Prostate cancer is the second leading cause of death from cancer in men. Prostate cancer can lead to decreased muscle mass, impaired physical function, fatigue, and worse quality of life, which is particularly problematic for older patients. Most prostate cancers can be treated with combinations of chemotherapy drugs and androgen deprivation therapy (ADT) that blocks the hormones that fuel cancer growth. While treatment outcomes are quite good for early-stage disease, therapies can have negative side effects on patients. In particular, androgen deprivation therapies can exacerbate the loss of muscle mass and decrease quality of life for prostate cancer patients. Newer therapies that target androgens more aggressively could worsen these side effects. In a recent study, Dr. Jose Garcia at the University of Washington and the Veterans Affairs Puget Sound Health Care System sought to characterize the underlying factors that drive the decrease in muscle mass and physical function for prostate cancer patients.
Researchers have long been interested in understanding how to support physical function for cancer patients, but previous interventions have proven unsuccessful. “Prior trials of muscle wasting in cancer showed you can build muscle mass without improving how someone functions day to day. That disconnect is a real barrier to developing effective treatments, and it hadn't been examined in men on ADT. We wanted to understand what's driving how a patient feels and functions, not just what shows up on a scan,” says Garcia. Most of the work in the field has assumed that muscle mass is the most important factor for a patient’s quality of life. Garcia and his team challenged this paradigm by examining another critical driver of frailty and muscle dysfunction: mitochondrial function.
To start, the researchers enrolled study participants with prostate cancer prior to beginning ADT. They measured physical function and patient-reported well-being before beginning ADT, after 3 months of ADT, and after 6 months of ADT. They analyzed physical function in their participants by testing their strength and endurance at each timepoint. To assess strength, they measured stair climb power and grip strength. To assess endurance, they measured the six-minute walk distance and maximal oxygen uptake. Alongside these tests, each participant completed a questionnaire to assess well-being at each appointment. They also took muscle biopsies from patients at baseline and after 6 months of treatment to measure mitochondrial function. This approach allowed them to tease apart the impacts of muscle mass and mitochondrial function on patient well-being and symptom burden.
Garcia and his team found that greater endurance measured by the six-minute walk test and maximal oxygen uptake was associated with better patient outcomes and lower symptom burden in ADT-treated prostate cancer patients. Patients with more muscle mass at baseline had worse well-being outcomes. They next used their muscle biopsy samples to look at the expression of genes involved in mitochondrial biogenesis and function. They found that patients with higher baseline gene expression had better six-minute walk distances and higher maximal oxygen uptake than those with lower gene expression, indicating that mitochondrial function may influence patient physical function and well-being. These results were somewhat surprising for Garcia. “Having more lean mass at baseline was associated with worse patient-reported outcomes, which runs counter to the assumption that ‘more muscle is always better.’ It suggests we may be measuring and targeting the wrong thing in this population, and that mitochondria could be a real therapeutic target going forward,” he explains.
In the future, the group hopes that these results can be integrated into existing clinical practice or even beget new mitochondria-targeting therapies for prostate cancer patients. Interventions like structured exercise are recommended for cancer patients, but they are not usually prescribed by doctors or adopted by patients. “This study suggests that, before a patient starts ADT, we could measure their aerobic capacity (a simple, non-invasive test) to select who is most likely to experience a steep decline in function and quality of life. Those patients could then be prioritized for closer monitoring or a structured exercise program from day one, rather than waiting until they've already lost function to intervene,” says Garcia. He hopes that ongoing work at the Veterans Affairs Puget Sound Health Care System and Fred Hutch will validate these results and identify new pathways that can be targeted to improve outcomes for prostate cancer patients. “A time when we can use precision oncology to prevent and treat muscle wasting and associated symptoms such as fatigue in patients living with prostate cancer and undergoing ADT is within reach, but more research is needed.”
Dr. Jose Garcia provided comment in his capacity as a Professor of Medicine at the University of Washington.
This work was supported by funding from the US Department of Defense, the National Institutes of Health, the Department of Veterans Affairs, Biomedical Laboratory Research and Development Service, and the University of Washington.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. David Marcinek, Sina Gharib, and Jose Garcia contributed to this work.
Caeiro L, Anderson LJ, Dash A, Marcinek DJ, Kerr HL, Paulsen L, Miranda G, Jaramillo Quiroz S, Vaisar T, Krueger MA, Acosta-Vega NL, Gharib SA, Garcia JM. 2026. Muscle mitochondria, function, mass, and quality of life in prostate cancer during androgen deprivation therapy. Nat Commun. 2026 May 27. doi: 10.1038/s41467-026-73542-x.
Kelsey Woodruff is a PhD candidate in the Termini Lab at Fred Hutch Cancer Center. She studies how acute myeloid leukemia cells remodel the sugars on their membranes to reprogram cancer cell signaling. Originally from Indiana, she holds a bachelor's degree in Biochemistry from Ball State University. Outside of lab, you can find her crocheting and enjoying the Seattle summers.