What are we missing? Identifying clinically significant prostate cancer among patients with low <scp>PSA</scp> : the utility of the free‐to‐total <scp>PSA</scp> ratio

Prostate cancer (PCa) screening in Australia remains contentious, with ongoing debate regarding the optimal balance between early detection of clinically significant disease and avoidance of unnecessary investigation. Current guidelines rely on raised PSA and free-to-total PSA ratio (FTR) to screen for men requiring further investigation. However, proposed national guidelines emphasise age-adapted PSA alone and de-emphasise the role of the FTR. This commentary outlines the differences between current and proposed screening practices and argues that the utility of the FTR should not be overlooked. The FTR represents a simple and cost-effective test for refining patient selection for Medicare-rebated MRI, even among those with low PSA. Current GP guidelines, endorsed by the Royal Australian College of General Practitioners and Urological Society of Australia and New Zealand, suggest that men aged between 50 and 69 years should have an informed discussion about the benefits and risks of testing every 2 years. Repeat testing is suggested if the PSA level is >3 ng/mL, including a FTR [1]. The FTR enhances the diagnostic accuracy of PSA because a low proportion of free PSA is correlated with clinically significant PCa (csPCa). Subsequently, Medicare-rebated MRI is offered only when patients aged <70 years have repeat PSA levels of >3.0 ng/mL with a FTR of <25% or if the PSA level is >5.5 ng/mL (without a FTR). This threshold is reduced for patients with a significant family history of PCa to a PSA level of >2.0 ng/mL, and a FTR of <25%. The 2025 revision of the Australian PSA Guidelines, developed under the auspices of the Prostate Cancer Foundation of Australia and aligned with the National Health and Medical Research Council of Australia (NHMRC) standards, introduces a risk-adapted, harm-minimisation framework. This update is under public comment currently. These drafted guidelines emphasise age-adapted PSA thresholds and position MRI as the central triage tool for biopsy decision-making, while omitting the FTR from the diagnostic algorithm. Specifically, biennial PSA testing is recommended for men aged 50–69 years, with MRI triggered by repeat PSA levels of ≥3 ng/mL. Baseline testing may be considered for men aged 40–49 years, and testing in men ≥70 years is guided by clinical assessment. Age-related PSA cut-offs (≥1 ng/mL for men aged 40–49 years and ≥5.5 ng/mL for men aged ≥70 years) are proposed as triggers for further investigation. The incidence of csPCa among patients with PSA levels <3 ng/mL is not negligible. In fact, Moore et al. [2] found in a population screening study of 303 men aged 50–75 years that more than half of patients with a PSA level of <3 ng/mL had positive MRI findings and csPCa, defined as any Gleason pattern ≥4. Moreover, the Goteborg-2 Prostate Cancer Screening Trial discovered that 4.6% of patients with PSA levels between 1.8 and 3 ng/mL and Prostate Imaging-Reporting and Data System (PI-RADS) score 3–5 lesions had International Society of Urological Pathology (ISUP) Grade ≥2 PCa [3]. This brings into question the current and proposed PCa screening practices in Australia; particularly, what can be done to detect csPCa in patients with low PSA who would otherwise be missed? Novel Australian research using the Prostate Cancer Prevention Trial database analysed 406 patients with PSA levels ≤3.0 ng/mL and found that 31% had csPCa [4]. Importantly, the authors found that there was a clear relationship between increasing FTR and reduced probability of csPCa in this cohort. This held true for three PSA levels (2.0, 3.0 and 4.0 ng/mL) and for three at-risk ages (50, 60 and 70 years). Moreover, the FTR was not found to be collinear with age or PSA level. This highlights the utility of the FTR in at-risk patients with low PSA, as a simple and cost-effective test to improve detection of csPCa. The FTR has previously been demonstrated to predict risk of developing lethal PCa, particularly when utilised with PSA level for risk stratification. A Swedish study found that a one-time result of PSA <2.0 ng/mL and FTR ≥25% for men aged 55–70 years predicted very low cancer-specific mortality [5]. These patients could, therefore, be considered for less frequent surveillance. The authors also found that there was a dose-dependent relationship between the FTR and cancer-specific mortality risk when dichotomising the cut-off from 25% to 18%. Therefore, patients who are not considered low risk based on these test parameters should warrant further investigation. However, the utility of the FTR appears to be falling out of favour with the increasingly availability and utility of MRI. The drawback to increasing MRI utilisation in PCa screening is the associated healthcare costs of scanning and the resultant over-diagnosis and over-treatment of non-lethal PCa. In Australia in 2024, there were just over 52 000 MRIs funded by Medicare to investigate men with elevated PSA, with 25 604 men proceeding to biopsy [6]. According to the new guidelines, men can avoid biopsy if the MRI shows PI-RADS 1–2 lesions or PI-RADS 3 with a low PSA density (<0.15 ng/mL/mL). While this approach will, indeed, reduce the number of unnecessary biopsies performed, there will still be a large burden of healthcare cost in obtaining the MRI scans. The incorporation of the FTR to the initial screening process of the new guidelines will limit the over-investigation with MRI and still utilise the proposed age-related PSA cut-offs. A smaller proportion of men aged between 50 and 69 years with low PSA (between 2.0 and 3.0 ng/mL) and csPCa will still be undetected under the new guidelines. Nonetheless, the authors contend that this update reflects progress in detecting younger men aged between 40 and 49 years in whom csPCa would otherwise be missed with the current guidelines. Australian urologists’ ability to manage PCa has continued to evolve over the last decade with the increased accessibility to robot-assisted surgery and the availability of the novel androgen receptor pathway inhibitors for metastatic disease. So too, must our screening practices reflect the developing literature and ensure we are not missing the mark. The proposed update in PSA screening utilises age-related PSA cut-offs and de-emphasises the FTR when selecting patients for further investigation with MRI. Utilising the FTR, in conjunction with PSA levels, is a simple test that can guide selection of patients who would benefit from further investigation. Consideration should be given to incorporating at-risk men aged between 50 and 69 years with PSA levels >2 ng/mL and a low FTR into the proposed guidelines for a Medicare-rebated MRI prostate. Nil. None declared.