Recruitment begins for the PRIME Study

Dr. Veeru Kasivisvanathan University College London and UCLH PRIME Chief Investigator

primestudy@ ucl.ac.uk Twitter: @veerukasi

Ms. Aqua Asif University College London and University of Leicester PRIME Research Assistant

Twitter: @AquaOishee

Background Multiparametric MRI (mpMRI) is internationally recommended for men who present with suspicion of prostate cancer. This change in guidelines recommendation has created a new demand on resources.

We believe that every man who needs an MRI should have access to one.

Would removing the dynamic contrast enhanced (DCE) images from mpMRI help in delivering our goal? The DCE sequence can be time and labour consuming due to the use of intravenous contrast. Recent data has suggested that the DCE sequence may not be necessary and the biparametric (T2W and DWI) sequences may detect as much clinically significant prostate cancer (csPCa).

Replacing the mpMRI scan with a bpMRI scan can increase the number of MRI scans performed in any given day, reduce costs from the need for medical staff to be present and reduce the need for use of contrast medium. This would make meeting the high demand of MRI scans now required in prostate cancer diagnosis more feasible.

Limitations of some of the previous studies in this area: • Small sample size, single institution retrospective studies • No true blinding of the radiologists reporting the bi-parametric MRI to the DCE sequence • Using an MRI scoring system that already assumes that DCE has no role in differentiating between who needs a biopsy and who doesn’t • No MRI-targeted biopsies

Aim The PRIME study, therefore, aims to assess whether bi-parametric MRI (T2W & DWI) is non-inferior to multi-parametric MRI (T2W, DWI and DCE) in the diagnosis of clinically significant prostate cancer.

Sample size 500 patients

Intended length of recruitment 24 months

Patient eligibility criteria Key inclusion criteria: 1. Men at least 18 years of age referred with clinical suspicion of prostate cancer 2. Serum PSA ≤ 20ng/ml 3. Able to provide written informed consent

Key exclusion criteria: 1. Prior prostate biopsy or prostate MRI 2. Contraindication to MRI or prostate biopsy

Study design PRIME (NCT04571840) is a prospective, international, within-patient, multicentre, level 1–evidence clinical trial evaluating whether bpMRI is noninferior to mpMRI in the detection of csPCa. Men with clinical suspicion of PCa undergo mpMRI as per standard of care. The DCE sequence is then blinded from the radiologists to report the bpMRI. The DCE sequence will then be unblinded to the radiologist to report the full mpMRI. All MRI scans are reported using Likert and PI-RADS v2.1 scores.

Patients with non-suspicious MRI (scores 1 or 2) on bpMRI and mpMRI and low risk of PCa will be recommended to undergo PSA surveillance. Patients with suspicious MRI (scores 3,4 or 5) on either bpMRI or mpMRI will undergo MRI-targeted biopsy. Suspicious areas will be labelled with their location and whether they were suspicious on either bpMRI or mpMRI. Targeted biopsy cores will be stored separately from areas that were uniquely suspicious on DCE so that conclusions can be made on whether the pathology was from suspicious areas on the bpMRI or mpMRI or both. Systematic biopsies will also be taken. The simplified study schema is shown below in Figure 1.

Primary outcome: The proportion of men with clinically significant cancer detected (Gleason score ≥ 3+4) / Gleason Grade Group 2 or greater).

Key secondary outcomes: 1) Agreement between bpMRI and mpMRI in score of suspicion; 2) Proportion of men with clinically insignificant cancer detected (Gleason grade 3+3 / Gleason grade group 1) and; 3) Agreement between bpMRI and mpMRI on treatment decision eligibility

Mr. Vinson Wai-Shun Chan University College London and University of Leeds PRIME Research Assistant

Twitter: @VinsonChan

Mr. Arjun Nathan University College London and UCLH PRIME Academic Clinical Fellow

Twitter: @ArjunSNathan

Study recruitment and current status We are delighted to announce that the PRIME study has attracted over 60 sites from 22 countries expressing interest to take part. Sites thereafter undergo quality control of their MRI facilities to assess their eligibility, using the Prostate Imaging Quality (PI-QUAL) scoring system (1). The PI-QUAL scoring system was developed from the PRECISION study (2), and gives a score of 1-5 for an MRI scan relating to its image quality. A score of 1 means no mpMRI sequences are of diagnostic quality, a score of 3 means mpMRI quality was of sufficient diagnostic quality and a score of 5 means each sequence is independently of optimal diagnostic quality (1). Sites are helped to improve their MRI quality so that they can take part in the study. The full site recruitment process is shown in Figure 2.

Current Status MRI quality control has occurred for 40 centres, with now 32 of them achieving an optimal PI-QUAL score of 5. Currently, there are 26 sites in the set-up stage. The coordinating site, University College London Hospital (UCLH), is the first site to have completed the site initiation visit. Our team looks forward to opening more sites internationally throughout 2022. We anticipate recruitment to close by Q1 2024.

