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)

Michael R. Harrison; Paul G. Davis; Michel G. Khouri; David B. Bartlett; Rajan T. Gupta; Andrew J. Armstrong; Megan A. McNamara; Tian Zhang; Monika Anand; Kelly Onyenwoke; Sara Edwardson; Danielle Craig; Meghan Michalski; Yuan Wu; Taofik Oyekunle; Brian Coyne; Aubrie Coburn; Lee W. Jones; Daniel J. George

doi:10.1038/s41391-022-00519-4

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)

Michael R. Harrison, Paul G. Davis, Michel G. Khouri, David B. Bartlett, Rajan T. Gupta, Andrew J. Armstrong, Megan A. McNamara, Tian Zhang, Monika Anand, Kelly Onyenwoke, Sara Edwardson, Danielle Craig, Meghan Michalski, Yuan Wu, Taofik Oyekunle, Brian Coyne, Aubrie Coburn, Lee W. Jones, Daniel J. George

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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

Original language	English (US)
Pages (from-to)	58-64
Number of pages	7
Journal	Prostate Cancer and Prostatic Diseases
Volume	25
Issue number	1
DOIs	https://doi.org/10.1038/s41391-022-00519-4
State	Published - Mar 2022
Externally published	Yes

ASJC Scopus subject areas

Oncology
Urology
Cancer Research

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Harrison, M. R., Davis, P. G., Khouri, M. G., Bartlett, D. B., Gupta, R. T., Armstrong, A. J., McNamara, M. A., Zhang, T., Anand, M., Onyenwoke, K., Edwardson, S., Craig, D., Michalski, M., Wu, Y., Oyekunle, T., Coyne, B., Coburn, A., Jones, L. W., & George, D. J. (2022). 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, 25(1), 58-64. https://doi.org/10.1038/s41391-022-00519-4

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). / Harrison, Michael R.; Davis, Paul G.; Khouri, Michel G. et al.
In: Prostate Cancer and Prostatic Diseases, Vol. 25, No. 1, 03.2022, p. 58-64.

Research output: Contribution to journal › Article › peer-review

Harrison, MR, Davis, PG, Khouri, MG, Bartlett, DB, Gupta, RT, Armstrong, AJ, McNamara, MA, Zhang, T, Anand, M, Onyenwoke, K, Edwardson, S, Craig, D, Michalski, M, Wu, Y, Oyekunle, T, Coyne, B, Coburn, A, Jones, LW & George, DJ 2022, '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, vol. 25, no. 1, pp. 58-64. https://doi.org/10.1038/s41391-022-00519-4

Harrison MR, Davis PG, Khouri MG, Bartlett DB, Gupta RT, Armstrong AJ 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 and Prostatic Diseases. 2022 Mar;25(1):58-64. doi: 10.1038/s41391-022-00519-4

Harrison, Michael R. ; Davis, Paul G. ; Khouri, Michel 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). In: Prostate Cancer and Prostatic Diseases. 2022 ; Vol. 25, No. 1. pp. 58-64.

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title = "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)",

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",

author = "Harrison, {Michael R.} and Davis, {Paul G.} and Khouri, {Michel G.} and Bartlett, {David B.} and Gupta, {Rajan T.} and Armstrong, {Andrew J.} and McNamara, {Megan A.} and Tian Zhang and Monika Anand and Kelly Onyenwoke and Sara Edwardson and Danielle Craig and Meghan Michalski and Yuan Wu and Taofik Oyekunle and Brian Coyne and Aubrie Coburn and Jones, {Lee W.} and George, {Daniel J.}",

note = "Funding Information: 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 Information: 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 Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

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month = mar,

doi = "10.1038/s41391-022-00519-4",

language = "English (US)",

volume = "25",

pages = "58--64",

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TY - JOUR

T1 - 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)

AU - Harrison, Michael R.

AU - Davis, Paul G.

AU - Khouri, Michel G.

AU - Bartlett, David B.

AU - Gupta, Rajan T.

AU - Armstrong, Andrew J.

AU - McNamara, Megan A.

AU - Zhang, Tian

AU - Anand, Monika

AU - Onyenwoke, Kelly

AU - Edwardson, Sara

AU - Craig, Danielle

AU - Michalski, Meghan

AU - Wu, Yuan

AU - Oyekunle, Taofik

AU - Coyne, Brian

AU - Coburn, Aubrie

AU - Jones, Lee W.

AU - George, Daniel J.

N1 - Funding Information: 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 Information: 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 Information: 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. Funding Information: 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. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2022/3

Y1 - 2022/3

N2 - 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

AB - 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

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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)

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