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A randomized controlled trial comparing changes in fitness with or without supervised exercise in patients initiated on enzalutamide and androgen deprivation therapy for non-metastatic castration-sensitive prostate cancer (EXTEND)

Prostate Cancer and Prostatic Diseases volume 25, pages 58–64 (2022)Cite this article

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Abstract

Background

Androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSI) are associated with deleterious physical effects, which exercise may mitigate; however, exercise has never been studied in patients initiating treatment with ADT and an ARSI. Our objective was to determine whether supervised exercise prior to and during initial therapy could mitigate adverse effects of ADT plus enzalutamide.

Methods

We conducted a single center trial in patients with recurrent prostate cancer treated with ADT and enzalutamide. We randomized 26 patients to 16 weeks of supervised exercise (aerobic and resistance), starting 4 weeks before initiation of ADT and enzalutamide, or usual care. The primary endpoint was change in peak oxygen uptake (VO2peak) as a measure of cardiorespiratory fitness (CRF). Secondary endpoints were functional capacity, maximal strength, body composition, patient-reported outcomes, safety, and feasibility. Analysis of covariance was used to compare outcomes for groups at Week 17 adjusted for baseline values.

Results

The usual care group (N = 13) showed declines from baseline to week 17 in both absolute CRF (−0.31 L/min, −10.9%; p < 0.01) and relative CRF (−3.2 mL/kg/min, −8.9%; p = 0.04); worse fatigue (p = 0.01); and worse quality of life (p = 0.01). At week 17, the exercise group (N = 13) demonstrated improved absolute CRF (between-group change +0.20 L/min, p = 0.05), leg strength (+48.6 kg, p < 0.01) and functional capacity (+21.0 m, p = 0.01) at week 17.

Conclusions

This is the first randomized controlled trial demonstrating a clinically significant decline in CRF in patients initiating ADT and enzalutamide. We show the effectiveness of short-term supervised exercise to mitigate declines in absolute CRF, and improve maximal leg strength and functional capacity.

ClinicalTrials.gov Identifier

NCT02256111

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Fig. 1: Cardiorespiratory fitness (VO2peak) and muscle strength (one-repetition maximum [1RM]) between usual care and exercise training groups.
Fig. 2: Physical function and patient-reported outcomes between usual care and exercise training groups.

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Acknowledgements

We would like to thank all of the exercise physiologists and research staff at Duke, UNCG, and MSKCC, and especially the patients and their families, for making this study possible. M. Harrison was supported by Duke Cancer Institute (DCI) P30 CA014236 grant and the DCI shared resources for biostatistics. The work was partially funded by Department of Defense grants W81XWH-13-PCRP-CCA, W81XWH-17-2-0021 and W81XWH-14-2-0179 (MRH, AJA, DJG; Duke).

Funding

Funding for the conduct of the trial and study drug (enzalutamide) were provided by Pfizer (formerly Medivation) and Astellas through an investigator-initiated research grant to Duke University.

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Authors and Affiliations

  1. Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University Medical Center, Durham, NC, USA

    Michael R. Harrison, Michel G. Khouri, David B. Bartlett, Rajan T. Gupta, Andrew J. Armstrong, Megan A. McNamara, Tian Zhang, Monika Anand, Kelly Onyenwoke, Yuan Wu, Taofik Oyekunle & Daniel J. George

  2. Department of Kinesiology, UNC-Greensboro, Greensboro, NC, USA

    Paul G. Davis

  3. Duke University Health System, Durham, NC, USA

    Sara Edwardson, Danielle Craig, Brian Coyne & Aubrie Coburn

  4. Memorial Sloan Kettering Cancer Center, New York City, NY, USA

    Meghan Michalski & Lee W. Jones

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Contributions

The authors listed have made substantial contributions to the intellectual content of the paper in the various sections described as follows: conception and design (MRH, LWJ, DJG); acquisition of data (MRH, PGD, MGK, RTG, AJA, MAM, TZ, MA, KO, SE, DC, AC, BC, DJG); analysis and interpretation of data (MRH, DBB, YW, TO, DJG); drafting of the manuscript (MRH); critical revision of the manuscript for important intellectual content (MRH, PGD, MGK, DBB, AJA, MAM, TZ, MA, KO, BC, AC, LWJ, DJG); statistical analysis (YW, TO); obtaining funding (MRH, LWJ, DJG); administrative, technical or material support (MA, MM, LJW), and supervision (MRH, DJG).

