Patients with high-risk features on active surveillance for prostate cancer

Abstract

Background/objectives

With the increasing incidence of prostate cancer worldwide, active surveillance (AS) remains a cornerstone in the management of men with low-risk disease. While the criteria for AS in low-risk prostate cancer are well established, its appropriateness for men with higher-risk features is less clearly defined. This review aims to evaluate the evidence supporting AS in men with a family history of prostate cancer, Prostate Imaging Reporting and Data System (PI-RADS) 4 or 5 lesions, and favorable intermediate-risk International Society of Urological Pathology (ISUP) Grade Group (GG) 2 disease.

Methods

A comprehensive literature review was conducted using PubMed, Embase, and The Cochrane Library. Eligible studies included those assessing outcomes of AS in men with higher-risk features, including family history of prostate or associated malignancies, PI-RADS 4–5 lesions on magnetic resonance imaging, or favorable risk ISUP GG2 disease. Studies were excluded if participants had a life expectancy of less than 10 years or had previously received definitive treatment for prostate cancer.

Results

Recent evidence suggests that a family history of prostate cancer may confer an increased risk of disease progression on AS; however, current data do not justify exclusion from surveillance on this basis alone. Two single-center studies demonstrated that men with PI-RADS 5 lesions at AS enrolment exhibited a higher rate of disease upgrading, with 70% progressing to ISUP GG2 and 25–33% to GG3 or higher at confirmatory biopsy. Increasing evidence supports the inclusion of selected men with favorable GG2 disease in AS protocols, provided the absence of high-risk clinical, biochemical, or radiological features. Approximately 50% may require definitive treatment within five years.

Conclusions

AS remains a viable management option for appropriately selected men with higher-risk features, accompanied by rigorous monitoring and informed patient counselling. The emerging role of prostate-specific membrane antigen positron emission tomography imaging in risk stratification for intermediate-risk disease warrants further investigation through prospective studies.

1. Introduction

Following the introduction of prostate-specific antigen (PSA) screening in men, there has been an increase in the early detection of small, clinically insignificant prostate cancers. This refers to disease that is unlikely to have prostate cancer-related morbidity or death. The recommended management for low-risk indolent disease is active surveillance to avoid overtreatment and associated morbidity.¹ There is now increased uptake of active surveillance in patients with higher-risk disease features but the evidence supporting this practice is not abundant. This review aims to evaluate men who have higher risk features such as strong family history, Prostate Imaging Reporting & Data System (PI-RADS) 4 or 5 lesions on magnetic resonance imaging (MRI) and favorable risk International Society of Urological Pathology (ISUP) Grade Group (GG) 2 disease undergoing active surveillance (AS).

2. Methods

A comprehensive review of current literature was performed on PubMed, Embase, and The Cochrane Library. Studies were included which described men with high-risk features including a family history of prostate cancer or other associated cancers, PI-RADS 4 or 5 lesions on MRI and intermediate-risk GG2 disease who had been placed on active surveillance. Studies were excluded if they were not relevant to the review, included men with life expectancy of <10 years, or had previously received active treatment for prostate cancer. The most recent European Association of Urology (EAU), National Comprehensive Cancer Network (NCCN), American Urology Association (AUA), and National Institute for Health and Care Excellence (NICE) guidelines were also evaluated (Table 1). Studies were excluded if they included patients with a life expectancy of less than 10 years, in line with major guideline recommendations for active surveillance. The EAU recommends active surveillance for patients with a life expectancy greater than 10 years, while watchful waiting is advised for those with a life expectancy under 10 years. Similarly, the NCCN uses a 10-year life expectancy threshold, recommending active surveillance for patients expected to live longer than 10 years and observation for those with a shorter life expectancy.^1,2

Table 1.

