Development and validation of an AI-derived digital pathology-based biomarker to predict benefit of long-term androgen deprivation therapy with radiotherapy in men with localized high-risk prostate cancer across multiple phase III NRG/RTOG trials.
Bibliographic record
Abstract
5001 Background: Androgen deprivation therapy (ADT) improves survival and reduces risk of metastasis in men with high-risk localized prostate cancer (PC) receiving radiotherapy (RT). Predictive biomarkers are needed to guide ADT duration to maximize benefits and minimize risks. We sought to train and validate the first predictive biomarker for long-term (LT) vs short-term (ST) ADT using multiple phase III NRG Oncology randomized trials. Methods: Pre-treatment prostate biopsy slides were digitized from six phase III NRG/RTOG randomized trials of men receiving RT +/- ADT. The artificial intelligence (AI)-derived clinical and histopathological predictive biomarker was trained on RTOG 9408, 9413, 9902, 9910, and 0521 to predict differential benefit of LTADT on distant metastasis (DM). After the AI biomarker was locked, it was validated on RTOG 9202, which randomized men to RT + STADT (4 mo) vs LTADT (28 mo). The predictive utility of the AI biomarker was evaluated for the primary and secondary endpoints of DM and PC-specific mortality (PCSM), respectively, for ADT duration with Fine-Gray interaction models. Event rates were estimated by the cumulative incidence method. Deaths from other causes were treated as competing risks. Results: The AI-derived biomarker was trained on 2,641 men (median follow-up of 9.8 years, IQR [8.2, 11.5]) and validated on 1,192 men from RTOG 9202 (median follow-up of 17.2 years, IQR [9.1, 19.6]), where 80% had at least one high/very high (H/VH) risk feature (cT3-4, Gleason 8-10, PSA > 20, or primary Gleason pattern 5). Consistent with published results, LTADT significantly improved DM (subdistribution HR [sHR] 0.64, 95% CI 0.50-0.82, p < 0.001) in the validation cohort. The AI biomarker was prognostic for DM (sHR 2.35, 95% CI 1.72-3.19, p < 0.001). A significant biomarker-treatment interaction was observed (p = 0.04), in which AI-biomarker (+) men (n = 785, 66%) had reduced DM with LTADT (sHR 0.55, 95% CI 0.41-0.73, p < 0.001), but no benefit was observed (sHR 1.06, 95% CI 0.61-1.84, p = 0.84) for AI-biomarker (-) men (n = 407, 34%). The 10-year DM rate difference between RT + LTADT vs RT + STADT was 13% in AI-biomarker (+) men vs 2% in AI-biomarker (-) men. Similar trends were observed for PCSM outcomes. Risk classification (NCCN intermediate [n = 221, 43% (+)] vs other H/VH risk [n = 954, 71% (+)]) was prognostic but not predictive of LTADT benefit. Conclusions: We have successfully validated the first predictive biomarker of LTADT benefit with RT in localized high-risk PC using an AI-derived digital pathology-based platform in the phase III NRG/RTOG 9202 trial. The predictive AI biomarker identified 34% of men that could derive similar benefit with STADT, avoiding the side effects of prolonged ADT, and 43% of intermediate risk men who would benefit from LTADT.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.006 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".