IMbassador250

IMbassador250 enrolled 759 men with metastatic castration-resistant prostate cancer whose disease had progressed on abiraterone and randomised them open-label to atezolizumab with enzalutamide or enzalutamide alone. The primary endpoint of improved overall survival was not met in the unselected population: stratified hazard ratio 1.12 (95 percent confidence interval 0.91 to 1.37, p=0.28), with an acceptable safety profile.

The value of the trial is in its translational work, which is the best published account of why immunotherapy fails in prostate cancer. Archival tumour samples showed comparatively low expression of key immune biomarkers. DNA damage-response alterations, PTEN status and PD-L1 expression were similar between hormone-sensitive and castration-resistant tumours, so the disease does not become more immunogenic as it progresses.

In planned biomarker analysis, longer progression-free survival with atezolizumab was seen in men with high PD-L1 on immune cells (IC2/3), high CD8 expression and established immune gene signatures, and exploratory analysis linked progression-free survival to immune genes including CXCL9 and TAP1 and to PTEN alterations. The authors' conclusion is the honest one: the biology associated with checkpoint response is present in prostate cancer, in fewer men, and careful patient selection would be required for any of it to matter.

KEYNOTE-641 (pembrolizumab with enzalutamide, 1,244 men), KEYNOTE-921 (pembrolizumab with docetaxel, 1,030 men) and KEYNOTE-991 (pembrolizumab with enzalutamide and androgen deprivation in hormone-sensitive disease, 1,251 men) all reached the same conclusion afterwards.