In the phase III IMbassador 250 study, a combination of an immune checkpoint inhibitor (ICI) atezolizumab with a second-generation oral androgen receptor (AR) antagonist enzalutamide did not improve survival (OS) over enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease progressed on abiraterone. However, translational study uncovered genomic and immune biomarkers that may identify patients deriving benefit. The findings are published by Prof. Thomas Powles of the Barts Cancer Institute, Queen Mary University of London in London, UK and colleagues on 10 January 2022 in the Nature Medicine.
Enzalutamide significantly prolongs survival and improves quality-of-life outcomes in patients with mCRPC before and after chemotherapy. However, patients inevitably acquire resistance to enzalutamide over the course of treatment. In addition to its effect on the AR pathway, enzalutamide has direct immunomodulatory effects.
Single-agent ICIs have shown mixed results in prostate cancer, probably due to prostate cancer having features typical of immunologically ‘cold’ tumours. Investigations are under way to evaluate ICI in combination with other agents to overcome the barriers to their activity in these patients. Early clinical data indicate that some patients with CRPC may benefit from PD-L1 inhibition, especially with enzalutamide.
The phase III IMbassador250 study examined the efficacy and safety of atezolizumab and enzalutamide versus enzalutamide alone in men with mCRPC previously treated with abiraterone. The study had a primary endpoint of OS while also providing the opportunity to explore the immunobiology of prostate cancer. In the Nature Medicine paper, the study team reported the primary efficacy and safety results from IMbassador250, as well as an analysis of the immunobiology of prostate cancer.
The IMbassador250 study enrolled 759 men with mCRPC whose disease progressed on abiraterone. Addition of atezolizumab to enzalutamide in this open-label randomised study did not meet the primary endpoint of improved OS in unselected patients with stratified hazard ratio 1.12 (95% confidence interval 0.91, 1.37; p = 0.28), despite an acceptable safety profile.
Secondary endpoints, including radiographic progression-free survival (PFS), time to PSA progression, overall response rate and duration of response, also failed to show a benefit for the treatment combination versus enzalutamide alone.
A key aspect of this study was the exploration of potential biomarkers. In archival tumour samples, prostate tumours showed comparatively low expression of key immune biomarkers. DNA damage-response alterations, PTEN status and PD-L1 expression levels were similar between hormone-sensitive and castration-resistant tumours.
In planned biomarker analysis, longer PFS was seen with atezolizumab in patients with high PD-L1 IC2/3, CD8 expression and established immune gene signatures. Exploratory analysis linked PFS in the atezolizumab arm with immune genes such as CXCL9 and TAP1, together with other potentially relevant biomarkers including PTEN alterations.
Together these data indicate that the expected biology associated with response to ICI is present in prostate cancer, although in fewer patients. Overall, a key strength of this phase III randomised controlled study was the high rate of tumour sample acquisition. Additionally, the unbiased gene sequencing approach allowed for extensive biomarker analysis. However, the biomarker work is limited by the small size of some of the resulting biomarker subpopulations.
The authors concluded that the study findings indicate that there is no role for atezolizumab in combination with enzalutamide in unselected patients with CRPC and suggested that patient selection may be essential for future drug development. Studies similar to IMbassador250, with other ICIs alone, are ongoing.
The study was supported by F. Hoffmann-La Roche Ltd./Genentech, Inc., a member of the Roche Group.
Powles T, Yuen KC, Gillessen S, et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nature Medicine; Published online 10 January 2022. DOI: https://doi.org/10.1038/s41591-021-01600-6