Prostate cancer androgen receptor splice variant 7 biomarker study - a multicentre randomised feasibility trial of biomarker-guided personalised treatment in patients with advanced prostate cancer (the VARIANT trial) study protocol.

Prostate cancer is the most common male cancer with one in four developing non-curable metastatic disease. Initial treatment responses to hormonal therapies are transient and further management options lie between (1) further hormone therapy or (2) a non-hormonal approach involving additional chemotherapy or molecular radiotherapy (radium-223). There is no clear rationale for choosing between these mechanistically different treatment approaches. The biology of hormone resistance is driven through abnormal androgen receptor activity and we can assay this through a blood test measuring androgen receptor variant 7 (AR-V7) expression in circulating tumour cells. Despite increasing evidence supporting AR-V7's role as a prognostic marker, the clinical utility of such measures remains unknown in helping personalise treatment decisions. The VARIANT feasibility trial is a pragmatic design, to be run over 18 months with participants randomised into the intervention arm receiving biomarker (AR-V7) guided clinical treatment and participants randomised into the control arm with conventional standard management (no biomarker guidance). AR-V7 positive participants (likely to be insensitive to further hormone treatment) will receive chemotherapy or in other cases radium-223 (where routinely available). Seventy male ≥18 years old participants with metastatic castrate resistant prostate cancer clinically indicated to proceed to further hormone therapy or chemotherapy, will be recruited from three National Health Service Trusts based in England, Scotland and Wales. The feasibility primary outcome is willingness of patients to be randomised and clinicians to recruit to a biomarker-based treatment strategy, with trial data informing the basis of a definitive and appropriately powered randomised control trial. Formal ethics review was undertaken with a favourable opinion, through Wales NRES Committee 2 18/WA/0419. Findings to be disseminated through patient and professional organisations that have expressed their support, media outlets and peer-reviewed journal publication. ISRCTN10246848; pre-results.

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Competing interests: SJ reports personal fees from Astellas, personal fees from Bayer, personal fees from Janssen, personal fees from Boston Scientific, personal fees from Almac Diagnostics, personal fees from Sanofi Genzyme, personal fees from Movember, outside the submitted work. AB reports research funding and advisory roles with Sanofi and Janssen and an advisory role with Astellas and Bayer, outside the submitted work. RJ reports grants and personal fees from Astellas, grants and personal fees from AstraZeneca, personal fees and non-financial support from Bristol Myers Squibb, grants, personal fees and non-financial support from Bayer, grants and personal fees from Exelixis, personal fees and non-financial support from Janssen, personal fees and non-financial support from Ipsen, personal fees from Merck Serono, personal fees and non-financial support from MSD, personal fees from Novartis, personal fees from Pfizer, grants and personal fees from Roche, personal fees from Sanofi Genzyme, personal fees from EUSA, outside the submitted work. JS reports non-financial support from Bayer and personal fees from Janssen and Astellas outside of the submitted work. SJC has an honoraria/advisory role with Roche, Clovis Oncology, Bayer, Janssen Cilag and Merck and receives research support from AstraZeneca, Astex Pharmaceuticals and Clovis Oncology.