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

Abstract

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.

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Fig. 1: IMbassador250 CONSORT diagram.
Fig. 2: Clinical efficacy in the atezolizumab + enzalutamide versus enzalutamide treatment arms.
Fig. 3: Ad hoc analysis: comparison of DDR alterations, PTEN status and Teff.
Fig. 4: Ad hoc analysis: immune biomarker expression in kidney, bladder and prostate cancer.
Fig. 5: Preplanned biomarker analysis: PFS in the atezolizumab + enzalutamide versus enzalutamide treatment arms.

Data availability

Qualified researchers may request access to individual patient-level data through the clinical study data request platform (https://vivli.org/). Further details on Roche’s criteria for eligible studies are available at https://vivli.org/members/ourmembers/. For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm. IMbassador250 raw data analyzed in this study have been submitted to the European Genome-Phenome Archive (EGA) with accession no. EGAS00001004852. Raw RNA-seq data from IMmotion150 and IMvigor210 have been submitted to EGA with accession no. EGAS00001004386.

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Acknowledgements

The study was supported by F. Hoffmann-La Roche Ltd./Genentech, Inc., a member of the Roche Group. Disclosure forms, Methods and a data-sharing statement provided by the authors are available within the full text of this article at nature.com/nm. G.L.B. is partially funded by the Kaiser Permanente NCI National Community Oncology Research Program (grant no. SUG1CA189821-08). We thank the patients who participated in the trial and the clinical site investigators. Medical writing assistance for this manuscript was provided by P. Hong of Health Interactions, Inc. and was funded by F. Hoffmann-La Roche Ltd.

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Conceptualization was the responsibility of K.F., S.G., E.E.K., S.M., N.M., T.P., G.R., C.J.S. and P.W. Methodology was performed by A.D., S.M., N.M. and C.J.S. Validation was carried out by N.M. Formal analysis was conducted by A.D., P.W. and K.C.Y. Investigation was the responsibility of B.A., G.L.B., C.D., K.F., B.K., S.M., N.M., B.M., J.M.P., G.R., C.J.S. and P.J.W. Resources were acquired by B.A., G.L.B., K.F., N.M., J.M.P., G.R. and C.J.S. A.D., E.E.K., N.M., J.M.P., P.W. and K.C.Y. performed data curation. Writing, review and editing were done by B.A., G.L.B., A.D., J.F.D., C.D., K.F., S.G., E.E.K., B.K., S.M., N.M., B.M., J.M.P., T.P., G.R., D.R., C.J.S., P.W., P.J.W. and K.C.Y. Visualization was done by B.A., G.L.B., A.D., E.E.K., T.P., C.J.S. and K.C.Y. S.M., N.M., T.P., C.J.S. and P.W. carried out supervision. Project administration was done by S.M., N.M., T.P. and P.W. Funding acquisition was the responsibility of B.A. All authors were involved in further drafts of the manuscript and revised it critically for content. All authors gave final approval of the version to be published. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Corresponding authors

Correspondence to Thomas Powles or Christopher J. Sweeney.

