Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial

Early clinical data indicate that some patients with castration-resistant prostate cancer may benefit from program death ligand-1 (PD-L1) inhibition, especially with enzalutamide. The IMbassador250 trial (no. NCT03016312) enrolled 759 men with metastatic castration-resistant prostate cancer whose disease progressed on abiraterone. The addition of atezolizumab to enzalutamide in an open-label randomized trial did not meet the primary endpoint of improved overall survival in unselected patients (stratified hazard ratio 1.12, 95% confidence interval (0.91, 1.37), P = 0.28), despite an acceptable safety profile. In archival tumor samples, prostate tumors showed comparatively low expression of key immune biomarkers. DNA damage-response alterations, phosphatase and tensin homolog status and PD-L1 expression levels were similar between hormone-sensitive and castration-resistant prostate cancers. In planned biomarker analysis, longer progression-free survival was seen with atezolizumab in patients with high PD-L1 IC2/3, CD8 expression and established immune gene signatures. Exploratory analysis linked progression-free survival in the atezolizumab arm with immune genes such as CXCL9 and TAP1, together with other potentially relevant biomarkers including phosphatase and tensin homolog alterations. Together these data indicate that the expected biology associated with response to immune checkpoint inhibitors is present in prostate cancer, albeit in fewer patients. Careful patient selection may be required for immune checkpoint inhibitors to identify subgroups of patients who may benefit from this treatment approach.