Randomized Prospective Multi Center Cohort Study for Primary Diagnosis of Clinically Significant Prostate Cancer With Combination of PSA/DRE and Multi Parametric Magnetic Resonance Imaging

Study Overview
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Brief Summary
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This randomized prospective multi center study is designed to confirm a new diagnostic pathway in primary diagnosis of clinically significant prostate cancer by combination of serum levels of prostate specific antigen (PSA), digitorectal examination (DRE), and multiparametric magnetic resonance imaging (mpMRI). Men at the age of 50 to 75 with an elevated PSA (>= 4 ng/ml) and /or suspicious DRE receive an upfront multi parametric MRI. Only men with MRI results suspicious of clinically significant prostate cancer will be biopsied. Those will be randomized into arm A and arm B. Arm A undergoes only targeted MRI/US fusion-guided biopsies (= TB with a maximum of 3 targets and 2 cores per target). Arm B receives systematic biopsies (= SB with 12 biopsy cores) and TB. Men with normal mpMRI will be observed in a structured manner but will not be biopsied (arms C and D). The primary objective comprises the demonstration of non-inferiority of the detection clinically significant prostate cancer (ISUP grade group 1) of TB (arm A) compared to TB+SB (arm B). Overall, our study aims to improve patient care by reducing the number of patients biopsied, by reducing the number of biopsy cores per patient, and by lowering the risk of overdiagnosis of indolent prostate cancer. The results of this study will directly influence clinical practice, will have a positive impact on patients' lives, and will lower the financial burden due to reduced overdiagnosis and over treatment.

Detailed Description
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Men at the age of 50 to 75 years with an elevated PSA (≥ 4ng/ml) and/or suspicious DRE receive a multiparametric MRI (mpMRI) and will be stratified based on MRI results. Only men with suspicious MRI, PI-RADS 4/5, and PI-RADS 3 in conjunction with high PSA density (PSAD > 0.15) are biopsied. These will be randomized into arms A nd B. While patients in arm A undergo only targeted MRI/US fusion-guided biopsies (TB), patients in the combined arm B receive systematic biopsies (SB) and TB. The primary objective is to demonstrate non-inferiority in detecting clinically significant prostate cancer (ISUP grade group ≥ 2) and superiority in avoiding detection of clinically insignificant prostate cancers (ISUP grade group 1) of TB (arm A) compared to TB+SB (arm B). Interventions that are conducted within the PRIMA trial include PSA testing, digital rectal examination of the prostate (DRE), multiparametric prostate MRI, systematic and MRI/US fusion-guided biopsies as well as MRI inbore biopsies. Arms A + B: Men with PI-RADS 4/5 and PI-RADS 3 in conjunction with PSAD > 0.15 will be randomized into arm A or arm B and biopsied as explained above. Men with PI-RADS 3 and PSAD > 0.15 with negative biopsy results will receive a follow-up MRI annually and PSA every 6 months for 3 years. In case of upgrade to PI-RADS 4/5, men will be re-biopsied. Men with PI-RADS 4/5 without cancer diagnosis or with clinically insignificant cancer in the subsequent biopsy will be offered an additional MRI inbore biopsy. If MRI inbore biopsy is negative or with clinically insignificant cancer in men with PI-RADS 4/5, men will be followed-up with MRI annually and PSA every 6 months for 3 years. In the case of persistent PI-RADS 4/5, men will be re-biopsied. Men with an upgrade to PI-RADS 4/5 or an increase in PSAD will be randomized for biopsy into arms A or B. Arm C: Men with PI-RADS 3 and PSAD <= 0.15 will be classified as arm C with MRI annually and PSA every 6 months for 3 years. Arm D: Men with unsuspicious findings on MRI (PI-RADS 1 or 2) will be assigned to arm D with PSA every 6 months for 3 years. A control MRI will be performed after 3 years. At any time, a follow-up can be performed in case of clinical suspicion of PCa or a relevant PSA increase (> 1.0 ng/ml/a).

