The prostate and prostate cancer is inherently dependent on androgens for differentiation, proliferation, and cell survival. Androgens are the key driver of metabolic pathways in the prostate and prostate cancer, with well-established roles in regulating lipogenesis and energy metabolism. The androgen receptor remains the central target in advanced prostate cancer, with a growing pipeline of new drugs targeting the androgen axis. While the intent of androgen targeted therapies (ATT) is for therapeutic benefit, physiologically ATT systemically reprograms the equilibrium of interlinked endocrine pathways with induction of features of metabolic syndrome, including hyperinsulinaemia, dyslipidaemia, and dysregulation of adipokines which in turn drive cancer cell metabolism. Prostate tumours adapt to survive ATT by activation activate androgen-repressed gene networks, many of which also directly alter tumour cell metabolism to promote cell survival and treatment resistance. Our aim has been to target the activated adaptive pathways in advanced prostate cancer and the systemic endocrine responses to ATT. We have used well-established drugs repurposed for this context, such as anti-diabetic and other metabolic drugs, as well as novel agents to target tumour cell metabolism directly. During these studies we have found complex adaptive interlinkages between metabolic pathways which underpin treatment resistance and prostate cancer progression that may offer new therapeutic insights.