Background/Objectives: This study explored whether a multimodal artificial intelligence (MMAI) model integrating digitized histopathology and clinical features can identify prostate cancer patients who may benefit from neoadjuvant hormonal therapy (NHT) and whole-pelvic radiotherapy (WPRT). Methods: This secondary analysis of NRG/RTOG 9413 included NHT-treated patients with digitized biopsy slides and clinical data who were not part of the MMAI model optimization. A previously validated MMAI model estimated long-term risk, and Fine-Gray models evaluated interactions between MMAI-derived scores and the radiation field (WPRT vs. prostate-only RT [PORT]) for biochemical failure (BF), chosen over progression-free survival because of extended follow-up and distant metastasis (DM), with subgroup analyses by predefined MMAI strata. Results: Among 81 eligible patients, the MMAI-by-treatment interaction for BF did not confirm a differential effect (p = 0.30). Therefore, subgroup findings should be interpreted as descriptive and hypothesis-generating. Nevertheless, the magnitude effect of WPRT was numerically greater in the MMAI high-risk subgroup (5-yr: 41% vs. 79%; 10-yr: 47% vs. 79%; aHR 0.35 [0.14-0.86]) than in the low-intermediate group (5-yr: 18% vs. 33%; 10-yr: 44% vs. 57%; aHR 0.66 [0.29-1.48]). Conclusions: Although no statistically significant treatment-by-MMAI interaction was demonstrated, these findings are hypothesis-generating and support further investigation of MMAI approaches for guiding WPRT in NRG/RTOG 0534, 0924, GETUG-01, and POP-RT trials.
Cancers. 2026 Jun 18*** epublish ***
Mutlay Sayan, Huei-Chung Huang, Erin L Stewart, Timothy N Showalter, Adam P Dicker, George Daniel Grass, Elizabeth M Gore, Andrew Michael McDonald, J Daniel Pennington, Mark A Hallman, Igor J Barani, I-Chow Hsu, Michael Rooney, Stephanie L Pugh, Paul L Nguyen, Phuoc T Tran, Mack Roach Iii
Mass General Brigham and Dana-Farber Cancer Institute, Boston, MA 02115, USA., Artera, Los Altos, CA 94022, USA., Thomas Jefferson University, Philadelphia, PA 19107, USA., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA., Clement J Zablock VAMC and the Medical College of Wisconsin, Milwaukee, WI 53295, USA., University of Alabama at Birmingham, Birmingham, AL 35294, USA., Southeast Clinical Oncology Research Consortium NCORP, Winston Salem, NC 27103, USA., Fox Chase Cancer Center, Philadelphia, PA 19111, USA., St. Joseph's Hospital & Medical Center, Phoenix, AZ 85013, USA., The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., NRG Oncology Statistics and Data Management Center, Philadelphia, PA 19103, USA., UCSF Medical Center-Mount Zion, San Francisco, CA 94115, USA.