Active surveillance guidelines—inclusion criteria for intermediate-risk prostate cancer/ISUP GG2

Guidelines	PSA value	DRE	Histopathology features
EAU 2024	<10 ng/mL	≤ cT2a	≤3 positive cores of Gleason 3 + 4 ≤50% core involvement
NCCN 2024	10–20 ng/mL (without other risk factors)	cTc-b (without other risk factors)	≤50% core involvement GG2
AUA/ASTRO 2022	<10 ng/mL Low PSA density	≤ cT2a	<50% core involvement Low-volume pattern 4 Low tumour volume GG2
NICE 2019 (updated 2021)	10–20 ng/mL	cT1–cT2	GG2

Ref. ¹. 978-94-92671-19-6 EGEpatEACMI. EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2023. ISBN 978-94-92671-19-6. 2. Schaeffer EM, Srinivas S, Adra N, An Y, Barocas D, Bitting R, et al. Prostate Cancer, Version 4.2023, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network. 2023; 21(10):1067-96. 3. Eastham JA, Auffenberg GB, Barocas DA, Chou R, Crispino T, Davis JW, et al. Clinically Localized Prostate Cancer: AUA/ASTRO Guideline, Part I: Introduction, Risk Assessment, Staging, and Risk-Based Management. J Urol. 2022; 208(1):10-8. 4. Excellence NNIfHaC. Prostate cancer: diagnosis and management. 2019 (2021 Revision).

ASRTO, American Society for Radiation Oncology; AUA, American Urology Association; EAU, European Association of Urology; DRE, digital rectal examination; NCCN, National Comprehensive Cancer Network; NICE, National Institute for Health and Care Excellence; PSA, prostate-specific antigen.

2.1. AS overview

AS has been shown to have similar oncological outcomes while reducing treatment-related morbidity in select patient cohorts.^{3, 4, 5} AS has a predefined schedule for monitoring low-intermediate-risk prostate cancer including the use of digital rectal examination (DRE), PSA tests, MRI, and surveillance biopsies, to identify disease progression early. The aim of AS is one of curative intent for those patients in which progression is identified. AS is recommended for men with low-risk or select intermediate-risk prostate cancers and a life expectancy of greater than 10 years.^{6, 7, 8, 9}

• 1.EAU

The EAU guidelines categorize prostate cancer into low-, intermediate- and high-risk features based on histological features from prostate biopsy and PSA value. Active surveillance is recommended for all men who have low-risk prostate cancer (ISUP GG1 disease and PSA <10 ng/mL).² More recently, AS has also been indicated in men with intermediate-risk prostate cancer (ISUP GG2 and PSA 10–20 ng/mL). Favorable intermediate-risk features for GG2 disease include PSA <10 ng/mL, DRE which is </ = cT2a, and low disease extent on imaging and biopsy (</ = 3 positive cores of G3+4 with </ = 50% core involvement).¹

• 2.NCCN

Similar changes are also reflected in the NCCN guidelines for AS, which now includes men with a life expectancy of >10 years and favorable intermediate-risk disease, defined as a low percentage of Gleason 4 disease (ISUP GG2), low tumour volume, low PSA density, and low genomic risk.²

• 3.AUA

The AUA endorses AS for men with GG1 disease and considers it appropriate for men with low-volume GG2 disease with additional favorable features, including PSA <10 ng/mL, low PSA density, and low tumour volume and a low percentage of Gleason pattern 4 disease on biopsy. However, AS is not recommended for men with GG3 or higher-risk disease.¹⁰

• 4.NICE

The NICE guidelines also recommend offering AS to men with GG1 disease and supports its consideration in carefully selected men with GG2, while emphasizing the importance of MRI and repeat biopsies for ongoing risk stratification.¹¹

3. High-risk features—what are they & what is their safety profile?

This review article aims to evaluate men enrolled in an active surveillance program who had higher risk features of prostate cancer that increase the risk of disease progression. For these men, patient education and counselling on the risk disease progression and management options is essential for a shared decision-making patient care model.

• 1.Family history

Family history of prostate cancer is a well-established risk factor for developing prostate cancer, which is influenced by both genetic and environmental factors.^12,13 Family history includes men with one or more first- or second-degree relatives diagnosed with prostate cancer who do not themselves have hereditary prostate cancer. Hereditary prostate cancer is defined as three or more first-degree relatives with prostate cancer, three successive generations of prostate cancer, or two first-degree relatives under 55 years with prostate cancer.^1,14,15 Studies have shown that men with hereditary prostate cancer syndromes or genetic mutations such as the breast cancer susceptibility gene BRCA2 are at a greater risk of developing more aggressive prostate cancer.¹⁶ However, the risk of developing aggressive prostate cancer with a positive family history has been discrepant in the literature.¹⁵

