ABSTRACT The incidence of metastatic prostate cancer has increased 3% per year since 2012, and the survival rate is only 29%. Muscle mass is important for metastatic prostate cancer survival and quality of life (QoL). Androgen deprivation therapy (ADT) with an androgen signaling inhibitor is the backbone of treatment for men with metastatic castration sensitive prostate cancer (mCSPC). But the androgen blockade diminishes muscle mass and contributes to adverse health outcomes critical to mCSPC survivors, such as fatigue, and declines in physical function, independence, insulin sensitivity, and QoL. Resistance training (RT) can preserve muscle mass and improve health outcomes in non-metastatic CSPC survivors receiving ADT. The addition of creatine monohydrate supplementation to an RT program amplifies the effects of RT in cancer-free older adults and other clinical populations. Evidence also suggests that creatine supplementation can complement cancer treatment. Thus, creatine monohydrate supplementation with RT (Cr+RT) is a strategy that addresses an important knowledge gap pertaining to survivorship needs of mCSPC survivors. We hypothesize that Cr+RT will preserve muscle mass and improve health outcomes greater than RT alone, and that creatine use will lead to favorable changes in markers of cancer progression in mCSPC survivors receiving ADT. Here we propose a parallel, double-blind randomized controlled trial to test the effects of 52-weeks of Cr+RT compared with placebo (PLA) and RT (PLA+RT) with our team's established, effective, home-based, telehealth RT program in 200 mCSPC survivors receiving ADT. We will evaluate muscle mass (primary outcome), health outcomes (fatigue, physical function, independence, insulin sensitivity, QoL), and markers or cancer progression (PSA, cfDNA) at baseline, 24-, and 52-weeks. RT will be carried out twice weekly with elastic resistance bands, and we will utilize an established creatine supplementation protocol for creatine and PLA delivery. Our trial builds on work done by our investigative team, and addresses an evidence gap listed in this RFA (CA-22-027: Research to Understand and Address Survivorship Needs of Individuals Living with Advanced Cancer) re: “Interventional research to determine the best ways to improve the quality of care and QoL for individuals living with likely incurable cancer”, identified gaps in the literature, and unmet needs of mCSPC survivors. Our approach addresses a major facilitator to RT in mCSPC survivors, a home-based RT program, while utilizing a supervised model for safety. Our approach can be translated on a large-scale as it can be adopted by institutions who use an established telemedicine system, and creatine monohydrate supplementation and elastic resistance bands are inexpensive and widely available. These findings will improve delivery of comprehensive survivorship care by providing a multicomponent, patient-centered lifestyle strategy to preserve muscle mass, improve health outcomes and QoL, and complement cancer treatment.

PROJECT NARRATIVE Androgen deprivation therapy (ADT), with an androgen signaling inhibitor, is the backbone of treatment for men with metastatic castration sensitive prostate cancer (mCSPC), but diminished muscle mass due to androgen blockade is linked with poor overall survival, and adverse changes in health outcomes important to mCSPC survivors (e.g., fatigue, physical function, independence, insulin sensitivity, and quality of life). Resistance training (RT) is an effective approach to preserve muscle mass and improve these health outcomes in non-metastatic CSPC survivors receiving ADT; however, there is a gap in our understanding of how RT impacts outcomes in mCSPC survivors, and the impact of 52-weeks of RT in a home-based setting, a setting that is more practical for sustained adherence and the reported preferred setting for exercise in mCSPC survivors receiving ADT. Furthermore, the addition of creatine monohydrate supplementation to an RT program (Cr+RT) enhances the effects of RT in cancer-free older adults and individuals with advanced head and neck cancer, and creatine supplementation has demonstrated anti-cancer effects in preclinical models including prostate cancer; as such, this 52-week, randomized, double-blind placebo-controlled trial will compare our established, effective, home-based, telehealth RT program with creatine or placebo (PLA; Cr+RT vs. PLA+RT) in order to identify the superior strategy to preserve muscle mass, improve health outcomes, and attenuate cancer progression in mCSPC survivors receiving ADT.