Official Title
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Randomized Prospective Multi Center Cohort Study for Primary Diagnosis of Clinically Significant Prostate Cancer With Combination of PSA/DRE and Multi Parametric Magnetic Resonance Imaging

Conditions
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Prostate Cancer

Intervention / Treatment
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* Diagnostic Test: PSA test
* Device: multiparametric prostate Magnetic Resonance Imaging (mpMRI)
* Procedure: targeted MRI/US fusion-guided biopsy
* Procedure: combined prostate biopsy (systematic biopsy plus targeted MRI/US fusion-guided biopsy)
* Procedure: MRI inbore biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men aged from 50 to 75 years elevated PSA ≥ 4 ng/ml and/or cancer suspicious DRE Exclusion Criteria: Men with known prostate cancer men with prior prostate biopsy men with non-MRI compatible devices men with acute prostatitis

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Men with PI-RADS 4/5 or PI-RADS 3 in conjunction with PSAD ≥ 0.15 that are randomized into arm A will undergo only targeted MRI/US fusion-guided biopsies. Men with PI-RADS 3 and PSAD > 0.15 with negative biopsy results will receive a follow-up MRI annually and PSA every 6 months for 3 years. In case of upgrade to PI-RADS 4/5, men will be re-biopsied. Men with PI-RADS 4/5 without cancer diagnosis or with clinically insignificant cancer in the subsequent biopsy will be offered an additional MRI inbore biopsy. If MRI inbore biopsy is negative or with clinically insignificant cancer, men will be followed-up with MRI annually and PSA every 6 months for 3 years. In the case of persistent PI-RADS 4/5, men will be re-biopsied. | Diagnostic Test: PSA test<br>* testing for blood levels of PSA<br>Device: multiparametric prostate Magnetic Resonance Imaging (mpMRI)<br>* mpMRI acquisition and reporting will be performed according to the current version of the Prostate Imaging-Reporting and Data System (PI-RADS). MpMRI will be performed at the different study centers on a 3 Tesla MR scanner using multi-phased array surface coil. MpMRI includes T1-weighted and T2-weighted imaging (T1WI, T2WI), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced imaging (DCE-MRI). Hyoscine butyl bromide will be administered to optimize image quality. Prostate imaging quality will be assessed by the prostate imaging quality score (PI-QUAL). In case of contraindications to MRI contrast agents, DCE will be omitted. In case of contraindications to hyoscine butyl bromide, it will be omitted. Lesions with a PI-RADS score of ≥ 4 and 3 with PSAD > 0.15 will considered suspicious for csPCa.<br>Procedure: targeted MRI/US fusion-guided biopsy<br>* Targeted MRI/US fusion-guided biopsy (TB) are performed using transrectal ultrasound (max. 6 cores from 3 targets). MRI/US fusion-guided biopsies can be performed transrectally or transperineally. Ultrasound-guided biopsies will be performed with a 3-D probe and with local or general anesthesia. Coverage with antibiotics has to be provided as per local standard of care for all biopsies.<br>Procedure: MRI inbore biopsy<br>* MRI inbore biopsies will be offered after negative initial MRI/US fusion-guided biopsy or diagnosis of only clinically insignificant PCa in initial biopsy in arms A or B. Before performing MRI inbore biopsy the PI-RADS scoring will be re-confirmed. The number of cores will be 2 per target. In case of inaccurate needle position additional cores are allowed to ensure correct targeting. Needle position will be verified in 2 planes. Coverage with antibiotics has to be provided as per local standard of care.<br>|
