Design of debunking the frailty-sarcopenia-ADT axis in metastatic prostate cancer with multicomponent exercise: the FIERCE Trial protocol

Rebekah L Wilson^1,2Anderson Vulczak^1,2,3Alicia K Morgans^1,2Mary Norris¹Jocelyn Greer¹Jennie Votta⁴Maria Vamvini⁴David Einstein^2,5Hajime Uno^1,2Michael Hayden Rosenthal^1,2,6Matthew G Vander Heiden^1,7Christina Dieli-Conwright^1,2*

• ¹Dana–Farber Cancer Institute, Boston, United States
• ²Harvard Medical School, Boston, Massachusetts, United States
• ³Department of Biomolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
• ⁴Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, United States
• ⁵Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States
• ⁶Department of Radiology, Brigham and Women’s Hospital, Boston,, United States
• ⁷Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States

Introduction: Metastatic prostate cancer (mPCa) incidence is growing despite a decrease in the prevalence of prostate cancer (PCa). Androgen deprivation therapy (ADT), the mainstay of systemic treatment for mPCa, is accompanied by numerous side effects including decline in muscle mass and physical function, leading to the exacerbation of age-related frailty and sarcopenia. Exercise plays a key role in ameliorating or preventing further deterioration of ADT-related side effects and improving muscle mass, fitness, and strength. However, exercise interventions in patients with mPCa have been understudied, with a lack of studies focusing on frailty and sarcopenia and the mechanisms by which exercise could address these issues. Purpose: Thus, we have designed the FIERCE Trial to assess the effects of a 16-week multicomponent exercise intervention, encompassing resistance and aerobic training on frailty and sarcopenic status and their potential mechanistic biomarkers, as well as on cancer cell proliferation (NCT06040125). Methods: The FIERCE trial is a prospective study aiming to recruit 80 pre-frail/frail men with mPCa receiving ADT who will be randomized to an exercise or attention control group. The 16-week exercise intervention will include thrice weekly clinic supervised, resistance exercise circuit training, and self-directed home-based aerobic exercise. The attention control group will receive a stretching program and will be offered the exercise program following the study period. The primary outcome will be frailty, measured by the Fried Frailty phenotype (i.e., muscle loss, exhaustion, physical activity, gait speed, and strength) and frailty associated biomarkers (IL-6, TNF-α, CRP). Secondary outcomes include sarcopenia, measured using dual energy x-ray absorptiometry scans and sarcopenia associated muscle biopsy-driven biomarkers (myokines and insulin pathway markers). An exploratory outcome will assess how exercising patient-derived plasma will affect proliferation of prostate cancer cells (LNCaP cells). Conclusions: This first of its kind study targets a vulnerable, understudied population, frail mPCa. If positive, our findings will establish the efficacy of a multicomponent exercise intervention on frailty and sarcopenic status providing the foundation for future larger phase-II and phase-III trials to confirm the findings and potentially establish exercise as a safe and necessary part of standard of care for frail metastatic prostate cancer patients.