SUO 2024: Prostate Cancer Screening with Biomarkers and MRI–A European Perspective

Dr. Nordström began his presentation by discussing the case of a 55-year-old Scandinavian man with no family history of prostate cancer, who wanted to know if he had the disease and if the benefits of screening outweigh harms. He highlighted that in Sweden, 5% of men die from prostate cancer, while 20% are diagnosed with it. Dr. Nordström then presented data from the Göteborg randomized population-based prostate cancer screening trial. This study randomized men in a 1:1 ratio to either a screening group, which was invited for PSA testing every 2 years, or a control group, which was not invited for testing. The results showed that prostate cancer mortality was reduced by nearly half over 14 years.¹

Similarly, data from the European Randomized Study of Screening for Prostate Cancer (ERSPC) compared a group of men invited for prostate cancer screening based on PSA levels to a control group without active intervention. Active screening led to a statistically significant reduction in prostate cancer mortality, with the number needed to invite (NNI) to prevent one death from prostate cancer is 570, and the number needed to treat (NNT) to prevent one death was 18. However, the data remains contradictory. After almost 17 years of median follow-up from the US-based Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), no significant reduction in prostate cancer mortality was observed in the screening group compared to the usual care arm.^2,3

However, using Cox regression analysis to evaluate death from prostate cancer and estimating mortality reduction in the ERSPC and PLCO trials, with adjustments for participant age at randomization and extended analysis across different study sites (University of Michigan, Fred Hutchinson Cancer Research Center, and Erasmus University Medical Center), the extended analysis revealed an approximately 30% reduction in prostate cancer mortality in both the ERSPC and PLCO studies,⁴ as illustrated below:

The recently published ProScreen trial in Finland (organized screening) randomized 61,193 men aged 50 to 63 years, who were free of prostate cancer, in a 1:3 ratio to either be invited or not invited for prostate cancer screening. The screening protocol involved an initial PSA test, followed by a four-kallikrein panel for men with a PSA ≥3 ng/mL. Those with a score ≥7.5% were referred for mpMRI, and men with PI-RADS scores ≥3 underwent a prostate biopsy. The screening protocol detected one additional high-grade cancer per 196 men and one low-grade cancer per 909 men in the screening group compared to the control group.⁵

Dr. Nordström presented data from a population-based study he led, showing that despite prostate cancer screening not being recommended in Sweden during the study period (2003-2011), unstructured PSA testing was prevalent. Up to 65% of men aged 50-69 were tested within five years. Additionally, 38% of men with a PSA <1 were retested within two years, and 39% of men aged 80-89 were also retested in the same period. The likelihood of PSA retesting remained high regardless of the initial PSA level or age group, which contrasts with current clinical recommendations.⁶

The current diagnostic process for the early detection of prostate cancer typically follows this path: patients are invited to undergo PSA testing, and if the results are abnormal, they receive an MRI. Based on the MRI findings, patients may then be referred for a prostate biopsy as outlined below:

Dr. Nordström discussed the population-based, screen-by-invitation STHLM3-MRI paired randomized clinical trial, which enrolled Swedish men aged 50 to 74 years. A total of 12,750 participants underwent blood sampling, including PSA testing and Stockholm3. A biparametric MRI was performed if PSA ≥ 3 ng/mL and/or Stockholm3 test >0.11 if PSA≥1.5 ng/mL, with men showing lesions with a PI-RADS score ≥ 3 referred for targeted and systematic biopsies or to standard biopsies if the MRI had a PIRADS 1-2, and the pathology was centralized. The investigators found that the percentage of clinically insignificant cancers (Gleason 6) was lower in the experimental biopsy group compared to the standard biopsy group, while the percentage of clinically significant cancer detection was higher in the MRI-positive biopsy group. Furthermore, the percentage of benign biopsies or biopsy procedures was lower in the experimental arm. These findings emphasize that biopsies in MRI-positive men reduce overdiagnosis and the number of biopsies required in screening.⁷

Similarly, in the GÖTEBORG-2 Trial, investigators invited men aged 50 to 60 years to undergo regular PSA screening. Participants with a PSA level ≥ 3 ng/mL underwent prostate MRI; if the MRI showed no abnormalities, patients did not undergo a biopsy. Those with positive MRI findings were randomly assigned to a reference group, which underwent both systematic biopsy and targeted biopsy of suspicious lesions, while the remaining participants were assigned to the experimental group, which only underwent MRI-targeted biopsy. Avoiding systematic biopsies in favor of MRI-directed biopsies reduced the detection of Gleason score 6 cancers by half, but at the cost of delaying detection of intermediate-risk tumors (Gleason 3+4) in a small proportion of patients (n=10).⁸

Notably, there is a high proportion (≈63%) of negative MRIs (PI-RADS 1-2) in the screening cohorts of the STHLM3-MRI trial, the GÖTEBORG-2 Trial, and the OPT Sweden cohort. We are now dealing with a lot of men having negative MRIs. 