A meta-analysis published in 2024 including eight studies which examined the progression of disease for men on AS found that family history may be an independent risk factor for disease progression. The pooled adjusted risk had a hazard ratio (HR) of 1.31 (95% confidence interval: 1.2–1.5). However, the evidence was insufficient to conclude that these men should be excluded from AS if selected appropriately, due to the low certainty of evidence.¹⁷

A single-center study of 656 men on AS for GG1 prostate cancer examined the association between family history and risk of reclassification of low-risk prostate cancer at the time of follow-up confirmatory biopsy. It showed that men with a positive family history had an increased risk of being upstaged from GG1 to GG2 or higher. A positive family history together with high volume GG1 disease; defined as >33% of cores or 50% of any core involved, high PSA density, or suspicious MRI findings, had the most significant risk of progression at the time of confirmatory biopsy. Interestingly, despite the risk of upstaging, positive family history did not compromise oncological safety or outcomes following treatment deferment on AS. ¹⁸ Another sizeable single-center study of over 3,000 men from 2022 evaluated both a family history of prostate cancer and a family history of any cancer. Another sizeable single-center study of over 3,000 men from 2022 found that although a family history of prostate cancer was linked to increased progression risk on AS, wide confidence intervals limit its clinical significance. Furthermore, a family history of any cancer showed no association; therefore, neither alone should exclude patients from AS in the absence of a known hereditary cancer syndrome.¹⁹

All studies emphasized that men should not be excluded from AS based on family history alone and the importance of individualized discussions surrounding the risk of disease progression while on AS.

• 2.MRI characteristics

MRI is a vital tool in diagnosis and monitoring of prostate cancer. The EAU guidelines recommend that all men who are undergoing a biopsy have an MRI scan prior to the biopsy.¹ PI-RADS score is deemed a positive result if it was 4 or higher in most studies. Multiple studies have shown that higher PI-RADS scores of 4 or 5 are independent predictors of prostate cancer progression at the time of repeat biopsy in AS.^{20, 21, 22} Supporting this, a large cohort study published in 2020 demonstrated that in MRI-led AS, men with MRI-visible disease or a secondary Gleason pattern 4 at the baseline had significantly lower event-free and treatment-free survival at 5 years.²³ Among those with Gleason 3 + 3 cancer, EFS was 83% in men with nonvisible lesions and 72% with visible disease. In the Gleason 3 + 4 group, this dropped further to 63% and 34%, respectively (P < 0.01). This study also showed that MRI-based surveillance resulted in rates of discontinuation, mortality, and metastasis comparable to standard AS, while potentially reducing the need for routine biopsies.²³

A single-center study from 2021 evaluated 344 men on active surveillance with a PI-RADS score documented. PI-RADS category was shown to be associated with disease progression with 33% of men with PI-RADS 5 lesions having a progression to GG3 or greater while on active surveillance, with 31 months average time to disease progression.²⁴ In comparison, 18% of men with PI-RADS 4 lesions and 17% of men with PI-RADS 1-3 had progression to GG3, with 74 and 76 months to progression, respectively.²⁴ Similar results were shown in another study with >70% of men with PI-RADS 5 imaging features and GG1 disease upgrading to GG2 or higher at confirmatory biopsy, with 50% of these patients requiring radical treatment at four years; however, this study had a very small inclusion sample group of 21 patients.²⁰

Tumour volume and bilateral disease on MRI are important predictors of prostate cancer progression during active surveillance. One 2017 study found that tumour volume increased measurably in over a third of men with prostate cancer undergoing AS after two years and decreases in Apparent Diffusion Coefficent (ADC) on MRI were associated with this growth.²⁵ Another study showed that patients with bilateral disease and PSA density at the baseline had a significantly higher risk of progression (HR: 2.2) and earlier time to progression compared to those with a unilateral disease.²⁶ Accurately assessing disease burden and histological grade, however, can be limited by variability in biopsy technique, number of cores taken, and core length.

• 3.Intermediate-risk disease

A growing body of evidence supports offering AS to men with intermediate-risk ISUP GG2 if they have favorable risk features. This is reflected in all current major guidelines, which now include the recommendation of AS for select men with GG2 disease.^1,2,24 Guidelines currently do not recommend AS for men with GG3 disease.

