Development and Validation of an Artificial Intelligence Digital Pathology Biomarker to Predict Benefit of Long-Term Hormonal Therapy and Radiotherapy in Men With High-Risk Prostate Cancer Across Multiple Phase III Trials
- PMID: 40239134
- PMCID: PMC12228211
- DOI: 10.1200/JCO.24.00365
Development and Validation of an Artificial Intelligence Digital Pathology Biomarker to Predict Benefit of Long-Term Hormonal Therapy and Radiotherapy in Men With High-Risk Prostate Cancer Across Multiple Phase III Trials
Abstract
Purpose: Long-term androgen deprivation therapy (ADT) improves survival in men with high-risk localized prostate cancer (PCa) receiving radiotherapy (RT). Predictive biomarkers are needed to guide ADT duration.
Methods: A multimodal artificial intelligence (MMAI)-derived predictive biomarker was trained for long-term (LT) versus short-term (ST) ADT using pretreatment digital prostate biopsy images and clinical data (age, prostate-specific antigen, Gleason, and T stage) from six NRG Oncology phase III randomized radiotherapy trials. The novel MMAI-derived biomarker was developed to predict the differential benefit of LT-ADT on the primary end point, distant metastasis (DM). MMAI predictive utility was validated on a seventh randomized trial, RTOG 9202 (N = 1,192), which randomly assigned men to RT + ST-ADT (4 months) versus RT + LT-ADT (28 months). Fine-Gray and cumulative incidence analyses for DM, and secondarily, death with DM, were performed. Deaths without DM were treated as competing risks.
Results: In the validation cohort (median follow-up, 17.2 years), LT-ADT significantly improved DM from 26% to 17% (subdistribution hazard ratio [sHR], 0.64 [95% CI, 0.50 to 0.82], P < .001). A significant biomarker-treatment predictive interaction was observed (P = .04) for DM, whereby MMAI biomarker-positive men (n = 785, 66%) had reduced DM with LT-ADT versus ST-ADT (sHR, 0.55 [95% CI, 0.41 to 0.73], P < .001), whereas no treatment benefit was observed for MMAI biomarker-negative men (n = 407; sHR, 1.06 [95% CI, 0.61 to 1.84], P = .84). The estimated 15-year DM risk difference between RT + LT-ADT and RT + ST-ADT was 14% in MMAI biomarker-positive men and 0% in MMAI biomarker-negative men. The MMAI biomarker was also prognostic for DM, irrespective of treatment (sHR, 2.35 [95% CI, 1.72 to 3.19], P < .001).
Conclusion: To our knowledge, the MMAI model is the first validated predictive biomarker to guide ADT duration with RT in localized/locally advanced PCa. Approximately one third of men with high-risk PCa could safely be spared the additional 24 months of ADT and the associated morbidity.
Conflict of interest statement
Conflicts of Interest
Drs Augspurger, Carson, El-Gayed, Gore, Lee, Mohamad, Monson, Morgan, Peters, and Mr. Rodgers have nothing to disclose.
Dr. Armstrong received research funding from Dendreon, Bayer, Pfizer, Novartis, Janssen Oncology, Astellas Pharma, Gilead Sciences, Roche/Genentech, Bristol-Myers Squibb, Constellation Pharmaceuticals, Merck, AstraZeneca, BeiGene, Amgen, and Forma Therapeutics; consulting fees from Bayer, Dendreon, Pfizer, Astellas, AstraZeneca, Merck, Bristol-Myers Squibb, Janssen, FORMA Therapeutics, Novartis, Exelixis, Myovant Sciences, and GoodRx; travel support from Astellas; has patents for circulating tumor cell novel capture technology.
Dr Chen declares support for the present manuscript from Artera, Inc as an employee of Artera.
Ms DeVries declares support for the present manuscript from NCI Grant U24CA196067 to NRG Oncology/UCSF supporting the Biospecimen Bank.
Dr Esteva declares support for the present manuscript from Artera, Inc as an employee of Artera, Inc., declares in the last 36 months support for attending meetings and/or travel, patents planned, issued or pending, participation on a data safety monitoring board or advisory board, leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, stock or stock options and other financial or non-financial interests from Artera, Inc.
