71-0.78) for RSIrs, ADC, and PI-RADS, respectively. RSIrs significantly outperformed ADC (p<0.01) and was comparable to PI-RADS (p=0.31). The combination of RSIrs and PI-RADS outperformed either alone. Combining RSIrs with PI-RADS, age, and PSA density in a multivariable model achieved the best discrimination of csPCa. Conclusions and Clinical Implications. RSIrs is an accurate and reliable quantitative biomarker that performs better than conventional ADC and comparably to expert-defined PI-RADS for patient-level detection of csPCa. RSIrs provides objective estimates of probability of csPCa that do not require radiology expertise.

Tyler M. Seibert. reports honoraria from CorTechs Labs, Varian Medical Systems, WebMD, GE Healthcare, and Janssen; has an equity interest in CorTechs Labs, Inc, and serves on its scientific advisory board; and has received in-kind research support from GE Healthcare via a research agreement with the University of California, San Diego. These companies might potentially benefit from the research results. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. Michael E. Hahn reports honoraria from Multimodal Imaging Services Corporation and research funding from GE Healthcare. Anders M. Dale. is a founder of and holds equity in CorTechs Labs, Inc, and serves on its scientific advisory board; he also is a member of the scientific advisory board of Human Longevity, Inc, and receives funding through research agreements with GE Healthcare. Rebecca Rakow-Penner Human Longevity Inc: Consultant Cortech Labs: Stock options Curemetrix: Stock options, consultant Imagine Scientific, advisory board. SBIR GE Healthcare, research agreement Bayer consultant Michael Liss Founder/President of Oncobiomix with no relation to this manuscript. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA279667. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Sean Woolen Research grants paid to institution from Siemens Healthineers and General Electric

This work was supported, in part, by the National Institutes of Health (NIH/NIBIB K08EB026503, NIH UL1TR000100), the American Society for Radiation Oncology, the Prostate Cancer Foundation (PCF20YOUN01), and the U.S. Department of Defense (DOD/CDMRP PC220278).

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