Although GG2 disease is a risk factor for disease progression and the subsequent need for active management (up to 50% needing treatment within five years), AS should be considered for men that meet the criteria for favorable intermediate-risk disease.²² Cribriform histology, intraductal and predominant ductal carcinoma of the prostate, and small cell and lymphovascular or perineural invasion are higher-risk histological features described by a pathology consensus group for which AS should not be recommended if present on biopsy.^27,26

A large meta-analysis of 25 studies published in 2022 found that intermediate-risk prostate cancer had a comparable treatment-free survival interval but a higher risk of metastasis and cancer-specific mortality compared to low-risk prostate cancer. However, when performing a subgroup analysis comparing low-risk with only GG2 intermediate-risk disease (and excluding GG3 disease), outcomes were similar. The study emphasized the differences between patients who had favorable versus unfavorable intermediate-risk prostate cancer and the importance of appropriate patient selection within this group.²⁸

A multicenter study on AS for GG2 prostate cancer revealed that GG2 patients had a significantly higher treatment rate (58%) compared to GG1 patients (34%) over five years. Despite similar rates of upstaging at the time of confirmatory biopsy between the two groups, GG2 patients who were not upstaged were treated at much higher rates than their GG1 counterparts. Notably, there were no significant differences in adverse pathology or biochemical recurrence rates between GG1 and GG2 patients who underwent treatment. This suggests that low-volume GG2 disease may be managed effectively with AS.²⁹ Another study found that AS is a safe management strategy for carefully selected men with GG2 prostate cancer, showing a treatment-free survival rate of 61% at five years and no distant metastases during follow-up. Overall survival was high at 97% at five years, with treatment triggers mainly based on patient preference and disease progression.³⁰

4. Diagnostic adjuncts to improve stratification of high-risk disease

As AS criteria expand to include patients with higher-risk features, it becomes increasingly important to optimize patient selection. Genomic profiling and advanced imaging serve as valuable diagnostic adjuncts to improve risk stratification and identify patients best suited for AS.

4.1. Genomic profiling

Genomic testing, such as Prolaris (Myriad Genetics, Utah, USA) and Decipher (Veracyte, California, USA), provides an individualized risk profile, aiding treatment decisions and improving patient selection for AS. Prolaris estimates mortality risk by measuring tumour cell-cycle progression via a 31-gene RNA signature, while Decipher utilizes a 22-gene genomic classifier to predict adverse pathology and disease progression.

Recent retrospective evidence emphasizes the utility of these tools in sub-stratifying patients with biopsy GG 1 and GG2 disease. A large retrospective cohort study of over 3,000 patients with NCCN intermediate-risk prostate cancer demonstrated that patients undergoing genomic testing with Prolaris were 2x more likely to initially select and 1.5x more likely to remain on AS at the three-year follow-up.³¹ A 2025 systematic review also found that genomic tests reclassified risk levels as same or lower for approximately 5–34% of patients; however, one randomized trial within the review indicated that genomic classifier testing led to fewer choices for AS. There is need for further validation of these conflicting results in prospective settings with more specific patient populations.³²

Serum and tissue-based biomarkers could provide an additional layer of risk stratification. Beyond PSA, biomarkers such as the 4Kscore Test (OPKO Diagnostics, Florida, USA) and Prostate Health Index (Beckman Coulter, California, USA) have been studied for their ability to predict aggressive disease and aid in active surveillance selection.^33,34 A 2017 meta-analysis of 12 studies determined a pooled area under the curve of 0.81 to discriminate for high-grade prostate cancer using the 4Kscore.³⁵ SelectMDx (MDxHealth, Herstal, Belgium), a urine-based test, was found to have a pooled sensitivity and specificity of 81% and 73%, respectively, in the detection of clinically significant prostate cancer, comparable to MRI.^{36, 37, 38} While these biomarkers are not yet widely integrated into AS protocols or standard clinical care, they offer the potential for individualized risk assessment when used alongside existing imaging and genomics.

