The Impasse of PSA-Based Screening
For decades, the prostate-specific antigen (PSA) test has served as the cornerstone of prostate cancer (PCa) screening. However, its clinical utility has been perpetually clouded by significant limitations, most notably its poor specificity and the subsequent risk of overdiagnosing indolent cancers that would never have caused clinical harm. The urological community has long grappled with the ‘diagnostic grey zone’—men with mildly elevated PSA levels who undergo invasive biopsies, often only to find benign results or low-grade disease (ISUP Grade Group 1). Conversely, PSA levels can sometimes be misleadingly low in the presence of aggressive disease. In response to these challenges, the PROSA trial (Primary Noncontrast Magnetic Resonance Imaging for Prostate Cancer Screening) was designed to evaluate a bold alternative: using noncontrast biparametric magnetic resonance imaging (bpMRI) as the primary screening tool, regardless of PSA levels.
The PROSA Trial: Study Design and Methodology
The PROSA trial was a single-center, randomized controlled trial that enrolled 816 asymptomatic men aged 49 to 69 years. Inclusion criteria were expanded to include men as young as 40 if they had a documented family history of prostate cancer. The participants were randomized into two distinct screening arms to compare the efficacy of an imaging-first approach against the traditional biochemical-first approach.
Arm A: The MRI-First Strategy
In Arm A, all participants underwent bpMRI screening regardless of their PSA concentration. This ‘imaging-first’ strategy aimed to bypass the diagnostic limitations of PSA by using structural and functional imaging to identify suspicious lesions directly.
Arm B: The PSA-Triggered Strategy
In Arm B, participants followed a more traditional pathway. They only received a bpMRI if their PSA levels met specific thresholds: ≥3 ng/ml for the general cohort, or ≥2.5 ng/ml for those with a positive family history.In both arms, the imaging protocol utilized a contrast-free biparametric approach (T2-weighted imaging and diffusion-weighted imaging), which eliminates the need for intravenous gadolinium, reducing both cost and potential side effects. Men with a Prostate Imaging Reporting and Data System (PI-RADS) score of 3 or higher were referred for a targeted biopsy. Clinical significant prostate cancer (csPCa) was defined as International Society of Urological Pathology (ISUP) grade group ≥2. To ensure scientific rigor, both imaging and pathology assessors were blinded to the randomization arm.
Primary Outcomes: A New Benchmark for Detection
The results of the PROSA trial, published in European Urology, suggest a significant shift in how we might approach PCa detection. Among the 759 men who completed the protocol, the detection rates for both biopsy and csPCa were markedly higher in the MRI-first group.
Detection Rates and Relative Risk
In Arm A (MRI-first), 10.8% of participants underwent a biopsy, compared to 5.2% in Arm B (PSA-triggered). More importantly, the detection rate for clinically significant prostate cancer was 4.6% in Arm A, versus only 1.8% in Arm B. This represents a relative risk (RR) of 2.6 (95% CI 1.1–6.1; p = 0.05). In simpler terms, the MRI-first strategy more than doubled the detection rate of cancers that actually require clinical intervention. These findings highlight a critical gap in traditional screening: a substantial number of significant cancers are likely being missed when we rely solely on PSA to trigger further investigation.
Redefining Benefit-Harm Metrics in Urologic Screening
A primary concern in any screening program is the balance between the benefit of early detection and the harm of unnecessary procedures. The PROSA trial utilized several metrics to evaluate this balance, all of which favored the MRI-first strategy.
Grade Selectivity and Biopsy Efficiency
Grade selectivity—a measure of how effectively a screening tool identifies high-grade disease over low-grade disease—was higher in the MRI-first group (1.89 vs. 1.75). Furthermore, biopsy efficiency (the ratio of csPCa detected to the total number of biopsies performed) was 0.74 in Arm A compared to 0.54 in Arm B. This indicates that when a biopsy was performed in the MRI-first arm, it was significantly more likely to yield a clinically meaningful result.
Biopsy Avoidance
One of the most compelling findings was the rate of biopsy avoidance. The imaging-first pathway allowed 23.1% of men to avoid biopsies that they might have otherwise undergone under different protocols, compared to 11.9% in the PSA-triggered arm. By using bpMRI as the filter, clinicians can more confidently reassure men with negative imaging, reducing the psychological and physical burden of invasive procedures.
The Economic Argument for Biparametric MRI
Critics of MRI-based screening often point to the high upfront costs of imaging compared to a simple blood test. The PROSA trial addressed this by calculating the incremental cost-effectiveness ratio (ICER) from a healthcare payer perspective. The MRI-first strategy yielded an ICER of €2201.75 per csPCa case detected. In the context of modern oncology, where many interventions cost tens of thousands of dollars per quality-adjusted life year (QALY), this figure is remarkably favorable. By using a biparametric (noncontrast) protocol, the study minimized the time required for each scan (often under 15 minutes) and eliminated the costs associated with contrast agents and specialized nursing care for IV administration.
Expert Commentary and Study Limitations
The PROSA trial provides high-quality evidence that imaging can and perhaps should precede or operate independently of PSA in the screening hierarchy. The biological plausibility of these results is well-supported: we know that some aggressive prostate cancers do not shed high amounts of PSA, but they are often visible on diffusion-weighted imaging due to high cellular density. However, several caveats must be considered. First, this was a single-center study, which may limit the generalizability of the results to centers with less experienced radiologists. The expertise required to accurately interpret bpMRI, particularly PI-RADS 3 lesions, is substantial. Second, the trial utilized a single-round design with relatively short follow-up. Long-term data are still needed to determine if this increased detection translates into a definitive reduction in prostate cancer-specific mortality. Finally, while the cost-effectiveness appears favorable, the infrastructure required to provide MRI screening for the general population would necessitate significant investment in imaging hardware and radiological training.
Conclusion
The PROSA trial marks a pivotal moment in the evolution of prostate cancer screening. By demonstrating that a contrast-free, MRI-first pathway significantly improves the detection of clinically significant disease while enhancing benefit-harm metrics, it challenges the long-standing PSA-centric model. For clinicians and health policy experts, these data suggest that the future of prostate health may lie in ‘seeing’ the disease before measuring it in the blood. As we move toward more personalized and precise medicine, the integration of bpMRI into early detection programs offers a promising route to reducing both the overdiagnosis of indolent disease and the underdiagnosis of aggressive cancers.
References
1. Messina E, Borrelli A, Sciarra A, et al. Primary Noncontrast Magnetic Resonance Imaging for Prostate Cancer Screening: A Randomized Clinical Trial (PROSA). Eur Urol. 2025;S0302-2838(25)04847-X. doi:10.1016/j.eururo.2025.11.024.
2. Eklund H, Jäderling F, Discacciati A, et al. MRI-Targeted or Standard Biopsy in Prostate Cancer Screening. N Engl J Med. 2021;385(8):683-693.
3. Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J Med. 2018;378(19):1767-1777.