INTERVAL - Intense Exercise Trial for Men With Metastatic Castrate-Resistant Prostate Cancer

Exercise as Non-Pharmacologic Adjuvant Therapy for Prostate Cancer: Identifying and evaluating low-toxicity adjuvant interventions that can be combined with standard therapy to improve outcomes for men with prostate cancer is a high priority and has the potential to have a large impact on the clinical and public health burden of prostate cancer. The investigators summarise briefly below promising observational, pre-clinical, and pilot clinical data that support the hypothesis that exercise improves overall survival and health-related quality-of-life (QOL) among men with advanced prostate cancer: * Vigorous aerobic exercise after diagnosis was associated with a 60% risk of fatal prostate cancer and a 49% risk of all-cause mortality among men initially diagnosed with localised disease. * Loading of bone inhibited growth of metastatic tumours in animal models. * Resistance exercise and programs with both resistance and aerobic exercise improved physical function and quality-of-life in men without metastases on androgen deprivation therapy (ADT) for prostate cancer. * Treatment-related fatigue is a common side effect in men with advanced prostate cancer and exercise may decrease fatigue and increase adherence to treatment regimens. * New standard treatments for advanced prostate cancer cause adverse metabolic effects (e.g., weight gain, insulin resistance) that may be avoided or attenuated by exercise. Potential mechanisms of exercise influencing prostate cancer tumour biology Potential mechanisms by which exercise may reduce the risk of prostate cancer progression, the incidence and progression of comorbidities, treatment side effects, and overall death among men with advanced prostate cancer include: Endocrine - Exercise influences all hormonal systems in the body with key hormones relevant to prostate cancer being testosterone, growth hormone, and insulin-like growth factor-1 (IGF-I). The androgen receptor and its transactivation by ligand are one of the most important determinants of prostate cancer progression. Measurements of serum androgens provide an important biomarker for effectiveness of androgen deprivation and prostate cancer progression. Current studies are inconclusive as to the effects of exercise on serum androgen levels. In part, these studies are limited by low patient numbers and inadequate methods for measuring testosterone levels in the low ranges seen in men on androgen deprivation therapy. This is especially true with the cyp17 inhibitors, such as Abiraterone. Immune System, Inflammation, and Cytokines - High levels of inflammatory biomarkers are associated with an increased risk of prostate cancer-specific mortality, and exercise is known to levels of circulating inflammatory biomarkers (e.g., interleukin- 6 (IL-6)) in elderly populations. In addition, exercise may enhance natural killer cell cytotoxicity and immune surveillance, improving immune defence against prostate cancer. Further, adipokines may also have pro- or anti-oncogenic roles in angiogenesis and cell proliferation. For example, adiponectin has anti-inflammatory effects and its serum concentration is inversely correlated with adiposity. Resistin is associated with insulin resistance through AMP kinase down-regulation. It up-regulates pro-inflammatory cytokines (IL-6, tumour necrosis factor alpha (TNFα)) which act via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκb) pathway to increase transcription of proteins involved in cell proliferation, inflammation and anti-apoptosis. In addition, activation of NFκb is implicated in prostate cancer, nuclear expression being associated with nodal metastasis. IL-6 and TNFα are both elevated in the serum of patients with metastatic carcinoma compared to patients without metastases. Interestingly, both are elevated in prostate carcinoma in direct proportion to disease stage, and increases occur at the time of biochemical (PSA) disease progression. Energy Metabolism - Exercise improves insulin sensitivity and glucose metabolism. While ADT in principle is targeting the prostate cancer tumour, the systemic treatment in patient's results in a range of alterations associated with metabolic syndrome. One of the earliest changes following ADT, within 2-6 a reduction in insulin sensitivity leading to a rise in circulating insulin (hyperinsulinemia); the rise in insulin levels precedes changes in adiposity and increased lipids, sarcopenia, and bone loss. High insulin levels are predictive of more rapid progression to CRPC, and poor prognosis. Insulin has been shown to have a direct action on prostate cancer growth and progression, and this can be inhibited by blocking insulin action. Additionally, high levels of C-peptide, a marker of insulin secretion, are associated with a more than 2-fold increased risk of prostate cancer-specific mortality. Further, over the (body mass index (BMI) \>25 kg/m2) men with high C-peptide levels had a more than 4-fold increased risk of prostate cancer-specific mortality compared to normal the men with low C-peptide levels. Body composition - Cancer and its treatments cause substantial changes in body composition with sarcopenic obesity being a common outcome. This not only results in substantial impediment to functional ability and increased cardio-metabolic risk, but also alteration of adipokine and myokine balance, which may contribute to tumour progression. Exercise increases lean muscle mass and may cause loss of fat mass, thereby improving overall body composition. Epigenetics - Exercise can produce epigenetic modulations that may inhibit tumour cell proliferation, such as altering histone