Protocol for the PRIMARY clinical trial, a prospective, multicentre, cross-sectional study of the additive diagnostic value of gallium-68 prostate-specific membrane antigen positron-emission tomography/computed tomography to multiparametric magnetic resonance imaging in the diagnostic setting for men being investigated for prostate cancer.

Abstract

Pre-biopsy multiparametric magnetic resonance imaging (mpMRI) for the detection of clinically significant prostate cancer (csPCa) is now standard of care for suspected prostate cancer. However, due to the limited positive predictive value (PPV) of mpMRI (50-60%), many unnecessary prostate biopsies are still performed. Further, although mpMRI has a high negative predictive value (NPV) of 85-95%, false negatives occasionally delay diagnosis and treatment. Prostate specific membrane antigen (PSMA) positron emission topography (PET)/computed tomography (CT) is commonly used in pre-treatment staging and localising post-treatment recurrence but has recently been observed to show promising accuracy for detecting the intra-prostatic focus of csPCa. The primary objectives of this study are: To determine the additive value of PSMA-PET/CT when combined with mpMRI in detecting csPCa in men undergoing initial biopsy for suspicion of PCa To determine the proportion of men who could have avoided prostate biopsy with positive mpMRI (PI-RADS ≥ 3) but negative PSMA-PET/CT The secondary objectives of this study are: To determine the proportion of men who had csPCa detected only by PSMA-PET/CT or only by systematic prostate biopsy. Comparison of index lesion identification by template biopsies vs targeted lesions identified on mpMRI or PSMA-PET/CT To assess whether there may be a health-economic benefit or harm if PSMA-PET/CT is incorporated into the diagnostic algorithm; and To develop a nomogram which combines clinical, imaging and biomarker data to predict the likelihood of csPCa. The PRIMARY trial is a multicentre, prospective cross-sectional study that meets criteria for level 1 evidence in diagnostic test evaluation. PRIMARY will investigate if a limited (pelvic only) 68 Ga-PSMA-PET/CT in combination with routine mpMRI can reliably discriminate men with csPCa from those without csPCa. We conducted a power calculation based on pilot data and will recruit up to 600 men who will have 68 Ga-PSMA-PET/CT (PSMA, the index test), mpMRI (MRI, the standard test) and transperineal template + targeted (PSMA and/ or MRI) biopsies (TPB, the reference test). The conduct and reporting of the MRI and PSMA-PET/CT will be blinded to each other. The PRIMARY trial will measure and compare sensitivity, specificity, PPV and NPV of both mpMRI and PSMA-PET/CT against TPB. The results will be used to determine the proportion of men who could safely avoid biopsy without compromising detection of clinically significant cancers. Furthermore, we will assess whether there is a health economic benefit in incorporating PSMA-PET/CT into the diagnostic algorithm. This trial will provide robust prospective data to determine the diagnostic ability of PSMA-PET/CT in addition to mpMRI. It will establish if certain patients can avoid biopsy in the investigation of PCa.