Stockholm3 has been evaluated in several large clinical studies as well as in clinical practice. More than 75,000 men in Sweden and Norway have participated in clinical studies which include randomized and paired population-based screening studies, observational studies from routine clinical use and health economics studies. The scientific studies of Stockholm3 have been published in over 25 articles in leading scientific journals such as The Lancet Oncology and European Urology.

Population-based diagnostic studies

The purpose of the study was to develop and validate a testing method for identifying aggressive prostate cancer (Gleason score ≥7) with better precision than PSA tests.

The primary purpose was to increase the specificity compared with PSA tests without reducing the sensitivity for diagnosing aggressive prostate cancer. The STHLM3 study was a prospective population-based diagnostic study with a “paired design”, which means that the patient was their own control. Men between the ages of 50 and 69 without prostate cancer were randomly invited by birth date from the Swedish population register.

Stockholm3 was significantly better than PSA tests at detecting aggressive cancer (p <0.0001); AUC was 0.56 (95 per cent CI 0.55–0.60) for PSA and 0.74 (95 per cent CI 0.72–0.75) for Stockholm3. All variables used in Stockholm3 were significantly associated with aggressive prostate cancer (p <0.05) in a regression model.
The study showed that Stockholm3 reduces unnecessary biopsies with retained sensitivity for diagnostics of aggressive prostate cancer (Gleason score ≥7).

The purpose of this study was to compare a traditional screening method (PSA with systematic biopsies) with a strategy based on blood tests in combination with MR-targeted biopsies. The primary outcome variable was the detection of aggressive prostate cancer (Gleason score ≥7) in a prostate biopsy. The STHLM3-MRI study was a prospective population-based randomized open non-inferiority study conducted in Stockholm County. Men between the ages of 50 and 74 were randomly selected by SCB and invited via post to take part in the screening: those with elevated risk for prostate cancer, defined as either PSA ≥3.0 ng/ml or Stockholm3 Risk Score ≥0.11 were qualified for randomization.

12,750 men participated in the study; of these, 2,293 men with elevated risk were randomized. The AUC for aggressive prostate cancer was 0.76 for Stockholm3, which was significantly better than 0.60 for PSA. At the same sensitivity for detection of aggressive prostate cancer as PSA combined with MRI, Stockholm3 (0.15) combined with MRI yielded a reduction of 36 percent in the number of MRIs and 18 percent in unnecessary biopsies. Compared with PSA and systematic biopsies, screening with Stockholm3 (0.15) combined with  MRI had both improved sensitivity and specificity. Detection of aggressive prostate cancer increased to 122 percent while the number of unnecessary biopsies decreased 76 percent.

The study showed that Stockholm3 yielded a more precise risk assessment prior to MRI and targeted biopsies in screening for prostate cancer compared with PSA. By combining Stockholm3 with MRI-targeted biopsies for prostate cancer screening, overdiagnosis was reduced while retaining the ability to detect aggressive prostate cancer.

The purpose of the study was to compare strategies based on previous and current national guidelines, Stockholm3, and MRI to select patients for biopsy in a screening-by-invitation setting.

Recruitment for the study was carried out in the Värmland Region between 2019 and 2020. Invitations were sent to 8,764 men, of whom 2,511 participated in the study and submitted a PSA test. Men with PSA ≥ 3 (N = 272) also performed a Stockholm3 test and magnetic camera examination. The study evaluated four different diagnostic strategies: i) National guidelines in Sweden until 2019, ii) National guidelines in Sweden from 2020, iii) Magnetic camera, and iv) Stockholm3.

In brief the study showed that compared with current Swedish guidelines, Stockholm3 finds the same number of aggressive tumors, with a reduced number of magnetic camera examinations (-88 percent), reduced overdiagnosis (-18 percent) and fewer unnecessary biopsies (-15 percent). It also showed that compared with magnetic camera examinations, Stockholm3 finds more aggressive tumors (+7 percent), with a reduced number of supplementary magnetic camera examinations (-88 percent), reduced overdiagnosis (-23 percent) and fewer unnecessary biopsies (-39 percent).

Reality-based outcomes from clinical implementation

The purpose of this study was to describe a nurse-led structured diagnostic model for prostate cancer diagnosis based on Stockholm3 in combination with MRI. Men between the ages of 45 and 75 who had requested prostate cancer testing and had not previously been diagnosed with prostate cancer participated in the study. Those who had a Stockholm3 score of ≥11 were referred for an MRI examination, and subsequently a biopsy if the MRI displayed a positive result.

547 men underwent prostate cancer testing in the study. Compared with PSA ≥3.0 ng/ml, Stockholm3 together with MRI reduced the number of biopsies by 32 percent and increased sensitivity by more than 100 percent (8 percent positive cases against 3 percent). Healthcare costs decreased 17 percent compared with PSA testing in combination with MRI. The conclusion was that Stockholm3 compared with PSA increased detection of aggressive prostate cancer while simultaneously reducing overdiagnosis, the number of biopsies and costs.