Although health economic models suggest that advanced biomarkers are cost-effective by reducing unnecessary treatment, a significant gap remains due to high upfront costs. The field of prostate cancer genomic testing is still in its infancy, when compared to breast and colorectal cancer, and most major insurers do not universally cover these assays. Coverage policies are often restricted to high-risk or metastatic disease rather than low-to-intermediate-risk cohorts. In many regions, including Australia and Europe, these tests are not routinely subsidized, with a median cost of USD 3,001 per assay. Furthermore, as outlined by Viti et al., most economic evaluations are based on the American market-driven healthcare system, limiting their relevance to publicly funded systems in Europe or Australia where cost structures are significantly different to the US. The out-of-pocket financial burden creates a barrier to equitable access and may deter many patients with a strong familial history from pursuing genomic counselling or testing.^{39, 40, 41, 42}

4.2. Imaging biomarkers

There may be a role for imaging modalities such as prostate-specific membrane antigen (PSMA) positron emission tomography (PET) as an additional tool in screening and risk stratifying men for AS eligibility, particularly those with intermediate-risk disease. PSMA PET has some utility in predicting upstaging of prostate cancer grade. Studies have demonstrated that higher maximum standardized uptake values (SUVmax) correlated with higher ISUP GG. In one prospective single centre study, 9 % of patients experienced pathological upgrades after additional target cores were taken of any PSMA-avid lesion with an SUVmax value of ≥4, including cases initially classified as low-risk but later found to have more aggressive disease.⁴³ This was further supported in a systematic review in 2024, which evaluated the added benefit of PSMA PET for AS risk stratification by improving identification of patients at risk of pathological upstaging and detecting MRI occult or inconclusive lesions.⁴⁴ The review highlights that while PSMA PET SUVmax values correlate with higher-grade prostate cancer, an evidence-based cut-off for clinical use remains undetermined. Pepe et al. (2023), Heetman et al. (2023), and Xue et al. (2022) reported SUVmax thresholds of ≥4, ≥5, and ≥5.4, respectively, as predictors of pathological upgrading, with Xue et al. reporting 91% specificity and a negative predictive value of 94%.^{45, 46, 47} Additionally, Pepe et al. (2023) found that a SUVmax cut-off of 8 yielded 100% sensitivity for detecting GG ≥ 3 prostate cancer, reinforcing the utility of SUVmax in this context, though thresholds vary across cohorts.⁴⁶ The recently CONFIRM trial assessed whether PSMA PET can improve risk stratification in men on AS. Early results demonstrated PSMA-avid lesions in 73% of men under AS (n = 60) with 61% of these having clinically significant prostate cancer (GG 2+) some of which were MRI occult. Thirty-nine percent of men displayed no PSMA-avid lesions, providing reassurance for continued AS. PSMA PET changed management in 40% of patients following multidisciplinary team (MDT) discussion with PSMA directly impacting 20% of decisions.^45,48,49

4.3. Quantification of Gleason pattern 4

Increasing evidence suggests that the quantification of Gleason pattern 4 (GP4), including its length percentage, and spatial distribution can improve risk stratification for men on AS with GG2 prostate cancer.⁵⁰ Studies have shown that even in patients classified as favorable intermediate-risk based on standard Gleason grading, a higher burden of GP4 disease is associated with an increased likelihood of progression to clinically significant prostate cancer.^50,51 There were four methods of GP4 quantification—maximum percentage GP4 (HR = 1.3), overall percentage GP4 (HR = 1.6), total length of GP4 disease (HR = 2.5), and length of GP4 in the highest core (HR = 1.3). These have been associated with increased risk of biochemical recurrence at 3 years post radical prostatectomy. While biochemical recurrence is not directly applicable to men on AS, these findings make a strong case for GP4 quantification as an indicator of underlying prostate cancer risk.⁵¹

Furthermore, one limitation of current AS triggers for transition to treatment is that they are often based on GG upgrade from GG2 to GG3 or changes in the Gleason 3:4 ratio. To address this, one 2024 study proposed a substantial change in GP4 as an additional criterion, defined as an increase in GP4 length of >1 mm resulting in ≥2 mm of total GP4. In their cohort, this identified additional men who experienced clinically significant progression without a formal GG upgrade.⁵⁰ As this metric continues to be validated, it may serve a role as an important diagnostic adjunct for refining AS eligibility and monitoring strategies.

4.4. Artificial intelligence and radiomics

Artificial intelligence (AI)-driven image analysis and radiomics offer emerging tools for refining prostate cancer risk assessment. AI-assisted MRI interpretation can reduce interobserver variability between radiologists and improve the detection of aggressive lesions.⁵² Radiomics, which extracts quantitative imaging features, may further enhance predictive models by identifying subtle imaging characteristics associated with higher-risk disease.⁵³ AI-assisted pathological interpretations of histology are another area that show promise, particularly in diagnostics; however, robust evidence for its use falls short in relation to staging and prognostics. Larger data sets are needed to further advance and develop high preforming AI models.⁵⁴ While still in early stages, these advancements could complement existing diagnostic adjuncts to improve patient selection for AS.