| Active Comparator: Arm B<br>Men with PI-RADS 4/5 or PI-RADS 3 in conjunction with PSAD ≥ 0.15 that are randomized into arm B will undergo targeted MRI/US fusion-guided biopsies and systematic biopsies (standard of care). Men with PI-RADS 3 and PSAD > 0.15 with negative biopsy results will receive a follow-up MRI annually and PSA every 6 months for 3 years. In case of upgrade to PI-RADS 4/5, men will be re-biopsied. Men with PI-RADS 4/5 without cancer diagnosis or with clinically insignificant cancer in the subsequent biopsy will be offered an additional MRI inbore biopsy. If MRI inbore biopsy is negative or with clinically insignificant cancer, men will be followed-up with MRI annually and PSA every 6 months for 3 years. In the case of persistent PI-RADS 4/5, men will be re-biopsied. | Diagnostic Test: PSA test<br>* testing for blood levels of PSA<br>Device: multiparametric prostate Magnetic Resonance Imaging (mpMRI)<br>* mpMRI acquisition and reporting will be performed according to the current version of the Prostate Imaging-Reporting and Data System (PI-RADS). MpMRI will be performed at the different study centers on a 3 Tesla MR scanner using multi-phased array surface coil. MpMRI includes T1-weighted and T2-weighted imaging (T1WI, T2WI), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced imaging (DCE-MRI). Hyoscine butyl bromide will be administered to optimize image quality. Prostate imaging quality will be assessed by the prostate imaging quality score (PI-QUAL). In case of contraindications to MRI contrast agents, DCE will be omitted. In case of contraindications to hyoscine butyl bromide, it will be omitted. Lesions with a PI-RADS score of ≥ 4 and 3 with PSAD > 0.15 will considered suspicious for csPCa.<br>Procedure: combined prostate biopsy (systematic biopsy plus targeted MRI/US fusion-guided biopsy)<br>* The combined biopsy comprises systematic biopsy (SB) and targeted MRI/US fusion-guided biopsy (TB). They are performed using transrectal ultrasound (number of cores: SB 12 cores, TB max. 6 cores from 3 targets). MRI/US fusion-guided biopsies can be performed transrectally or transperineally. Ultrasound-guided biopsies will be performed with a 3-D probe and with local or general anesthesia. Coverage with antibiotics has to be provided as per local standard of care for all biopsies.<br>Procedure: MRI inbore biopsy<br>* MRI inbore biopsies will be offered after negative initial MRI/US fusion-guided biopsy or diagnosis of only clinically insignificant PCa in initial biopsy in arms A or B. Before performing MRI inbore biopsy the PI-RADS scoring will be re-confirmed. The number of cores will be 2 per target. In case of inaccurate needle position additional cores are allowed to ensure correct targeting. Needle position will be verified in 2 planes. Coverage with antibiotics has to be provided as per local standard of care.<br>|
| Other: Arm C<br>Men with PI-RADS 3 in conjunction with PSAD < 0.15 will not be biopsied, but followed-up with MRI annually and PSA every 6 months for 3 years. | Diagnostic Test: PSA test<br>* testing for blood levels of PSA<br>Device: multiparametric prostate Magnetic Resonance Imaging (mpMRI)<br>* mpMRI acquisition and reporting will be performed according to the current version of the Prostate Imaging-Reporting and Data System (PI-RADS). MpMRI will be performed at the different study centers on a 3 Tesla MR scanner using multi-phased array surface coil. MpMRI includes T1-weighted and T2-weighted imaging (T1WI, T2WI), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced imaging (DCE-MRI). Hyoscine butyl bromide will be administered to optimize image quality. Prostate imaging quality will be assessed by the prostate imaging quality score (PI-QUAL). In case of contraindications to MRI contrast agents, DCE will be omitted. In case of contraindications to hyoscine butyl bromide, it will be omitted. Lesions with a PI-RADS score of ≥ 4 and 3 with PSAD > 0.15 will considered suspicious for csPCa.<br>|