The question we should ask ourselves is how biomarkers might contribute to the early detection of prostate cancer within the current diagnostic framework. Dr. Nordström then discussed the Stockholm3 test, which combines proteins (plasma concentrations of total and free PSA, PSP94, GDF15, and KLK2), genetics (101 SNPs), and clinical patient data (age, family history of prostate cancer, previous biopsies, and use of 5-alpha reductase inhibitors). This test generates a risk score to predict the likelihood of clinically significant prostate cancer 

The Stockholm3 test outperformed PSA and reduced the need for MRI in the prospective, population-based, randomized, open-label, non-inferiority trial (STHLM3-MRI).⁹ The area under the receiver operating characteristic (ROC) curve for detecting clinically significant prostate cancer was 0.76 for Stockholm3, compared to 0.60 for PSA. In the experimental group, a Stockholm3 score of ≥ 0.11 was non-inferior to a PSA level of ≥ 3 ng/mL for detecting clinically significant prostate cancer (relative proportion 1.18, p < 0.0001). Additionally, Stockholm3 led to fewer MRI procedures (relative proportion 0.64 [0.55–0.82]) and fewer biopsy procedures. 

Similarly, in a study comparing a PSA level of ≥ 3 ng/mL versus a combination of PSA ≥ 3 ng/mL and a 4Kscore ≥ 7.5%, the AUC for the 4Kscore as a reflex test before MRI was calculated to be 0.84 (95% CI 0.79–0.89) for detecting intermediate- to high-grade prostate cancer. In this study, for every 1,000 men with elevated PSA, adding the 4Kscore would have resulted in avoiding MRI for 408 men (41%), diagnosing 23 low-grade cancers (a 23% reduction), while delaying the diagnosis of four men with intermediate-grade cancers (ISUP ≥ 2, 4%).¹⁰ Dr. Nordström noted that we should consider using this test in our clinical practice in some selected cases, which is now endorsed by clinical practice guidelines. 

Dr. Nordström mentioned that the 2024 clinical practice guidelines recommend using an additional serum or urine biomarker test in patients with a PSA ≥ 3 ng/mL and normal DRE for biopsy indication, provided these tests improve the specificity of screening, although the strength of these recommendations is weak. The NCCN guidelines recommend prostate health index (PHI), 4K Score, SelectMDx, ExoDX, MyProstateScore (MPS), and IsoPSA. In contrast, the EAU guidelines recommend PSA density, PHI, 4K, IsoPSA, PCA3, SelectMDx, ExoDx, and MPS. 

Despite the emergence of new biomarkers, unresolved questions remain, and it is crucial to evaluate whether the decision aids already available work in patients within our practice. Dr. Nordström and colleagues performed an external validation of risk calculators to assess their clinical applicability beyond the settings in which they were developed. They evaluated the performance of the Rotterdam Prostate Cancer Risk Calculator (RPCRC) and the Prostate Biopsy Collaborative Group Risk Calculator (PBCG-RC) using data from the prospective, population-based STHLM3 screening study, focusing on patients with PSA ≥ 3 ng/mL who underwent systematic prostate biopsies. They found that the distribution of risk predictions differed between the two calculators, with median risks for clinically significant prostate cancer of 3.3% for the RPCRC and 20% for the PBCG-RC. However, they noted that 36% of participants would receive concordant biopsy recommendations using these risk calculators. The AUC for the RPCRC was 0.74, and for the PBCG-RC, it was 0.70. This underscores the importance of assessing calibration to ensure the clinical value of risk prediction tools in each setting.¹¹

Validation of the Stockholm3 test in a multi-ethnic cohort for prostate cancer detection compared PSA and Stockholm3 in Asian, Black, and Hispanic men who are often underrepresented in prostate cancer clinical trials. The investigators found that Stockholm3 ≥ 0.15 showed non-inferior sensitivity (0.95) compared with PSA ≥4 ng/mL and nearly three times higher specificity (2.91).¹²

The results of the analysis were consistent across racial and ethnic subgroups, showing significant differences in the AUCs when comparing PSA and Stockholm3. Compared with PSA, Stockholm3 could reduce benign and ISUP 1 biopsies by 45% in the overall cohort, 46% in Asian and Black individuals, 53% in Hispanic individuals, and 42% in White individuals as shown below:

