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

Introduction: The incidence of metastatic prostate cancer (mPCa) is increasing despite a decrease in the prevalence of prostate cancer (PCa). Androgen deprivation therapy (ADT), the mainstay of systemic treatment for mPCa, is associated with numerous side effects, including a decline in muscle mass and physical function, which lead to the exacerbation of age-related frailty and sarcopenia. Exercise plays a key role in ameliorating or preventing the progression of ADT-related side effects and in 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 either an exercise or an 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 is 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, C-reactive protein (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 the proliferation of prostate cancer cells (LNCaP cells). Conclusion: This first-of-its-kind study targets a vulnerable, understudied population: frail men with mPCa. If successful, 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 III trials to confirm the findings and potentially establish exercise as a safe and necessary part of the standard of care for frail metastatic prostate cancer patients.