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Efficacy and Safety Results from a Phase 2, Randomized, Double-Blind Study of Enzalutamide Versus Placebo in Advanced Hepatocellular Carcinoma

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A Correction to this article was published on 27 February 2022

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Abstract

Background and Objective

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide. Despite recent advances, more effective therapeutic options for patients with advanced HCC are still required. The aim of this Phase 2, multicenter, multinational, randomized, double-blind, placebo-controlled study (NCT02528643) was to investigate the potential benefit of enzalutamide in the treatment of patients with advanced HCC.

Methods

Patients aged ≥ 18 years diagnosed with advanced HCC (Barcelona Clinic Liver Cancer stage B or C and Child-Pugh class A at screening who had progressed on, or were intolerant to, sorafenib or other anti-vascular endothelial growth factor therapies) were randomized 2:1 to receive either enzalutamide 160 mg daily or placebo. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and safety.

Results

In total, 165 patients were randomized to enzalutamide (n = 110) or placebo (n = 55). The hazard ratio (HR) (95% confidence interval [CI]) for OS was 1.15 (0.774–1.696) and median OS was 7.8 months and 7.7 months for enzalutamide and placebo, respectively. The HR (95% CI) for PFS was 1.04 (0.732–1.474) and median PFS was 2.2 months and 1.9 months for enzalutamide and placebo, respectively. The overall frequency of treatment-emergent adverse events (TEAEs) was broadly similar between the groups: 105 (98.1%) enzalutamide patients experienced ≥1 TEAEs compared with 49 (89.1%) placebo patients.

Conclusions

The results of this study indicate that enzalutamide does not provide a benefit in patients with advanced HCC. No unexpected safety findings were observed in the trial.

ClinicalTrials.gov identifier

NCT02528643.

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Acknowledgements

Medical writing and editorial assistance were provided by Caitlin Watson, PhD, and Rebecca Fletcher from Complete HealthVizion, funded by the study sponsors. A list of the study investigators and sub-investigators is provided in the supplementary material.

Author information

Author notes

  1. Bruno Daniele

    Present address: Oncology Unit, Ospedale del Mare, Naples, Italy

  2. Beatriz López

    Present address: Quantitative Sciences, Janssen R&D, Janssen Pharmaceutical Companies of Johnson & Johnson, Leiden, The Netherlands

Authors and Affiliations

  1. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

    Baek-Yeol Ryoo & Sook Ryun Park

  2. Liverpool CR UK/NIHR Experimental Cancer Medicine Centre, and The Clatterbridge Cancer Centre, Liverpool, UK

    Daniel H. Palmer

  3. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy

    Lorenza Rimassa

  4. Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

    Lorenza Rimassa

  5. School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK

    Debashis Sarker

  6. Department of Oncology, G. Rummo Hospital, Benevento, Italy

    Bruno Daniele

  7. Astellas Pharma Inc., Northbrook, IL, USA

    Joyce Steinberg

  8. Data Science, Astellas Pharma Inc., Leiden, The Netherlands

    Beatriz López

  9. Division of Hematology-OncologyDepartment of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

    Ho Yeong Lim

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Corresponding author

Correspondence to Baek-Yeol Ryoo.

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Author contributions

The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication; they take full responsibility for the scope, direction and content of the manuscript and have approved the submitted manuscript. The authors received no compensation related to the development of the manuscript. Study conception and design: B-YR, JS, and HYL. Material preparation, data collection and analysis: B-YR, DHP, SRP, LR, DS, BD, JS, BL, and HYL. Writing—original draft preparation: LR, JS, BL. Writing—review and editing: B-YR, DHP, SRP, LR, DS, BD, JS, BL, and HYL. Supervision: B-YR, JS.

Data availability

Researchers may request access to anonymized participant level data, trial level data and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com. For the Astellas criteria on data sharing see: https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx.

Funding

This study was funded by Astellas Pharma Inc. and Pfizer Inc., the co-developers of enzalutamide. The study sponsors were involved in the design and conduct of the study, the collection, management, analysis and interpretation of the data, and the review and approval of the manuscript.

Conflict of interest

B.-Y. Ryoo received grants from Astellas Pharma Inc. during the conduct of the study. D.H. Palmer received personal fees from Astellas Pharma Inc. during the conduct of the study; grants and personal fees from Bayer, NuCana, and Sirtex outside the submitted work; and personal fees from BMS, Celgene, Halozyme, and Targovax outside the submitted work. The institution of L. Rimassa received grants from Astellas Pharma Inc. during the conduct of the study; grants from Agios, ARMO Biosciences, AstraZeneca, Beigene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Services, Roche, and Zymeworks outside the submitted work; personal fees from AbbVie, Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Gilead, Hengrui Therapeutics, Incyte, Ipsen, IQVIA, Lilly, Merck Serono, MSD, Nerviano Medical Sciences, Roche, Sanofi and Zymeworks outside the submitted work; and non-financial support from Ipsen outside the submitted work. D. Sarker has received advisory board payments from Eisai, Ipsen, Novartis, and Surface Oncology outside the submitted work; honoraria from the speakers bureaus of AstraZeneca, Bayer, Eisai, Ipsen, MSD, and Pfizer outside the submitted work; and travel payments from Bayer, Eisai, and MiNA Therapeutics outside the submitted work. B. Daniele has received personal fees from Amgen, Astra Zeneca, Bayer, Ipsen, Lilly, MSD, Roche, and Sanofi outside the submitted work; and personal fees and payment for lectures from Eisai outside the submitted work. H.Y. Lim has received consulting fees or honorarium from AstraZeneca, Bayer, BMS, Eisai, and Ipsen outside the submitted work. J. Steinberg is an employee of Astellas Pharma Inc. and B. López was an employee of Astellas Pharma Inc. at the time of the study. S.R. Park reports no conflicts of interest.

Ethics approval

The study was performed in accordance with the Declaration of Helsinki and the International Conference on Harmonisation for Good Clinical Practice Guidelines. The trial protocol, patient information sheets, and consent forms were reviewed and approved by the independent ethics committee and/or institutional review board (IRB) of each participating institution. This study had 37 study sites and 27 approving IRBs; the full list of IRBs can be found in the supplementary material.

Informed consent

Informed consent was received from each patient prior to any study-related procedures.

Supplementary Information

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Ryoo, BY., Palmer, D.H., Park, S.R. et al. Efficacy and Safety Results from a Phase 2, Randomized, Double-Blind Study of Enzalutamide Versus Placebo in Advanced Hepatocellular Carcinoma. Clin Drug Investig 41, 795–808 (2021). https://doi.org/10.1007/s40261-021-01063-0

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