AI-Based Pathology Classifier Predicts Sensitivity to Enzalutamide in Metastatic Hormone-Sensitive Prostate Cancer: A Biomarker Analysis of the ENZAMET Trial

Purpose: The ENZAMET trial established that enzalutamide added to androgen deprivation therapy (ADT) improves overall survival (OS) in metastatic hormone-sensitive prostate cancer (mHSPC), but treatment response is heterogeneous. We tested whether the artificial intelligence pathology image classifier (APIC), previously developed and locked in CHAARTED, predicts OS benefit from enzalutamide in ENZAMET. Experimental Design: This biomarker study applied APIC to digitized hematoxylin and eosin specimens from ENZAMET [Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) 1304, NCT02446405]. ENZAMET randomized participants with mHSPC to ADT plus enzalutamide or nonsteroidal antiandrogen (NSAA), with early concurrent docetaxel permitted. APIC was applied without modification or retraining. The prespecified primary analysis evaluated the treatment-by-APIC interaction for OS using Cox models adjusted for standard clinical factors. Prespecified sensitivity analysis excluded participants receiving early concurrent docetaxel. Results: Among 1,125 participants, 492 with digitized tissue (median follow-up, 68.8 months) were eligible. APIC classified 316 (64%) as APIC negative and 176 (36%) as APIC positive. APIC significantly modified enzalutamide benefit (interaction P = 0.014). APIC-negative disease showed improved survival with enzalutamide versus NSAA [HR, 0.50; 95% confidence interval (CI), 0.35–0.73; 60-month OS, 76.5% vs. 58.3%], whereas APIC-positive disease showed limited evidence of benefit (HR, 1.04; 95% CI, 0.67–1.62; 60-month OS, 55.6% vs. 58.8%). In low-volume disease, enzalutamide improved survival in APICnegative (HR, 0.31; 95% CI, 0.16–0.62) but not APIC-positive disease (HR, 1.04; 95% CI, 0.53–2.06; interaction P = 0.015). For non–docetaxel-treated participants, enzalutamide benefit was greater in APIC-negative (HR, 0.40; 60-month OS 82% vs. 61.0%) than in APIC-positive participants (HR, 0.79; 60month OS, 62.8% vs. 57.6%). Conclusions: The presence of APIC-negative disease identified participants with a major improvement in OS with the addition of enzalutamide to ADT compared with the addition of NSAA.