Intermittent Fasting using a Fasting-Mimetic Diet to Improve Prostate Cancer Control and Metabolic Outcomes

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ABSTRACT Prostate cancer (PC) remains the most common cancer affecting men in the US, resulting in both a high number of deaths but also an even greater number of survivors experiencing treatment-related toxicities. Androgen deprivation therapy (ADT) is a cornerstone of therapy for both locally advanced and metastatic cases, though it results in myriad negative effects, including increased insulin resistance and incident diabetes. The intensified androgen receptor targeted agents (ARTA), while improving overall survival, exacerbate these negative effects. Most men with PC are older, thus at risk of, or already suffering from, comorbidities such as diabetes and heart disease; these often represent their greatest threat to mortality. The ADT-induced metabolic changes may also adversely impact men at high risk of PC death by promoting cancer progression. During ADT, insulin, leptin and IGF1 levels all increase; higher levels are linked with more aggressive PC and may drive castration resistance. We showed in human studies that intermittent fasting using a fasting-mimicking diet (FMD) can favorably change insulin, glucose and IGF1/IGFBPs. Our FMD trials involved patients consuming a very low-calorie plant-based FMD for 5 days while during days 6-28, patients ate what they wanted, but were encouraged to eat per European Society for Clinical Nutrition and Metabolism guidelines for cancer survivors. Further, we showed this approach can delay tumor progression in multiple mouse models including PC. Based upon the above, we hypothesize that intermittent fasting using a FMD will delay PC progression and improve metabolic health in men being treated with intensified ADT. To test this hypothesis, we propose a three-site randomized controlled trial of an intermittent fasting intervention using a FMD vs. standard of care for 6 months in patients with metastatic castration sensitive PC (mCSPC) starting on intensified ADT with or without chemotherapy. For the first time, we will test the effect of FMD on improvement in PSA nadir, an early clinical endpoint strongly correlated with better survival. We will also measure how changes in insulin and IGF1 associate with PSA nadir as one mechanism by which this dietary approach improves cancer outcomes and will further seek to define a molecular subset of PCs which are most responsive to this diet. The results of this trial will have immediate impact for PC patients, both metastatic and potentially the larger population who receive a course of ADT with definitive therapy. Thousands of men each year could be prevented from developing or having exacerbation of diabetes and other cardiovascular risk factors, which are their greatest mortality threat, by using a FMD. For men with metastatic PC, improving tumor control and delaying castration resistance would reduce morbidity, particularly skeletal complications, and improve survival. The PC research community will gain insight into metabolic toxicity and hormonal pathway interactions with the next- generation ARTA as well as identify molecular subtypes that benefit most from intermittent fasting using a FMD.