A new class of advanced risk stratification tools utilizes AI to analyze digital pathology slides from biopsies or prostatectomy specimens. The multimodal AI test, such as ArteraAI Prostate (FDA-approved July 2025), is designed to improve risk stratification by predicting 10-year outcomes, including distant metastasis and prostate cancer–specific mortality. These tools also offer predictive models to guide the use of short-term androgen deprivation therapy, though the NCCN panel recommends further validation in contemporary patients as many models were validated on trials from over 30 years ago.

5. Conventional active surveillance protocols—should we adapt?

As the criteria for patients eligible for AS expands to include a wider range of patients with various higher risk features, it raises the question—is there a need to adapt conventional AS monitoring regimes for clearer elucidation of risk and disease progression?

Current guidelines recommend using PSA, DRE, MRI, and surveillance biopsy to monitor patients on AS. However, optimal interval timing for surveillance investigations and biopsies remains unclear. Repeat biopsy is generally recommended at set intervals or if there is concern for disease progression based off PSA, DRE, or MRI results. EAU guidelines recommend yearly DRE, 6 monthly PSA testing, and confirmatory biopsy followed by surveillance biopsies 2–3 yearly for 10 years. They advise that serial MRI scanning can improve detection of aggressive cancers and progression on MRI mandates a repeat biopsy.¹ Similarly, the NICE guidelines recommend 3–4 monthly PSA surveillance in the first year of AS and bianually thereafter, yearly DRE, and 12–18 monthly MRI scanning.¹¹

It is essential to recognize that as our cohort of patients is expanding to include patients with higher risk disease features, both appropriate patient selection and stringent AS protocols are of vital importance. An early confirmatory biopsy at 12–18 months may still be warranted in this higher-risk group to confirm if AS is appropriate.

6. Discussion

The pool of prostate cancer patients eligible for AS has expanded to include those with intermediate-risk disease due to the growing body of evidence suggesting that it is safe to do so. It is important to consider the implications of higher-risk disease features during patient selection.

When identifying men with a family history of cancer or prostate cancer for AS, the intricacies of their family history are important. Men with concern for or known hereditary cancer syndromes such as BRCA2 mutations should be carefully counselled as there are known associations with more aggressive prostate cancer features necessitating immediate active treatment.^{14, 15, 16, 17, 18, 19} Men presenting with aggressive disease or adverse pathology at an early age, with a family history, should be referred for genetic testing in line with local guidelines. Men with a family history of prostate cancer are at greater risk of disease progression while on AS; however, overall oncological safety is not compromised. Conversely, the evidence shows that men with a family history of any cancer are not at greater risk of disease progression at confirmatory biopsy.^18,19,55 In summary, although a positive family history of prostate cancer may be associated with a modestly increased risk of disease progression during active surveillance, current evidence does not support its use as an independent exclusion criterion. Likewise, men with hereditary prostate cancer due to mutations such as BRCA2 are not excluded from active surveillance under current guidelines but are advised to undergo close monitoring as research continues to better define outcomes in this high-risk population.

Integrating advanced imaging for diagnosis and stratification of prostate cancer is essential for enrolling and monitoring patients on AS. MRI PI-RADS 4 or 5 lesions have a positive correlation with the likelihood of disease progression at the time of confirmatory or repeat prostate biopsy. Disease burden on MRI also impacts the likelihood of disease progression, where men with bilateral lesions are more likely to progress.⁵⁶

As we continue to grow our understanding of low- and intermediate-risk prostate cancer progression, PSMA PET shows promise as a valuable tool for AS patient selection and monitoring for disease progression. The landmark CONFIRM and PRIMARY trials investigate the utility of PSMA PET in improving patient selection for active treatments, improving detection of clinically significant prostate cancer and possibly filling the gap in areas where other imaging modalities fall short or are inconclusive.^48,49,57 Similarly, the role of ancillary investigations with genomic testing and emerging biomarkers is yet to be established, with the potential to further improve the diagnostic pathway. These tools could help to identify disease progression early and to identify men in which repeat biopsy can be avoided or delayed.³³ However, it is important to note that these investigations are associated with significant expenditure and access is not universal.