| Other: Arm D<br>Men with PI-RADS 1 or 2 will not be biopsied, but followed-up with PSA every 6 months for 3 years. A control MRI will be performed after 3 years. At any time, a follow-up can be performed in case of clinical suspicion of PCa or a relevant PSA increase (> 1.0 ng/ml/a). | Diagnostic Test: PSA test<br>* testing for blood levels of PSA<br>Device: multiparametric prostate Magnetic Resonance Imaging (mpMRI)<br>* mpMRI acquisition and reporting will be performed according to the current version of the Prostate Imaging-Reporting and Data System (PI-RADS). MpMRI will be performed at the different study centers on a 3 Tesla MR scanner using multi-phased array surface coil. MpMRI includes T1-weighted and T2-weighted imaging (T1WI, T2WI), diffusion-weighted imaging (DWI), and dynamic contrast-enhanced imaging (DCE-MRI). Hyoscine butyl bromide will be administered to optimize image quality. Prostate imaging quality will be assessed by the prostate imaging quality score (PI-QUAL). In case of contraindications to MRI contrast agents, DCE will be omitted. In case of contraindications to hyoscine butyl bromide, it will be omitted. Lesions with a PI-RADS score of ≥ 4 and 3 with PSAD > 0.15 will considered suspicious for csPCa.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| detection rate of clinically significant and insignificant prostate cancers | The composite primary endpoint comprises the detection rate of clinically significant prostate cancers (ISUP grade group >= 2) and the detection rate of clinically insignificant prostate cancers (ISUP grade group 1) of TB (arm A) compared to TB + SB (arm B) | 84 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain score (Visual Analogue Scale [VAS]) | Patient Reported Outcomes (PROs) - diagnostic burden in arm A and B | 84 months | 
| Patient Reported Outcomes (PROs) - operation/intervention time | operation/intervention time in arm A and B | up to 84 months | 
| Patient Reported Outcomes (PROs) - complications after biopsy | 30-day complication-rate after biopsy in arm A and B | 30-day | 
| Patient Reported Outcomes (PROs) - quality of life according to EORTC-QLQ-C30 | quality of life according to EORTC-QLQ-C30 (European Organisation for Research and Treatment of Cancer - Quality of Life of Cancer Patientes; Scoring according to manual) in all different study arms | 84 months | 
| Patient Reported Outcomes (PROs) - quality of life according to EPIC-26 | quality of life according to EPIC-26 (Expanded prostate cancer index composite; Scoring according to manual) in all different study arms | 84 months | 
| Patient Reported Outcomes (PROs) - fatigue | fatigue according to fatigue module EORTC-QLQ-FA12 (Scoring according to manual) in all different study arms | 84 months | 
| Patient Reported Outcomes (PROs) - sleep quality | sleep quality according to PSIQ (Pittsburgh Sleep Quality Index; a global score is calculated from several component score whereat a lower score represents healthier sleep quality; Scoring according to manual) in all different study arms | 84 months | 
| Patient Reported Outcomes (PROs) - cognitive function | cognitive function according to FACT-cog (Functional Assesment of Cancer Therapy - Cognitive Function; 5-point-Likert Scale; Scoring according to manual) in all different study arms | 84 months | 
| Patient Reported Outcomes (PROs) - anxiety and depression | anxiety and depression according to PHQ-4 (Patient Health Questionaire; 4-point-Likert-Scale; Scoring according to manual) in all different study arms | 84 months | 
| number of biopsies avoided | Number of biopsies avoided with pre-biopsy mpMRI | 84 months | 
| detection rate of MRI inbore biopsy | Detection rate of MRI inbore biopsy after negative TB | 84 months | 
| detection rate of biparametric MRI | Detection rate of biparametric MRI (no perfusion imaging) | 84 months | 
| Number of up- and downgrading of PI-RADS score | Number of up- and downgradings of PI-RADS (Prostate Imaging - Reporting and Data System) score in follow-up mpMRIs | 84 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PSA, prostate cancer diagnosis, multiparametric Magnetic Resonance Imaging (mpMRI), detection of clinically significant prostate cancer, avoidance of over diagnosis, prostate cancer