Eoin Dinneen1,2,3, Gregory L Shaw1,2,3,4, Roseann Kealy3,5, Panos Alexandris3, Kier Finnegan3, Kimberley Chu3, Nadia Haidar3, Sara Santos-Vidal6, Sakunthala Kudahetti6, Caroline M Moore1,2, Alistair D R Grey1,2,4, Daniel M Berney6,7, Anju Sahdev8, Paul J Cathcart9, R Timothy D Oliver3, Prabhakar Rajan1,2,4,10, Jack Cuzick3, Jack Cuzick3, Sanjeev Madaan11, Jhumur Pati12, Abdul M Chowdhury12, Brian R P Birch13, Timothy J Dudderidge13, Caroline M Moore1,2, Alistair D R Grey1,2,4, Gregory L Shaw1,2,3,4, Kieran P Jefferson14, Howard G Kynaston15, Prabhakar Rajan1,2,4,10, James S A Green4, Paul J Cathcart9, Daniel M Berney6,7, Thomas Powles6, R Timothy D Oliver3, Anju Sahdev8, Roseann Kealy3,5, Victoria Kemp3, Panos Alexandris3, Kier Finnegan3, Kimberly Chu3. 1. Division of Surgery and Interventional Science University College London London UK. 2. Department of Urology, University College Hospital at Westmoreland Street University College Hospital London NHS Foundation Trust London UK. 3. Centre for Prevention, Detection and Diagnosis, Wolfson Institute of Population Health, Cancer Research UK Barts Centre Queen Mary University of London London UK. 4. Department of Urology, The Royal London Hospital Barts Health NHS Trust London UK. 5. Present address: Cancer Prevention Trial Unit, School of Cancer & Pharmaceutical Sciences King's College London London UK. 6. Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Cancer Research UK Barts Centre Queen Mary University of London London UK. 7. Department of Cellular Pathology, The Royal London Hospital Barts Health NHS Trust London UK. 8. Department of Radiology, St Bartholomew's Hospital Barts Health NHS Trust London UK. 9. Department of Urology, Guy's Hospital Guy's and St Thomas' NHS Foundation Trust London UK. 10. Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Cancer Research UK Barts Centre Queen Mary University of London London UK. 11. Department of Urology, Darent Valley Hospital Darent and Gravesham NHS Trust Dartford UK. 12. Department of Urology, Homerton University Hospital Homerton University Hospital NHS Foundation Trust London UK. 13. Department of Urology, Southampton General Hospital University Hospitals Southampton NHS Foundation Trust Southampton UK. 14. Department of Urology, University Hospital Coventry University Hospitals Coventry and Warwickshire NHS Trust Coventry UK. 15. Department of Urology University Hospital of Wales Cardiff UK.
Abstract
Objectives: To test the feasibility of a randomised controlled trial (RCT) of aspirin and/or vitamin D3 in active surveillance (AS) low/favourable intermediate risk prostate cancer (PCa) patients with Prolaris® testing. Patients and Methods: Newly-diagnosed low/favourable intermediate risk PCa patients (PSA ≤ 15 ng/ml, International Society of Urological Pathology (ISUP) Grade Group ≤2, maximum biopsy core length <10 mm, clinical stage ≤cT2c) were recruited into a multi-centre randomised, double-blind, placebo-controlled study (ISRCTN91422391, NCT03103152). Participants were randomised to oral low dose (100 mg), standard dose (300 mg) aspirin or placebo and/or vitamin D3 (4000 IU) versus placebo in a 3 × 2 factorial RCT design with biopsy tissue Prolaris® testing. The primary endpoint was trial acceptance/entry rates. Secondary endpoints included feasibility of Prolaris® testing, 12-month disease re-assessment (imaging/biochemical/histological), and 12-month treatment adherence/safety. Disease progression was defined as any of the following (i) 50% increase in baseline PSA, (ii) new Prostate Imaging-Reporting and Data System (PI-RADS) 4/5 lesion(s) on multi-parametric MRI where no previous lesion, (iii) 33% volume increase in lesion size, or radiological upstaging to ≥T3, (iv) ISUP Grade Group upgrade or (v) 50% increase in maximum cancer core length. Results: Of 130 eligible patients, 104 (80%) accepted recruitment from seven sites over 12 months, of which 94 patients represented the per protocol population receiving treatment. Prolaris® testing was performed on 76/94 (81%) diagnostic biopsies. Twelve-month disease progression rate was 43.3%. Assessable 12-month treatment adherence in non-progressing patients to aspirin and vitamin D across all treatment arms was 91%. Two drug-attributable serious adverse events in 1 patient allocated to aspirin were identified. The study was not designed to determine differences between treatment arms. Conclusion: Recruitment of AS PCa patients into a multi-centre multi-arm placebo-controlled RCT of minimally-toxic adjunctive oral drug treatments with molecular biomarker profiling is acceptable and safe. A larger phase III study is needed to determine optimal agents, intervention efficacy, and outcome-associated biomarkers.
Objectives: To test the feasibility of a randomised controlled trial (RCT) of aspirin and/or vitamin D3 in active surveillance (AS) low/favourable intermediate risk prostate cancer (PCa) patients with Prolaris® testing. Patients and Methods: Newly-diagnosed low/favourable intermediate risk PCa patients (PSA ≤ 15 ng/ml, International Society of Urological Pathology (ISUP) Grade Group ≤2, maximum biopsy core length <10 mm, clinical stage ≤cT2c) were recruited into a multi-centre randomised, double-blind, placebo-controlled study (ISRCTN91422391, NCT03103152). Participants were randomised to oral low dose (100 mg), standard dose (300 mg) aspirin or placebo and/or vitamin D3 (4000 IU) versus placebo in a 3 × 2 factorial RCT design with biopsy tissue Prolaris® testing. The primary endpoint was trial acceptance/entry rates. Secondary endpoints included feasibility of Prolaris® testing, 12-month disease re-assessment (imaging/biochemical/histological), and 12-month treatment adherence/safety. Disease progression was defined as any of the following (i) 50% increase in baseline PSA, (ii) new Prostate Imaging-Reporting and Data System (PI-RADS) 4/5 lesion(s) on multi-parametric MRI where no previous lesion, (iii) 33% volume increase in lesion size, or radiological upstaging to ≥T3, (iv) ISUP Grade Group upgrade or (v) 50% increase in maximum cancer core length. Results: Of 130 eligible patients, 104 (80%) accepted recruitment from seven sites over 12 months, of which 94 patients represented the per protocol population receiving treatment. Prolaris® testing was performed on 76/94 (81%) diagnostic biopsies. Twelve-month disease progression rate was 43.3%. Assessable 12-month treatment adherence in non-progressing patients to aspirin and vitamin D across all treatment arms was 91%. Two drug-attributable serious adverse events in 1 patient allocated to aspirin were identified. The study was not designed to determine differences between treatment arms. Conclusion: Recruitment of AS PCa patients into a multi-centre multi-arm placebo-controlled RCT of minimally-toxic adjunctive oral drug treatments with molecular biomarker profiling is acceptable and safe. A larger phase III study is needed to determine optimal agents, intervention efficacy, and outcome-associated biomarkers.
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