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Efficacy of enzalutamide in subgroups of men with metastatic hormone-sensitive prostate cancer based on prior therapy, disease volume, and risk

Prostate Cancer and Prostatic Diseases volume 25, pages 274–282 (2022)Cite this article

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Abstract

Background

While enzalutamide plus androgen deprivation therapy (ADT) significantly reduces the risk of radiographic progression-free survival (rPFS) and improves overall survival in metastatic hormone-sensitive prostate cancer (mHSPC), the efficacy in clinically relevant subgroups of patients based on prior local and systemic therapy, disease volume, and risk has not been analyzed to date. These post hoc analyses of the phase 3 ARCHES trial (NCT02677896) evaluated the efficacy of enzalutamide plus ADT according to prior local and systemic treatment, disease volume, and risk, assessed at trial baseline.

Methods

In ARCHES, a global, double-blind, placebo-controlled, phase 3 study, 1150 patients with mHSPC were randomized 1:1 to receive enzalutamide (160 mg/day) plus ADT or placebo plus ADT, stratified by prior docetaxel therapy and disease volume. Primary endpoint was rPFS. Secondary endpoints included time to prostate-specific antigen progression, symptomatic skeletal events, and prostate-specific antigen and radiographic responses. Analyses of clinical endpoints were completed by prior local therapy, prior docetaxel exposure, CHAARTED (NCT00309985)-defined disease volume, and LATITUDE (NCT01715285)-defined risk groups.

Results

Patients were randomized to enzalutamide plus ADT (n = 574) and placebo plus ADT (n = 576). Enzalutamide plus ADT significantly improved rPFS (hazard ratio: 0.39; p < 0.0001), with similar improvements reported in all subgroups based on prior local and docetaxel treatment, disease volume, and risk. Treatment benefits were observed with enzalutamide plus ADT in multiple secondary clinical endpoints in the overall population and all subgroups.

Conclusions

Enzalutamide plus ADT demonstrated clinical benefit across all patients with mHSPC, irrespective of prior local and systemic treatment, disease volume, and risk.

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Fig. 1: rPFSa according to prior treatmentb, disease volume, or risk subgroups.
Fig. 2: Kaplan–Meier curve of rPFS in ARCHES in patient subgroups defined by prior local therapy and prior docetaxel treatment.
Fig. 3: Subgroup treatment effects for clinical secondary endpoints according to prior treatmenta.
Fig. 4: PSA undetectable rate and ORR per RECIST version 1.1, according to patient subgroups.

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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. All authors had full access to all data and the corresponding author had final responsibility for the decision to submit for publication.

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Acknowledgements

Medical writing and editorial assistance was provided by Beatrice Vetter-Ceriotti, PhD, Folabomi Oladosu, PhD, and Lauren Smith from Complete HealthVizion, funded by the study sponsors. The authors developed the analysis plan and all stages of the manuscript in collaboration with Astellas and Pfizer.

Funding

The study was funded by Astellas Pharma Inc. and Pfizer Inc., the codevelopers of enzalutamide. The sponsors had a role in study design, data analysis and interpretation, and writing of the report.