In the extended follow-up (4 years) of the population-based trial led by Hugosson et al.,¹³ an MRI screening strategy that omitted biopsy in patients with negative MRI results eliminated more than half of diagnoses (RR 0.43) of clinically insignificant prostate cancer (ISUP Grade 1), as shown in the graphic below:

Recently, data from the population-based, screen-by-invitation STHLM3-MRI randomized clinical trial, which evaluated cancer detection during the second screening round at 2-3 years, found that 73% of MRI-naïve individuals still had negative MRI results, and 86% of the MRIs performed were negative. Only 3% of previously negative MRI individuals developed new MRI lesions (PI-RADS ≥4), and 6% had PI-RADS 3 lesions. Cancer detection in re-screened participants was very limited: ISUP 1: 0.7%, ISUP ≥2: 3%, ISUP ≥3: 0.8%.⁷ This raises more questions than answers regarding how to design re-screening trials. We need to make screening more efficient so we can provide value to the patient but also to increase the diagnosis of clinically significant prostate and avoid diagnosis low-risk prostate cancers.

Moreover, in a secondary analysis of the STHLM3-MRI randomized clinical trial, the Stockholm3 test at different cut-offs (≥0.11 and ≥0.15) increased the diagnosis of clinically significant prostate cancer (ISUP ≥2 and ISUP ≥3) compared to a PSA ≥3 ng/mL. This strengthens the evidence that risk stratification using Stockholm3 performs well in the second screening setting.

An economic evaluation study from a lifetime healthcare perspective used a microsimulation model to compare no screening with screening strategies among adult men in Sweden, using parameters from the STHLM3-MRI study (NCT03377881). The results showed that compared with no screening, the screening strategies reduced lifetime prostate cancer–related deaths by 6% to 9%. The moderate cost per QALY compared to no screening was $53,736, which is classified as a moderate cost per QALY gained in Sweden. MRI-based screening was found to be cost-effective compared to traditional PSA screening and standard biopsies.¹⁴

In the economic evaluations of the STHLM3-MRI study, adding biomarker-based tests like Stockholm3 showed a moderate cost per QALY (€47,000) for Stockholm3 + MRI compared to no screening. The combination of PSA ≥2 ng/ml + Stockholm3 ≥0.15 + MRI + targeted/systematic biopsy had the lowest cost per QALY. Using Stockholm3 could reduce MRI usage by 60%. Screening with the Stockholm3 test at a reflex threshold of PSA ≥2 ng/ml, followed by MRI, was predicted to be cost-effective in Sweden.¹⁵

Dr. Nordström noted that screening for early detection of prostate cancer in Europe is characterized by a strong movement toward structured early detection programs. However, it remains unclear whether this will be a short race, quickly gaining traction for political decisions, or as is more usual in medicine, a long-distance marathon.

He highlighted the European Union's Praise U smart early detection program, which is a 3-year program, running now for the second year. Praise U aims to improve early detection for prostate cancer and to develop several other healthcare policies. Specifically, PRAISE-U (PRostate cancer Awareness and Initiative for Screening in the European Union) program is an initiative under the EU4Health programme aiming to develop a cost-effective, nationally tailored, organized, early detection algorithm for prostate cancer screening across the EU.

In Sweden, organized prostate cancer testing by invitation has yielded several valuable lessons. A centralized organization for testing is critical to ensure consistency and efficiency. Referral processes for further work-up after initial screening is feasible within this framework and is of utmost importance to have good quality control for the organized screening programs. The program has achieved a 35% participation rate, although there is notable regional variability in the proportion of positive PSA tests. This variability underscores the need for tailored approaches to screening and follow-up based on local demographics and healthcare capacities.

Dr. Nordström concluded his keynote presentation with the following messages:

• Risk prediction tools shift the benefit/harm balance of prostate cancer early detection.
• Biomarker-based tests such as Stockholm3 can save about a third of MRIs per testing round while maintaining sensitivity.
• Alternatively, biomarker tests can be used to improve case detection while maintaining the use of imaging.
• Adding biomarkers to PSA and MRI in prostate cancer detection is health-economically attractive.
• Quality control is essential for the effective implementation of these strategies.
• European initiatives for organized prostate cancer screening are now being conducted.

Presented by: Tobias Nordström, MD, Associate Professor Consultant Urologist of Karolinska Institutet, Solna (KI).

Written by: Julian Chavarriaga, MD – Urologic Oncologist at Cancer Treatment and Research Center (CTIC) Luis Carlos Sarmiento Angulo Foundation via Society of Urologic Oncology (SUO) Fellow at The University of Toronto. @chavarriagaj on Twitter during the 2024 Society of Urologic Oncology (SUO) annual meeting held in Dallas, between the 3^rd and 6^th of December, 2024. 

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