29th November 2025, A/Prof Chee L Khoo
We all know how complicated that question is – to screen or not to screen for prostate cancer? There are so many questions that we need to answer when we consider that question. We thought we have the answers when a series of clinical trials from Europe, UK and US reported over the last 15 years. Unfortunately, while they answered some questions, they raised even more questions. The European Randomized Study of Screening for Prostate Cancer (ERSPC) recently reported its final analysis after 23 years of follow up (1). In order for us to make sense of this final analysis, we have to re-examine what those initial studies concluded over the years.
Both the European and US trials reported at the same time in March 2009. The European Randomized Study of Screening for Prostate Cancer (ERSPC) was initiated in the early 1990s to determine whether a reduction of 25% in prostate cancer mortality could be achieved by PSA-based screening (2). 182,000 men were identified through registries in a number of European countries. The core age group was 55 and 69 years although some countries screened up to 75 years old. Most centres used a PSA cutoff value of 3.0 ng/ml as an indication for biopsy. Some use 4 ng/ml as the threshold for digital rectal examination, calculation of free PSA to total PSA and biopsy. Some centres combined digital rectal examination, transrectal ultrasonography and PSA testing.
The screening interval at six of the seven centres was 4 years (accounting for 87% of the subjects). Sweden used a 2-year interval. In Belgium, the interval between the first and second rounds of screening was 7 years because of funding issues. In the first report after a mean follow up of 9 years, 82.2% of the men in the screening group were screened at least once. Cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. 16.2% of all tests were positive. Of the men who underwent biopsy for an elevated PSA value, 13,308 (75.9%) had a false positive result.
The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (p=0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with non-compliance) provided a rate ratio for death from prostate cancer of 0.73.
The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial had the same exploratory aims – does prostate screening reduce prostate cancer mortality? (3). 76,693 men between 55-74 were randomised to either annual PSA offer for 6 years and digital rectal examination for 4 years or placebo (no screening). Men with positive results for the PSA test (> 4 ng/ml) or suspicious findings on the digital rectal examination were advised to seek diagnostic evaluation. Diagnostic evaluation was decided by the patients and their primary physicians.
In the screening group, 85% accepted the offer for PSA testing and 86% for digital rectal examination. In the placebo group, rate of PSA testing was 40% in the first year and increased to 52% in the sixth year. For subjects who reported having undergone no more than one PSA test at baseline (89% of subjects), the rate of PSA testing was 33% in the first year and 46% in the sixth year. Thus, the placebo was not truly placebo. There was contamination of the placebo group.
When the trial reported in 2009, at 7 years, 2 years after the cessation of screening, prostate cancer had been diagnosed in more subjects in the screening group than in the control group (rate ratio: 1.22). At 10 years, with follow-up complete for 67% of subjects, the excess in the screening group persisted (rate ratio: 1.17).
The large majority of prostate cancers were stage II at diagnosis, regardless of the mode of detection in the screening group; nearly all were adenocarcinomas, and more than 50% had a Gleason score of 5 to 6. Overall, the numbers of subjects with advanced (stage III or IV) tumours were similar in the two groups, though the number of subjects with a Gleason score of 8 to 10 was higher in the control group than in the screening group. Perhaps, screening detect the cancers earlier?
Overall, the PLCO trial found that while prostate screening picked up more prostate cancers, it did not significantly reduce mortality over the 7-10 years of follow up. There were 50 deaths attributed to prostate cancer in the screening group and 44 in the control group (rate ratio, 1.13). Through year 10, with follow-up complete for 67% of the subjects, the numbers of prostate-cancer deaths were 92 in the screening group and 82 in the control group (rate ratio, 1.11). The confidence interval was very large though – it ranged from 25% reduction to 70% increase in mortality.
It was thought that perhaps, if the cut off for the PSA testing was lowered to 3 ng/ml (like the European study), they may have picked up more prostate cancer earlier. Further, the placebo group had more PSA tests done at baseline than they anticipated and the numbers increased as the trial went on. This may have diluted the comparison between the screening and placebo groups.
Medical complications from the diagnostic process occurred in 68 of 10,000 diagnostic evaluations after positive results on screening. These complications were primarily infection, bleeding, clot formation, and urinary difficulties. Treatment-related complications, which are generally more serious, include infection, incontinence, impotence, and other disorders.
Both studies extended their follow up after the trials ended and have been reporting regularly. In the ERSPC follow up, after the initial screening interval of 4 years (2 years in Sweden), screening was discontinued after three screening rounds in Belgium, Finland and Spain and after two rounds in France, but continued up to five rounds in the Netherlands and ten in Sweden. After a median follow up of 13 years, they reported again in 2014 (4). After 16 years of follow up, they reported again in 2019 (5). With each reporting, they concluded that there was a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect the longer the follow up.
Similarly, the PLCO trial continued to follow up the patients and reported in 2020 after a median duration of follow up of 17 years (6). Once again, they did not find any significant reduction in prostate cancer mortality in the intervention compared to usual care arm.
In the meantime, the Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported from UK in 2018 (7). Men aged 50 to 69 years were invited to receive a one off PSA screening test. 40% attended, 36% underwent screening. The results were compared with a non-screening control group. Of those with PSA >3 ng/ml, 85% underwent prostate biopsy. While there were more prostate cancer diagnosed in the intervention group (4.3% vs 3.6%, p< 0.001), there was no significant difference in prostate cancer mortality after a median follow-up of 10 years.
In October 2025, the ERSPC published its last report at 23 years follow up (1). They found that prostate cancer mortality was 13% lower in the screening group. One death from prostate cancer was prevented for every 456 men (95% CI, 306 to 943) who were invited for screening, and one death from prostate cancer was averted for every 12 men (95% CI, 8 to 26) in whom prostate cancer was diagnosed.
You can see that the latest study results are still conflicting. The European study continued to report mortality benefit while the US Preventative Services Task Force continue to advocate against screening for prostate cancer on the back of the negative studies from the PLCO. The screening protocols and methodologies are very different in both trials and it’s hard to compare them head to head. The UK based CAP trial were only looking at a one off screening test and the numbers screened were only 36% and may be under-powered to detect any benefit.
References
- Roobol MJ, de Vos II, Månsson M, et al. ERSPC Investigators. European Study of Prostate Cancer Screening – 23-Year Follow-up. N Engl J Med. 2025 Oct 30;393(17):1669-1680.
- Schröder FH, Hugosson J, Roobol MJ, et al. ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009 Mar 26;360(13):1320-8.
- Andriole GL, Crawford ED, Grubb RL 3rd, et al. PLCO Project Team. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009 Mar 26;360(13):1310-9.
- Schröder FH, Hugosson J, Roobol MJ, et al. ERSPC Investigators. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014 Dec 6;384(9959):2027-35.
- Hugosson J, Roobol MJ, Månsson M, et al. ERSPC investigators. A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer. Eur Urol. 2019 Jul;76(1):43-51
- Pinsky PF, Miller E, Prorok P, Grubb R, Crawford ED, Andriole G. Extended follow-up for prostate cancer incidence and mortality among participants in the Prostate, Lung, Colorectal and Ovarian randomized cancer screening trial. BJU Int. 2019 May;123(5):854-860.
- Martin RM, Donovan JL, Turner EL, et al. CAP Trial Group. Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial. JAMA. 2018 Mar 6;319(9):883-895