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.

Nature medicine. 2022 Jan 10 [Epub ahead of print]

Thomas Powles, Kobe C Yuen, Silke Gillessen, Edward E Kadel, Dana Rathkopf, Nobuaki Matsubara, Charles G Drake, Karim Fizazi, Josep M Piulats, Piotr J Wysocki, Gary L Buchschacher, Boris Alekseev, Begoña Mellado, Bogusława Karaszewska, Jennifer F Doss, Grozdana Rasuo, Asim Datye, Sanjeev Mariathasan, Patrick Williams, Christopher J Sweeney

Barts Cancer Institute, Queen Mary University of London, London, UK. ., Genentech, Inc., South San Francisco, CA, USA., Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland., Memorial Sloan Kettering Cancer Center, New York, NY, USA., National Cancer Center Hospital East, Chiba, Japan., Columbia University Irving Medical Center, New York, NY, USA., Gustave Roussy, University of Paris Saclay, Villejuif, France., Institut Català d'Oncologia-IDIBELL-CIBERONC, Barcelona, Spain., Jagiellonian University Medical College, Krakow, Poland., Kaiser Permanente Southern California, Los Angeles Medical Center, Los Angeles, CA, USA., Research Oncology Institute, Tomsk, Russia., Medical Oncology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic i Provincial, Barcelona, University of Barcelona, Barcelona, Spain., Przychodnia Lekarska KOMED, Konin, Poland., F. Hoffmann-La Roche Ltd, Basel, Switzerland., Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. .

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