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.

Gov identifier: NCT02256111.

Conflict of interest statement

Competing Interests Statement: 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.

Conflict of Interest: 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.

© 2022. The Author(s), under exclusive licence to Springer Nature Limited.

Figures

Fig. 1 –. Cardiorespiratory fitness (VO2peak) and muscle strength (one-repetition maximum [1RM]) between usual care and exercise training groups.

(A) Absolute cardiorespiratory fitness; (B) relative cardiorespiratory fitness; (C) relative cardiorespiratory fitness adjusted for lean body mass (lbm); (D) maximal leg press strength; (E) maximal chest press strength; (F) maximal seated row strength. Data are mean and standard error. *Significant (p≤0.05) between-group mean change at Week 17 by ANCOVA (adjusted for baseline)

Fig. 2 –. Physical function and patient-reported outcomes between usual care and exercise training groups.

(A) Distance covered during 6-minute walk test; (B) timed-up-and-go test; (C) number of chair stands completed in 30 seconds; (D) fatigue score; (E) quality of life score; (F) physical activity score. Data are mean and standard error. *Significant (p≤0.05) mean between-group change at Week 17 by ANCOVA (adjusted for baseline)