deacetylase pathways. Telomere - Short and/or variable telomere length in the prostate is a prognostic marker among men with prostate cancer. One study among 10 men with localised prostate cancer on active surveillance reported that a lifestyle program that included moderate exercise (as the as diet, stress management, and social support) increased telomere length in blood. Cholesterol - Epidemiological studies have suggested that high levels of cholesterol in the blood are associated with increased risk of prostate cancer and progression of prostate cancer. Exercise combined with dietary modification has been demonstrated to substantially reduce total cholesterol as the as improve the ratio of high density lipoprotein to low density lipoprotein cholesterol. Oxidative stress - Exercise has been demonstrated to modulate oxidative stress and improve antioxidant capacity. In a pilot study at the University of California, San Francisco, men with low risk, localised prostate cancer who reported ≥3 hours/the of vigorous physical activity had modulated expression of the nuclear factor erythroid 2-related factor 2 (Nrf-2) mediated oxidative stress response pathway in their normal prostate tissue compared to men who did less exercise. Oxidative stress is hypothesized to play a significant role in the initiation and progression of prostate cancer. As the burden of disease among men with prostate cancer advances, a rapid, significant deterioration in QOL is observed. Bone pain which is reported in up to 80% of patients with metastatic disease throughout their treatment, makes the largest single contributor to QOL deterioration in this population. Other symptoms which compromise QOL include urinary frequency, sexual dysfunction, nausea and vomiting, loss of appetite and dyspnoea. The benefits of exercise training on QOL for men with non-metastatic prostate cancer are the described, and include improvements in general QOL and also cancer-specific concerns including fatigue and sexual health. Whether exercise can improve QOL among men at the end stage of this disease is not known. Metastatic spread of prostate cancer occurs primarily to sites in the axial skeleton including the femur, pelvis and vertebrae. Metastatic lesions, which are typically osteoblastic, lead to significant bone pain and compromised skeletal quality. Skeletal complications, such as bone fractures, orthopaedic intervention or spinal cord compression, which develop due to bone metastases, result in significant patient morbidity and compromised QOL. Furthermore, compared to those who do not experience a symptomatic skeletal related event (SSE), the occurrence of a SSE is associated with increased patient mortality. A modular multi-modal approach to exercise training involving individualised prescription of exercise to reduce the forces going through the bone has been shown to be safe and feasible in men with bony metastases and not associated with increased risk of pathological fracture. This proposal will test whether exercise training delays time to SSE as the time to progression of pain and affects measures of pain severity and opiate use. Control or relief of pain and delay or prevention of SSE are both indications for approved therapeutic agents for men with metastatic prostate cancer. In addition to SSE and pain due to the infiltration of metastatic prostate cancer in bone, men with this disease also experience debilitating cancer-related fatigue and adverse cardio-metabolic health as a side effect of therapy. Cancer-related fatigue is a distinct phenomenon from fatigue experienced by healthy individuals and significantly health-related QOL. There are extensive data to support that exercise improves fatigue in men with a disease burden. This proposal will be the first to examine whether exercise improves or delays onset of cancer-related fatigue in men with metastatic prostate cancer. Rationale for Focus on Metastatic Castrate-Resistant Prostate Cancer (MCRPC), our overarching objective is to determine the effect of exercise on overall survival among men with advanced prostate cancer. The investigators have chosen to restrict our study population to men with progressive MCRPC because: 1) Men with progressive MCRPC are at high risk for death within a time frame that can be feasibly tested in the setting of a RCT (median OS on treatment = 3242 to 3543 months). 2) With the proper use of stratification variables (treatment and study site), it is possible to define a homogenous study population in terms of risk of death; 3) This is the largest group of patients that can be uniformly considered to have advanced prostate cancer and thus provides the largest patient pool for recruitment while also meeting criteria 1 \& 2; 4) while new therapies for MCRPC extend life, they also cause significant harm to metabolic and cardiac function and health-related QOL which may be attenuated or avoided through exercise; and 5) the investigators hypothesize that exercise will have the largest measurable effect on OS among men with documented evidence of progressing MCRPC (in contrast to men with stable M1 CRPC, non-castrate resistant disease, or non-metastatic disease). The primary endpoint for this randomised controlled trial will be overall survival (OS). OS was chosen as the primary endpoint because it has clear biological, clinical and public health significance and is a validated endpoint for approval of new treatments among men with MCRPC. Additionally, OS data can be obtained with minimal loss to follow-up through review of medical and death records. The median OS among men with MCRPC is 3242 to 3543 months. Thus, OS is a feasible outcome to examine within the budget and timeline of the proposed study.