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Competing interests

T.P. received honoraria from advisory/consultancy roles with AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono (EMD Serono), Astellas, Johnson & Johnson, Eisai and Roche; institutional research funding support from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Merck, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono (EMD Serono), Astellas and Johnson & Johnson; and travel, accommodation and expenses support from Roche, Pfizer, MSD, AstraZeneca and Ipsen. S.G. received honoraria from Janssen; advisory/consultancy fees to the institution from Active Biotech, Astellas Pharma, Bayer, Bristol Myers Squibb, Clovis Oncology, CureVac, Ferring, Innocrin, Janssen, Menarini Silicon Biosystems and Novartis; advisory/consultancy fees from Advanced Accelerator Applications, Amgen, MaxiVax, Orion Pharma, Roche and Sanofi; and travel, accommodations and expenses from Nektar and ProteoMediX. S.G. also holds a patent involving a method for biomarker (no. WO 3752009138392 A1). K.C.Y. is an employee of Genentech and has stock ownership of Roche. E.E.K. is an employee of Genentech and has stock ownership of Roche, Clinuvel, Epizyme, Mannkind and Merck. D.R. received advisory/consultancy fees from AstraZeneca, Bayer, Genentech and Janssen; and institutional research funding support from AstraZeneca, Celgene, Ferring, Genentech/Roche, Janssen, Medivation, Millennium, Novartis, Taiho Pharmaceutical, Takeda and TRACON. N.M. received advisory/consultancy fees from Janssen, MSD, Chugai and Sanofi; and institutional research funding support from Janssen, MSD, Chugai, Astellas, Eli Lilly, Taiho and Pfizer. C.D. received advisory/consultancy fees from AstraZeneca/MedImmune, Bristol Myers Squibb, Compugen, Janssen Oncology, Merck, Pfizer, Pierre Fabre, Potenza Therapeutics, Roche/Genentech and Tizona Therapeutics; received institutional research funding support from Bristol Myers Squibb; owns stock and other ownership interests in Compugen, Harpoon Therapeutics, Kleo Pharmaceuticals and Tizona Therapeutics; and received travel, accommodations and expenses support from AACR, ASCO, Merck Sharp & Dohme, Pfizer and Roche/Genentech. C.D. also licenses patents through the institution to Bristol Myers Squibb and Potenza Therapeutics. K.F. received honoraria from Astellas Pharma, Janssen and Sanofi; received advisory/consultancy fees from Amgen, Astellas Pharma, AstraZeneca, Bayer, CureVac, ESSA Pharma, Janssen Oncology, Orion Pharma, Roche/Genentech and Sanofi; and travel, accommodations and expenses support from Amgen and Janssen. J.M.P. received advisory/consultancy fees from Astellas Pharma, Bristol Myers Squibb, Clovis Oncology, Janssen Oncology, Merck Sharp & Dohme, Roche/Genentech and VCN Biosciences; research funding support from AstraZeneca/MedImmune, Bristol Myers Squibb, Incyte, Janssen Oncology, Merck Sharp & Dohme and Pfizer/EMD Serono; and travel, accommodations and expenses support from Bristol Myers Squibb, Janssen Oncology and Roche. P.J.W. received honoraria from advisory/consultancy roles with AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Immunicom, Janssen, MSD, Merck, Novartis, Pfizer, Pierre Fabre, Roche and Sanofi. G.L.B. declares no conflict of interest. B.A. received grants from P. Herzen Oncology Research Institute during the conduct of the study; grants from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Astellas, MSD, Eisai and Roche; personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Astellas, MSD, Sanofi, Ferring, Ipsen, Eisai and Roche; and nonfinancial support from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Astellas, MSD, Sanofi, Ferring and Roche. B.M. received advisory/consultancy fees to the institution from Amgen, Pfizer and Roche; advisory/consultancy fees from Astellas Pharma, AstraZeneca, Bayer, Janssen, Pfizer and Roche; research funding support from Bayer, Janssen and Roche; and travel, accommodations and expenses support from Janssen-Cilag and Roche. B.K. declares no conflict of interest. J.D. is an employee of Genentech and has stock ownership of Roche. G.R. is an employee of Roche and has stock ownership of Roche. A.D. is an employee of Roche and has stock ownership of Roche. S.M. is an employee of Genentech and has stock ownership of Roche. P.W. is an employee of Genentech and has stock ownership of Roche. C.J.S. received advisory/consultancy fees from Astellas, Pfizer, Janssen, Dendreon, Bayer, Genentech and Glaxo; and institutional research funding support from Astellas, Pfizer, Janssen, Dendreon, Bayer and Sanofi.

Additional information

Peer review information Nature Medicine thanks Lars Dyrskjøt and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Javier Carmona was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Forest plot of subgroup analysis.

(a) PFS and (b) rPFS in the intention-to-treat (ITT) population. P value and HR are from the unstratified Cox regression model. Prior local therapy included prior radical prostatectomy or radiotherapy. PD-L1–positive immune cells (IC) defined as: IC0, <1%; IC1/2/3, ≥1%; IC2/3, ≥5%.

Extended Data Fig. 2 Forest plot of known biomarkers in urothelial carcinoma, renal cell carcinoma and prostate cancer.

Biomarkers shown among urothelial carcinoma (IMvigor210), renal cell carcinoma (IMmotion150), and prostate cancer (IMbassador250) for PFS. DDR, DNA damage response; PD-L1, programmed death- ligand 1; PFS, progression-free survival; Teff, effector T cell, TMB, tumor mutational burden. Med refers to median PFS in months. HRs and CIs were calculated using Cox proportional hazards regression model, and P values were calculated using unstratified log-rank test without adjustment for multiplicity.

Extended Data Fig. 3 Exploratory analysis of DNA alterations in progression free survival.

PFS in the atezolizumab + enzalutamide vs enzalutamide treatment arms. 325 samples were included for analysis. DNA alteration biomarkers included Androgen Receptor (AR) amplification status, v-ets erythroblastosis virus E26 oncogene homolog (ERG) fusions, alterations of TP53, BRCA2, SPOP, CDK12 (at least a frameshift, nonsense or splice-site alteration) and ATM. In addition, frameshift mutation burden (FSB) was included. FSB was calculated by the number of frameshift mutations divided by length of genome examined. It was reported as the number of frameshift mutations per megabase (mut/Mb). The cutoff of FSB (8.7 mut/Mb) was previously established in prostate cancer. HRs and CIs were calculated using Cox proportional hazards regression model, and P values were calculated using log-rank test. MST refers to median survival time (PFS) in months.

Extended Data Fig. 4 Distribution of biomarkers and PD-L1 IC status.

Analysis of PTEN loss, Teff signature, DNA Damage Response (DDR) alterations and Androgen Receptor (AR) amplification status and PD-L1 IC status. IC0/1 were considered low IC whereas IC2/3 were considered high IC. Numbers on the bars indicate the number of patients being analysed.

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Powles, T., Yuen, K.C., Gillessen, S. et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med 28, 144–153 (2022). https://doi.org/10.1038/s41591-021-01600-6

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