Dr Feng declares in the last 36 months consulting fees from Medicine, Exact Sciences, Bristol-Myers Squibb, Varian Medical Systems (termed), Novartis, Roivant (termed), Myovant Sciences (termed), Bayer, BlueStar Genomics, Artera, Tempus, Genentech (termed), and stock or stock options from Artera, Inc, BlueStar Genomics, SerImmune.
Dr Griffin declares support for the present manuscript from Artera, Inc as an employee of Artera, Inc., declares in the last 36 months support for attending meetings and/or travel, patents planned, issued or pending and stock or stock options from Artera, Inc.
Dr Huang declares support for the present manuscript from Artera, Inc as an employee of Artera.
Mr Liu declares support for the present manuscript from Artera, Inc as an employee of Artera, Inc., declares in the last 36 months stock or stock options from Artera, Inc.
Dr McKay declares in the last 36 months consulting fees from AstraZeneca, Aveo, Bayer, Blue Earth Diagnostics, Bristol-Myers Squibb, Calithera, Caris, Dendreon, Eisai, Exelixis, Johnson & Johnson, Lilly, Merck, Myovant, Novartis, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics, Telix, Tempus, institutional research support from Artera AI, AstraZeneca, Bayer, Not related to this work Bristol-Myers Squibb, Exelixis, Oncternal, Tempus.
Dr Nguyen declares in the last 36 months grants or contracts from Bayer, Janssen, Astellas, consulting fees from Boston Scientific, Bayer, Janssen, Novartis, Blue Earth, Myovant, Nanocan, and stock or stock options from Reversal Therapeutics, Stratagen Bio Nanocan.
Dr Sandler declares in the last 36 months leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid as a member of the ASTRO board of directors.
Dr Sartor declares in the last 36 months grants or contracts from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, InVitae, Janssen, Lantheus, Merck, Progenics, and Sanofi, consulting or advisory role for AAA, AstraZeneca, Bayer, Blue Earth Diagnostics, Clarity Pharmaceuticals, Fusion, Isotopen Technologien Muenchen, Janssen, Myovant, Myriad, Noria Therapeutics, Novartis, NorthStar, POINT Biopharma, Pfizer, Sanofi, Tenebio, and Telix, support for attending meetings and/or travel from Lantheus, Novartis, and NorthStar, participation on a data safety monitoring board or advisory board at AstraZeneca, Merck and Pfizer, stock or stock options with AbVie, Cardinal Health, Clarity Pharmaceuticals, Convergent, Eli Lilly, Fusion Pharmaceuticals, Point Biopharma, Ratio, Pfizer, Telix, and United Health Group.
Mr Selvaraju declares support for the present manuscript from Artera, Inc as an employee of Artera, Inc., declares in the last 36 months stock or stock options from Artera, Inc.
Dr Simko declares support for the present manuscript from NCI Grant U24CA196067 to NRG Oncology/UCSF supporting the Biospecimen Bank, declares in the last 36 months stock with Alpenglow biosciences, Inc. Protean biosciences, inc. Triopsy Medical Inc.
Dr Spratt declares in the last 36 months consulting fees from Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen, Elekta, Varian, Novartis, Pfizer.
Dr Tran declares in the last 36 months grants or contracts from NIH/NCI U01CA212007, U01CA231776, R01CA271540 and U54CA273956 and DoD W81XWH-21–1-0296, royalties or licenses from patent “Compounds and Methods of Use in Ablative Radiotherapy” (patent#: 9114158) licensed with royalties from Natsar Pharmaceuticals, consulting fees from RefleXion Medical, Natsar Pharmaceuticals, Bayer Healthcare, Janssen, Lantheus, Pfizer and Regeneron, support from attending meetings and/or travel from RefleXion Medical, Natsar Pharmaceuticals, Bayer Healthcare, Janssen, Lantheus, Pfizer and Regeneron, leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid with NRG Oncology, ASTRO and AACR.
Dr Yamashita declares support for the present manuscript from Artera, Inc as an employee of Artera, Inc., declares in the last 36 months stock or stock options from Artera, Inc.
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