The objective of this study was to compare the number of tumors and biopsies that are required if Stockholm3 is to replace current clinical practice in Stockholm. The outcome was estimated by comparing biopsy results from 56,282 men who were tested in 2011 using PSA tests in accordance with current clinical practice in Stockholm with the 47,688 who were included in the validation cohort in the STHLM3 study between 2012 and 2015. The results showed that with retained sensitivity, as with current standard of care for diagnosis of aggressive prostate cancer (Gleason score ≥ 7), Stockholm3 would have reduced the number of men who needed to undergo a biopsy 53 percent, avoided 65 percent of unnecessary biopsies and reduced over-detection of Gleason score 6 tumors 23 percent.

The conclusion was that Stockholm3, compared with current standard of care, would retain sensitivity but substantially reduce the number of biopsies, thereby having the potential to improve prostate cancer diagnostics by improved precision in identifying men with high risk of aggressive prostate cancer.

The purpose of this study was to describe the experience of replacing PSA tests with Stockholm3 for the detection of prostate cancer in primary care. The study involved longitudinal observations for comparison of performance measures before and after the implementation of Stockholm3. General practitioners in the Stavanger region in Norway were instructed to replace PSA with Stockholm3 as the standard method for diagnosis of prostate cancer.

4,784 men were included in the study. The implementation of Stockholm3 resulted in a 29 percent reduction in referrals for biopsy. The proportion of positive biopsies with aggressive prostate cancer increased 89 percent after implementation. Similarly, the overdetection of non-aggressive prostate cancer decreased 26 percent. Direct healthcare costs were estimated to decrease between 23 and 28 percent per man tested.

The conclusion of this study was that replacement of PSA with Stockholm3 for early detection of aggressive prostate cancer in primary care was feasible. Implementation of Stockholm3 resulted in a reduced number of referrals for biopsy, an increase in the number of cases of aggressive prostate cancer detected at an early stage, and a decrease in direct healthcare costs.

Stockholm3 as a reflex test

The objective of this study was to investigate the use of Stockholm3 combined with MRI as a reflex test for men with elevated risk based on PSA testing. The study design was in the form of a prospective parade multicentre study that included 532 men ages 45 to 74 in Sweden and Norway.

The results showed that, compared with PSA combined with systematic biopsies, Stockholm3 combined with MRI reduced the number of biopsies 38 percent and increased the sensitivity in detecting aggressive prostate cancer 10 percent. Compared with PSA combined with MRI, Stockholm3 combined with MRI reduced the number of unnecessary biopsies 54 percent with a relative sensitivity for aggressive prostate cancer of 92 percent. The results showed that Stockholm3 combined with MRI reduced overdiagnosis and unnecessary biopsies.

Health economic assessment

The objective of the study was to assess the cost-effectiveness of screening for prostate cancer with Stockholm3 combined with MRI and PSA combined with MRI. Testing properties were based on the results of the STHLM3 MRI study. A cost-benefit analysis from a lifelong social perspective was conducted through microsimulation for men ages 55 to 69 in Sweden for four different strategies: no screening, and three strategies for screening every four years: PSA 3 ng/ml, and Stockholm3 with reflex test thresholds at PSA 1.5 and 2 ng/ml. Men with positive tests were examined using MRI, and the men who were MRI positive were examined with both targeted and systematic biopsies. Predictions included number of tests, incidence of cancer and mortality, QALY and ICER.
Compared with no screening, the screening strategies were predicted to reduce mortality from prostate cancer 7 to 9 percent over a lifetime and was considered as bearing moderate costs per QALY in Sweden. Stockholm3, with a reflex limit of PSA 2 ng/ml, resulted in a 60 percent reduction in the number of MRI examinations compared with screening using PSA tests. This Stockholm3 strategy was cost-effective, with a probability of 70 percent at a cost-efficiency threshold of EUR 47,218 (approximately SEK 500,000). The results showed that use of the Stockholm3 test could reduce screening-related injuries and costs while retaining the health advantages of early detection of aggressive prostate cancer.

The objective was to assess the long-term health effects and cost-effectiveness of PSA screening with Stockholm3 (S3M) which was used as a reflex test to PSA values above 1, 1.5 or 2 ng/ml compared with no screening of prostate cancer or PSA screening alone.

The study was carried out as a cost-effectiveness analysis from a lifetime social perspective. Using a microsimulation model, simulations were run for: (i) no screening for prostate cancer; (ii) screening with PSA tests; and (iii) screening with the S3M test as a reflex test for PSA values ≥ 1, 1.5 and 2 ng/ml. Screening strategies included forty-year retesting among ages 55 to 69 conducted by a general practitioner. Discounted costs, quality-adjusted life years (QALY) and incremental cost effectiveness ratio (ICER) were calculated.

In a comparison of S3M with a reflex limit of 2 ng/ml with screening via PSA test, S3M had increased efficacy, reduced lifetime biopsies by 30 percent and increased social costs by 0.4 percent. In relation to the PSA test, the S3M reflex thresholds at 1, 1.5 and 2 ng/ml had an ICER of EUR 170,000, 60,000 and 6,000 per QALY respectively. The S3M test was more cost-effective at higher biopsy costs. The conclusion was that prostate cancer screening with the S3M test for men with an initial PSA of ≥ 2.0 ng/ml was cost-efficient compared with screening with PSA alone.