Implications of study If bpMRI is non-inferior to mpMRI, then bpMRI will become the new standard of care for prostate cancer detection in men with suspected prostate cancer. This will allow a greater capacity to deliver MRI scans so that every man who needs a scan will be able to get one.

If however, the DCE sequence in mpMRI identifies a large proportion of significant cancer and significantly influences staging and treatment eligibility decisions, then mpMRI will be recommended to stay the standard of care.

Funding The PRIME Study (NCT04571840) is funded by Prostate Cancer UK, The John Black Charitable Foundation, the European Association of Urology Research Foundation, and the Dieckmann Foundation.

The Trial Management Group includes: Chief Investigator: Dr. Veeru Kasivisvanathan University College London NCITA Trials group: Prof. Caroline Moore, Dr. Pramit Khetrapal, Dr. Chris Brew-Graves, Dr. Nicola Muirhead, Ms. Réka Novota, Mr. Phil Ryan, Prof. Shonit Punwani, Prof. Mark Emberton, Mr. Alexander Ng, Ms. Aqua Asif, Mr. Vinson Wai-Shun Chan, Mr. Arjun Nathan, Ms. Marimo Rossiter Statistics by University of Birmingham Test Evaluation Research Group, Dr. Yemisi Takwoingi, Prof. Jon Deeks, Dr. Ridhi Agarwal. Chief Radiologists: Dr. Clare Allen, Dr. Francesco Giganti Chief Pathologists: Dr. Alex Freeman, Dr. Aiman Haider Health Economists: Prof. Laura Lorelle, Dr. Caroline Clarke, Miss Jessica Weng EAU Research Foundation: Dr. Wim Witjes, Ms. Christien Caris, Prof. Anders Bjartell, Ms. Joke Van Egmond Trial Network: PRECISION & START Consortium

Study website https://www.ucl.ac.uk/surgery/research/departmenttargeted-intervention/urology/prime-trial-information

Country Site Principal Investigator United Kingdom University College London Hospital Veeru Kasivisvanathan, Caroline Moore Royal Free Hospital Paras Singh Addenbrooke’s Hospital Tristan Barrett, Christof Kastner Whittington Hospital Maneesh Ghei Denmark Herlev Gentofte University Hospital Lars Boesen Finland Helsinki University Hospital Antti Rannikko Germany University Hospital Essen Claudia Kesch, Boris Hadaschik Martini-Klinik am UKE Lars Budaeus Heinrich Heine University Düsseldorf Jan Philipp Radtke, Lars Schimmöller University Hospital Frankfurt Felix Chun, Felix Preisser

Spain University Hospital Reina Sofía Enrique Gómez Gómez, Daniel José López Ruiz University Hospital La Moraleja Miguel Angel Rodríguez Cabello, Carolina Aulló Gonzanlez

United States of America Mayo Clinic, Rochester NYU Langone Lance A Mynderse Samir S. Taneja

Weill-Cornell Medical Center

Daniel Jason Aaron Margolis, Jim C Hu Icahn School of Medicine, Mount Sinai Ash Tewari France Sorbonne Université Raphaele Renard Penna Centre Hospitalier Universitaire de Bordeaux Gregoire Robert Centre Hospitalier Universitaire de Lille Arnauld Villers, Philippe Puech The Netherlands Radboud University Medical Center Maarten de Rooij, Bas Israël Belgium Ghent University Hospital Pieter De Visschere Italy University Hospital of Udine Rossano Girometti University of Rome Tor Vergata Roberto Miano San Giovanni Battista Hospital Marco Gatti, Giancarlo Marra San Raffaele Hospital Alberto Briganti Sapienza University of Rome Valeria Panebianco Singapore Tan Tock Seng Hospital Jeffrey J Leow Brazil Hospital Sírio-Libanês Publio Cesar Cavalcante Viana, Adriano Basso Dias Argentina Centre de Urologia CDU Marcelo Borghi, Hernando Rios Pita Canada Princess Margaret Cancer Centre Sangeet Ghai Australia Alfred Health, Monash University Jeremy Grummet, Richard O'Sullivan Peter MacCallum Centre Centre Declan Murphy Table 1: Sites undergoing contracting process and their principal investigators

References

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Kasivisvanathan V. Prostate Imaging Quality (PI-QUAL):

A New Quality Control Scoring System for Multiparametric

Magnetic Resonance Imaging of the Prostate from the

PRECISION trial. Eur Urol Oncol. 2020;3(5):615-9. 2. Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V,

Mynderse LA, Vaarala MH, et al. MRI-Targeted or

Standard Biopsy for Prostate-Cancer Diagnosis. New

England Journal of Medicine. 2018;378(19):1767-77.