Author information

Author notes

  1. Arun A. Azad

    Present address: Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

  2. These authors contributed equally: Arun A. Azad, Andrew J. Armstrong.

Authors and Affiliations

  1. Monash Health, Melbourne, VIC, Australia

    Arun A. Azad

  2. Duke Cancer Institute Center for Prostate & Urologic Cancers, Durham, NC, USA

    Andrew J. Armstrong

  3. Hospital Clinic de Barcelona, Barcelona, Spain

    Antonio Alcaraz

  4. The University of Chicago, Chicago, IL, USA

    Russell Z. Szmulewitz

  5. Yale Cancer Center, New Haven, CT, USA

    Daniel P. Petrylak

  6. The University of Kansas Medical Center, Kansas City, KS, USA

    Jeffrey Holzbeierlein

  7. Lille University, Lille, France

    Arnauld Villers

  8. Hertzen Moscow Cancer Research Institute, Moscow, Russia

    Boris Alekseev

  9. Osaka City University Graduate School of Medicine, Osaka, Japan

    Taro Iguchi

  10. Carolina Urologic Research Center, Myrtle Beach, SC, USA

    Neal D. Shore

  11. University Hospital, GITUR-IBSAL, University of Salamanca, Salamanca, Spain

    Francisco Gomez-Veiga

  12. Pfizer Inc., San Diego, CA, USA

    Brad Rosbrook

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

    Ho-Jin Lee & Gabriel P. Haas

  14. Eberhard Karls University of Tübingen, Tübingen, Germany

    Arnulf Stenzl

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Contributions

AJA had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: AJA, BA, TI, BR, H-JL, GPH, and AS. Acquisition of data: AAA, AJA, AA, RZS, DPP, JH, AV, BA, TI, NDS, FG-V, and AS. Analysis and interpretation of data: AAA, AJA, AA, RZS, DPP, JH, AV, BA, TI, NDS, FG-V, AS, BR, H-JL, GPH, and AS. Drafting of the manuscript: AAA, AJA, AA, RZS, DPP, JH, AV, BA, TI, NDS, FG-V, AS, BR, H-JL, GPH, and AS. Critical revision of the manuscript for important intellectual content: AAA, AJA, AA, RZS, DPP, JH, AV, BA, TI, NDS, FG-V, AS, BR, H-JL, GPH, and AS. Statistical analysis: H-JL. Administrative, technical, or material support: GPH.

Corresponding author

Correspondence to Andrew J. Armstrong.

