Title: The Prostate Cancer Androgen Receptor Splice Variant 7 Biomarker Trial (The VARIANT trial) - A multicentre feasibility study of biomarker-guided personalised treatment in advanced prostate cancer.
Funder: Department of Health and Social Care

Abstract: Background to the research Prostate cancer (PC) is the commonest male cancer in the UK with 1 in 4 presenting with, or progressing to advanced non-curable metastatic PC. Initial treatments in these advanced cases include hormonal approaches alone or chemotherapy with hormone treatment. However, the responses are transient and thereafter, management options lie between additional chemotherapy and in certain cases Radium-223, or further hormone manipulation with abiraterone or enzalutamide. There is no clear clinical rationale for choosing between these mechanistically different treatment approaches. Patients and clinicians often prefer the second option, being less toxic compared to chemotherapy. However, only 30-50% men respond well to additional hormonal treatment, with the remainder demonstrating a poor or an equivocal response. Hormonal treatments block testosterone (hormone) production and/or the androgen receptor (AR) signalling axis that drives cancer cell growth. A recent breakthrough in understanding the complex molecular biology of the development of hormone resistant cancer, revealed hormonal treatment generates a selective pressure at the cellular level that results in tumour resistance mediated by induced expression of an alternative type of androgen receptor called the AR mRNA splice variant (AR-V7). The autonomous activity of AR-V7 is not affected by additional hormonal treatment with enzalutamide and abiraterone, rendering these treatments ineffective in men expressing AR-V7. There is an emerging body of published evidence showing pre-clinical and clinical associative findings of AR-V7 expression and hormone resistance. The development of AR-V7 as a treatment stratification biomarker could identify those men likely to be sensitive to further hormonal treatment (AR-V7 negative patients) and avoid futile treatments in those predicted to be insensitive (AR-V7 positive patients). To date there have been no formal measures of the clinical utility of the AR-V7 biomarker. Aims A feasibility study to inform a formal randomised clinical trial comparing standard of care (without AR-V7 biomarker measure) with personalised treatment (with AR-V7 biomarker measure). The question to be addressed by this Research To address feasibility of using a AR-V7 blood biomarker assay in personalising treatment in men with advanced prostate cancer, and to ultimately confirm if biomarker-led treatment stratification for men with metastatic PC has clinical value (utility) in day-to-day UK clinical practice. Plan of investigation Multi-centre feasibility study randomising (1:1) between AR-V7 biomarker-guided clinical treatment or conventional standard treatment management (AR-V7 untested/unguided group). AR-V7 positive participants (likely to be insensitive to further hormone treatment), will receive chemotherapy or, if clinically indicated, Radium-223. The primary outcome measure is feasibility defined as: Willingness of patients to be randomise to a biomarker-based treatment strategy Willingness of clinicians to recruit patients to a biomarker-based treatment strategy Retention and compliance in relation to sample measurement, treatment completion, longitudinal quality of life assessment and follow-up with a view to informing sample size estimates for a larger definitive randomised control trial. We project to recruit across three centres, 35 patients per arm (1.94 patients/month/centre, 24% of all eligible patients). Recruitment to take 12 months. Participants will be followed up for 6 months to report 6 month survival and patient outcome data (including safety), assess compliance and completion of outcome measures. Summary of potential benefits to patients and the NHS As many patients can be insensitive to standard hormone treatments, there are considerable costs from ill guided management, both in terms of patient experience and outcomes (side effects and disease progression), including economic costs to the NHS (large burden of expensive treatments for the commonest male cancer). The AR-V7 biomarker, potentially affords a significant opportunity to identify treatment sensitivity, which is a clinical priority for both patients and service providers.

Lay abstract: Aim &ndash; to determine if the promising predictive findings of a blood biomarker (AR-V7) has value in routine clinical practice in personalising treatment in men with advanced prostate cancer (PC). Before embarking on a full trial, this study will confirm feasibility i.e. acceptability to both clinicians and patients to randomise to an experimental study where subsequent treatment is defined by a biomarker result. Background - PC is the commonest male cancer and 1 in 4 develop non-curable metastatic PC. Initial treatments include hormonal approaches or chemotherapy. However, the responses are transient and thereafter, management options lie between (1) additional chemotherapy and drug based internal radiotherapy (radium-223) or (2) further hormone manipulation. However, there is no clear biological rationale for choosing between these mechanistically different treatment approaches. As many patients can be insensitive to either treatment approach, there are considerable costs from ill-guided management, both in terms of patient experience and outcomes (side-effects and disease progression) and also economic costs to the NHS (large burden of expensive treatments for the commonest male cancer). The development of a biomarker to identify treatment sensitivity is a clinical priority for patients and service providers and the forerunner, the AR-V7 biomarker, potentially affords a significant opportunity to help personalise treatments. The biomarker could identify those likely to be sensitive to further hormonal treatment and avoid futile treatments in those that are predicted to be insensitive. Design/Methods - multi-centre feasibility study randomising between AR-V7 biomarker-guided clinical treatment or conventional management (AR-V7 unguided group). AR-V7 positive participants (likely to be insensitive to further hormone treatment) will receive chemotherapy or radium-223. Outcomes - Willingness of patients to randomise and clinicians to recruit Estimates to inform design of subsequent definitive trial: compliance in relation to sample measurement, treatment completion, longitudinal quality of life assessment and follow-up

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS