Biotechnology, and Targimmune, has participated in scientific advisory boards for Menarini Ricerche and Bioscience Institute, and is a cofounder of Medendi. BST has received honoraria and research funding from Genentech and participated in advisory boards for Boehringer Ingelheim and Loxo Oncology, a wholly owned subsidiary of Eli Lilly. SC has received a research grant from Daiichi Sankyo and consultancy fees from BMS, Context Therapeutics, Eli Lilly, Novartis, Revolution Medicines, and Sermonix Pharmaceutical. DMH reports stock ownership in Fount Therapeutics, has acted in a consultancy or advisory role for AstraZeneca,

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Prostate cancer (PCa) is a clinically heterogeneous disease and has poor patient outcome when tumours progress to castration-resistant and metastatic states. Understanding the mechanistic basis for transition to late stage aggressive disease is vital for both assigning patient risk status in the localised setting and also identifying novel treatment strategies to prevent progression. Subregions of intratumoral hypoxia are found in all solid tumours and are associated with many biologic drivers of tumour progression. Crucially, more recent findings show the co-presence of hypoxia and genomic instability can confer a uniquely adverse prognosis in localised PCa patients. In-depth informatic and functional studies suggests a role for hypoxia in co-operating with oncogenic drivers (e.g. loss of PTEN) and suppressing DNA repair capacity to alter clonal evolution due to an aggressive mutator phenotype. More specifically, hypoxic suppression of homologous recombination represents a “contextual lethal“ vulnerability in hypoxic prostate tumours which could extend the application of existing DNA repair targeting agents such as poly-ADP ribose polymerase inhibitors. Further investigation is now required to assess this relationship on the background of existing genomic alterations relevant to PCa, and also characterise the role of hypoxia in driving early metastatic spread. On this basis, PCa patients with hypoxic tumours can be better stratified into risk categories and treated with appropriate therapies to prevent progression.