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Competing interests

AAA has served in a consultant/advisory role for Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, MSD, Novartis, Noxopharm, Pfizer, Sanofi, Telix Pharmaceuticals, and Tolmar and on speakers’ bureaus for Astellas, Amgen, Bayer, Ipsen, Janssen, Merck Serono, Novartis, Pfizer, and Sanofi and has received investigator or institutional funding from Aptevo Therapeutics, Astellas, AstraZeneca, Bionomics, Bristol Myers Squibb, GlaxoSmithKline, Ipsen, Novartis, MedImmune, Merck Serono, Pfizer, Sanofi Aventis, and SYNthorx and travel accommodation/expenses from Amgen, Astellas, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar. AJA has served in a consultant/advisory role for Astellas, AstraZeneca, Bayer, Clovis, Dendreon, Janssen, Medivation, Merck, Novartis, Pfizer, and Sanofi and on speakers’ bureau for Bayer and Dendreon and has received research funding from Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Constellation, Dendreon, Janssen, Medivation, Merck, Novartis, Pfizer, Roche/Genentech, and Sanofi, honoraria from Dendreon, Janssen, and Sanofi, and travel accommodation/expenses from Astellas, Bayer, Dendreon, and Janssen. AA has received travel/accommodation/expenses from Astellas, Bayer, Ipsen, Janssen, and Olympus. RZS has served in a consultant/advisory role for AstraZeneca, AbbVie, Amgen, Astellas, Exelixis, Janssen Oncology, Merck, Sanofi, and Pfizer, has received research funding from Astellas, AbbVie, Incyte, Janssen Oncology, and Macrogenics, honoraria from Astellas, and travel accommodation/expenses from Corcept Therapeutics, and is the coinventor to Corcept Therapeutics patent licensed by The University of Chicago for combination AR/GR inhibition in prostate cancer. DPP has served in a consultant/advisory role for Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Exelixis, Incyte, Janssen, Lilly, Mirati, Monopteros, Pfizer, Pharmacyclics, Roche, Seattle Genetics, and Urogen, has received research funding from Ada Cap (Advanced Accelerator Applications), Agensys Inc, Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Eisai, Endocyte, Genentech, Innocrin, Lilly, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics, Replimune, Roche, Sanofi Aventis, and Seattle Genetics, and had stock ownership in Bellicum Pharmaceuticals (sold July 2020) and Tyme (sold October 2019). JH has received research funding from Astellas and has been an investigator for MDxHealth. AV has received research funding from Astellas and Ipsen and personal fees from Astellas. BA has served in a consultant/advisory role for Astellas, AstraZeneca, Bayer, BMS, Eisai, Ferring, Janssen, MSD, Pfizer, Roche, and Sanofi and on speakers’ bureau for Astellas, AstraZeneca, Bayer, BMS, Eisai, Ferring, Janssen, MSD, Pfizer, Roche, and Sanofi and has received research funding from Astellas, AstraZeneca, Bayer, BMS, Eisai, Ferring, Janssen, MSD, Pfizer, Roche, and Sanofi and travel accommodation/expenses from Astellas, AstraZeneca, Bayer, BMS, Eisai, Ferring, Janssen, MSD, Pfizer, Roche, and Sanofi. TI has served in a consultant/advisory role for Astellas, Bayer, and Janssen and on speakers’ bureau for Astellas, Bayer, Janssen, and Sanofi and has received research funding from Astellas and Bayer. NDS has served in a consultant/advisory role for Amgen, Astellas, AstraZeneca, Bayer, Dendreon, Ferring, Genentech/Roche, Janssen Scientific Affairs, Medivation, Myovant Sciences, Pfizer, and Tolmar and on speakers’ bureau for Bayer, Dendreon, and Janssen and has received research funding from Amgen, Astellas, AstraZeneca, Bayer, Dendreon, Ferring, Genentech/Roche, Janssen Scientific Affairs, Medivation, Myovant Sciences, Pfizer, and Tolmar and travel accommodation/expenses from Amgen, Astellas, AstraZeneca, Bayer, Dendreon, Ferring, Genentech/Roche, Janssen Scientific Affairs, Medivation, Myovant Sciences, Pfizer, and Tolmar. FG-V has served in a consultant/advisory role for AbbVie, Astellas, AstraZeneca, Bayer, Ferring, GE Healthcare, GlaxoSmithKline, Ipsen, Janssen, and Sanofi and has received honoraria from AbbVie, Astellas, AstraZeneca, Bayer, Ferring, GE Healthcare, GlaxoSmithKline, Ipsen, Janssen, and Sanofi and research funding from AbbVie, Astellas, and AstraZeneca. BR is an employee and has stock ownership in Pfizer. H-JL and GPH are employees of Astellas. AS has served in a consultant/advisory role for Alere, Astellas, Bristol Myers Squibb, Ferring, Ipsen Pharma, Janssen, Roche, Stebatiotechnology, and Synergo, as an investigator for Amgen, Astellas, AstraZeneca, Cepheid, CureVac, GeneDX Bioscience, Immatics, Janssen, Johnson & Johnson, Karl Storz AG, Medivation, Novartis, and Roche, and on speakers’ bureau for Astellas, CureVac, Ipsen Pharma, Janssen, and Sanofi Aventis, has received travel accommodation/expenses from CureVac, Ferring, Ipsen Pharma, Janssen, and Sanofi Aventis, has provided expert testimony for GBA, and has patents pending—A290/99, AT00/0001:C-Trap, and 2018/6579.

Ethics approval and consent to participate

The study protocol was approved by local independent review boards and conducted according to provisions of the Declaration of Helsinki and Good Clinical Practice Guidelines of the International Conference on Harmonisation. All patients provided written informed consent. An independent data safety monitoring board evaluated unblinded safety data on an ongoing basis.

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Azad, A.A., Armstrong, A.J., Alcaraz, A. et al. Efficacy of enzalutamide in subgroups of men with metastatic hormone-sensitive prostate cancer based on prior therapy, disease volume, and risk. Prostate Cancer Prostatic Dis 25, 274–282 (2022). https://doi.org/10.1038/s41391-021-00436-y

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