Corresponding author

Correspondence to Michael R. Harrison.

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Competing interests

MRH has received funding from the following: Astellas (PI), AstraZeneca (PI, Consultant), Bayer (PI), Bristol Myers Squibb (PI, Consultant), Clovis Oncology (PI), Exelixis (Speaker, PI, Advisory Board, Consultant), Fujifilm (Consultant), Genentech (PI), Merck (PI), Pfizer (PI, Advisory Board, Consultant), Seattle Genetics (PI, Advisory Board, Consultant). AJA has received funding from the following: - Dendreon Valeant Corp (PI, Consultant, Other), Astellas Pharma (PI, Consultant, Other), Clovis (Advisory Board, Consultant), AstraZeneca (PI, Advisory Board, Consultant), Janssen (PI, Consultant, Other), Bayer (PI, Consultant, Other), Merck (PI, Advisory Board, Consultant), BMS (PI, Advisory Board, Consultant), Amgen (PI), Pfizer (PI, Advisory Board, Consultant), Genentech/Roche (PI), Constellation (PI), Forma (PI, Consultant). TZ has received funding from the following: Novartis (PI), Merrimack (PI), AbbVie/Stemcentrx (PI), Merck (PI), Regeneron (PI), Mirati Therapeutics (PI), Exelixis (Advisory Board), Janssen (PI, Advisory Board), Pfizer (PI, Advisory Board, Consultant), QED Therapeutics (Advisory Board), BMS (Advisory Board), Dendreon (Advisory Board), OmniSeq (PI), Personal Genome Diagnostics (PI), Aravive (Consultant), Seattle Genetics (Advisory Board), Eisai (Advisory Board), MJH Associates (Consultant), Pacific Genuity (Consultant). DJG has received funding from the following: American Association for Cancer Research (Other), Astellas (PI, Advisory Board, Consultant), AstraZeneca (PI, Advisory Board, Consultant), Axess Oncology (Other), Bayer Pharmaceuticals (Speaker, Consultant, Other), BMS (Consultant, Research, Other - Steering Committee), Calithera (Research), Capio Biosciences (Advisory Board), Constellation Pharmaceuticals (Consultant), EMD Serono (Other - Honorarium), Exelixis, Inc (Research, Consultant, Speaker, Other - Honorarium, Travel Accommodations), Flatiron (Consultant), IDEO Oncology (Consultant), Ipsen (Other - Honorarium), Janssen Pharmaceuticals (Research, Consultant, Other - Independent Data Monitoring Committee), Merck Sharp & Dohme (Consultant), Michael J Hennessey Associates (Consultant, Other - Honorarium), Millennium Medical Publishing (Other - Co-Editor-in-Chief), Modra Pharmaceuticals B.V. (Advisory Board), Myovant Sciences, Inc (Consultant), NCI Genitourinary Steering Committee (Other - Member), Nektar Therapeutics (Other - Steering Committee), Novartis (Research), Physician Education Resource, LLC (Consultant), Pfizer (Research, Consultant, Other - Steering Committee, Honorarium), Propella TX (Consultant), RevHealth, LLC (Consultant), Sanofi (Research, Consultant, Speaker, Other - Honorarium, Travel Accommodations), UroGPO (Other - Honorarium), UroToday (Other - Honorarium, Travel Accommodations), Xcures (Consultant). PGD, MGK, DBB, RTG, MAM, MA, KO, SE, DC, MM, YW, TO, BC, AC, and LWJ declare no competing financial interests.

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Harrison, M.R., Davis, P.G., Khouri, M.G. et al. A randomized controlled trial comparing changes in fitness with or without supervised exercise in patients initiated on enzalutamide and androgen deprivation therapy for non-metastatic castration-sensitive prostate cancer (EXTEND). Prostate Cancer Prostatic Dis 25, 58–64 (2022). https://doi.org/10.1038/s41391-022-00519-4

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