We acknowledge that the decision to manage higher risk patients with AS is often nuanced and not binary. This is particularly evident when a patient has multiple high-risk features or conflicting features, for example, PI-RADS 5 lesion on MRI with low-grade histology. The use of multidisciplinary team meetings is a useful resource recommended in current guidelines for complex cases. Personalized risk assessment, supported by emerging diagnostic modalities and early confirmatory biopsy may enhance clinical decision-making and patient selection. As the evidence base for novel diagnostics continues to grow, improving patient selection and providing greater reassurance regarding oncological safety, clinician confidence in managing patients with active surveillance is likely to increase (Fig. 1). Limitations of this review include long-term evidence particularly around the area novel diagnostics. Furthermore, current guidelines referenced highlight using tools such as PSA, DRE, confirmatory biopsy, and imaging to monitor patients on AS. However, defined protocols for surveillance are limited, which is likely to lead to discrepancies between different facilities and clinicians. As our pool of patients suitable for AS expands, specific protocols to monitor these patients would be beneficial.

Fig. 1.

Multimodal risk assessment tools for active surveillance decision-making. Ref. 1. Tabriz AA, Boyer MJ, Gordon AM, Carpenter DJ, Gingrich JR, Raman SR, et al. Impact of genomic classifiers on risk stratification and treatment intensity in patients with localized prostate cancer. Annals of Internal Medicine. 2025; 178(2):218-28. 2. Filson CP, Zhu K, Huang Y, Zheng Y, Newcomb LF, Williams S, et al. Impact of prostate health index results for prediction of biopsy grade reclassification during active surveillance. J Urol. 2022; 208(5):1037-45. 3. Liu J, Harewood L, Bagguley D, Dundee P, Mirmilstein G, Murphy DG, et al. Early results from the CONFIRM ltrial: Utility of prostate-specific membrane antigen positron emission tomography/computed tomography in active surveillance for prostate cancer. European Urology Oncology. 2025;8(4):1118-25. 4. Paik I, Lee G, Lee J, Kwak T-Y, Ha HK. Artificial intelligence–driven digital pathology in urological cancers: current trends and future directions. Prostate International. 2025; 13(4):181-90. 5. Buteau JP, Moon D, Fahey MT, Roberts M, Thompson J, Murphy DG, et al. PRIMARY2: A phase III, multi-center, randomized controlled trial investigating the additive diagnostic value of [⁶⁸ Ga]Ga-PSMA-11 PET/CT in men with negative/equivocal MRI in the diagnosis of clinically significant prostate cancer. Journal of Clinical Oncology. 2023; 41(6_suppl):TPS397-TPS. MRI, magnetic resonance imaging; PET/CT, positron emission tomography/computed tomography.

7. Conclusion

This review highlights the importance of personalized decision-making for patients undergoing active surveillance (AS) for both low- and intermediate-risk prostate cancer. In particular, patients with intermediate-risk disease require careful, individualized assessment. The presence of higher-risk features, such as a family history of prostate cancer or suspicious MRI findings, does not necessarily exclude men from AS; however, clinicians should counsel patients that these factors may be associated with a higher risk of disease progression. Understanding an individual patient’s risk profile is essential to avoid underestimating disease aggressiveness while minimizing overtreatment in lower-risk disease.

The decision to manage patients with AS, especially when higher-risk features are present, is multifactorial and should be based on an overall assessment of cumulative risk rather than any single characteristic. While future evidence may allow the development of formalized risk stratification tools to guide patient selection and surveillance intensity, such tools are currently lacking. In their absence, nuanced clinical judgement and shared decision-making are particularly important in cases not clearly addressed by existing guidelines.

Although the use of AS in men with higher-risk features remains controversial, current evidence supports its role as a safe and reasonable option for carefully selected patients when combined with individualized assessment, informed counselling, and appropriate monitoring. Further studies are needed to better define long-term outcomes and refine selection criteria in this subgroup.

Informed consent statement

Not applicable.

Institutional Review Board Statement

Not applicable.

Data availability statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Funding

This research received no external funding.

Conflicts of interest

The authors declare no conflicts of interest.