James G. Kench

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 APIC-negative (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; 60-month 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.

Adverse event rates by APIC status in patients receiving enzalutamide versus NSAA

Clinical progression-free survival by treatment arm and APIC status

PSA progression-free survival by treatment arm and APIC status

Overall survival by treatment arm and APIC status

Multivariable Cox regression analysis of overall survival

Distribution of baseline serum PSA by APIC status

APIC and specimen type: score distribution and treatment outcomes within each specimen subgroup

Kaplan-Meier curves showing overall survival by APIC status within the enzalutamide and NSAA arms, stratified by early docetaxel use

Baseline cytokine fold differences by APIC status for different subgroups