Identifying Fundamental Mechanisms of Skeletal Muscle Ageing in Older Men Undergoing Androgen Deprivation Therapy: a Feasibility Study

Androgen Deprivation Therapy (ADT) is a well-established therapy for prostate cancer that improves overall survival rates, reduced rates of metastatic prostate cancer and death from prostate cancer . ADT is most commonly delivered through medical castration. It works due to the sensitivity of prostate cancer to androgen signalling. Gonadotropin-releasing hormone (GnRH) agonists or antagonists are used to lower systemic testosterone and oestrogen levels and thereby control the prostate cancer. However, the reduction of these hormones can lead to systemic side-effects including changes in body composition such as increased fat mass and reduced muscle mass and subsequently result in sarcopenia and metabolic side-effects.

Sarcopenia is a condition underpinned by profound reductions in muscle mass and quality that occur in such sufficient magnitude as to lead to impairments in muscle function, independence and mobility. Moreover, sarcopenia is known to increase risk of falls, lead to impairments in quality of life, and increase mortality (independent of activities of daily living, age, and other factors). Resistance exercise is the gold standard treatment for sarcopenia, although this non-pharmacological stimulus has been shown to increase testosterone levels. Despite the potential rise in testosterone levels, resistance exercise has been shown to improve prostate cancer-specific mortality as well as providing functional benefits. Thus, additional downstream pathways are likely upregulated during the ageing process in older men undergoing Androgen Deprivation Therapy .

Ageing is a heterogenous process characterised by cellular senescence, telomere shortening, systemic inflammation and mitochondrial dysfunction and other "hallmarks of ageing". In animal models it has been shown that targeting these processes can extend healthspan and reduce the development of age-related conditions. There are small scale studies in humans trialling the use of drugs that target these ageing processes, known as geroprotectors. However, the fundamental mechanisms underpinning skeletal muscle atrophy and changes in body composition in patients undergoing ADT for prostate cancer are not well understood.

This study will assess the feasibility and acceptability of an observational cohort study to identify the fundamental mechanisms by which ADT is associated with changes in body composition following ADT in older adults with prostate cancer. Older adults are the focus of this study as the risk of side effects from ADT increases with age and the older population is poorly represented in research, including in research with prostate cancer populations . By identifying what processes may be involved in muscle atrophy following ADT, we will be able to better understand how to prevent this occurring and potentially target these pathways using geroprotectors.

Inclusion criteria

• Age ≥65 years old at time of recruitment
• Able to provide informed consent to participate
• Known prostate cancer due to be initiated on ADT for the first time (with or without Androgen Receptor Targeted Agents (ARTA) or radiotherapy), or initiated within two weeks prior to recruitment.
• Individuals involved in other research will be eligible to participate so long as the other research does not involve potential changes to the standard ADT care the participant will be receiving and does not involve an intervention aimed at reducing the muscle atrophy associated with ADT.

Exclusion criteria

• Systemic anti-cancer therapy within one year of recruitment (for prostate cancer or any other concomitant cancer)
• Planned surgery (not including eye surgery or other minor surgery) within six months of ADT
• Any other condition previous or current which, in the judgement of the responsible clinician, is likely to interfere with the trial / assessments.
• Lacks capacity to consent

Exclusion criteria

for those consenting to optional muscle biopsy:

• On treatment with clopidogrel, high-dose aspirin, dipyridamole or anticoagulants
• Known bleeding disorder or platelets <75x103/mL