Comparative outcomes of radical prostatectomy, radiotherapy, and radiotherapy plus androgen deprivation therapy for high-risk and very high-risk prostate cancer: a narrative review

Introduction

High-risk and very high-risk prostate cancer (PCa) account for approximately 15–20% of newly diagnosed cases and are associated with substantial risk of disease progression, metastasis, and cancer-specific mortality (1,2). High-risk disease is typically defined by the presence of at least one of the following features: prostate-specific antigen (PSA) ≥20 ng/mL, Gleason score 8–10 [International Society of Urological Pathology (ISUP) grade group ≥4], or clinical stage ≥T3a (3,4). Very high-risk disease incorporates additional adverse features such as primary Gleason pattern 5, multiple high-risk factors, or extensive disease burden (5).

Definitive treatment options for high-risk PCa include radical prostatectomy (RP), external beam radiotherapy (EBRT), and radiotherapy combined with androgen deprivation therapy (RT + ADT) (6,7). Each modality has distinct oncologic efficacy profiles, toxicity patterns, and effects on quality of life. RP offers the theoretical advantages of complete tumor removal, accurate pathologic staging, and the option for adjuvant therapy based on surgical findings (8). RT-based approaches, particularly when combined with ADT, provide effective local control while avoiding surgical morbidity and may be preferable for patients with comorbidities or locally advanced disease (9,10).

Despite decades of clinical experience, the comparative effectiveness of these treatment modalities remains uncertain. No large-scale randomized controlled trial (RCT) has directly compared contemporary RP with modern dose-escalated RT + ADT in high-risk PCa (11). Existing evidence derives primarily from observational cohort studies, institutional series, and pooled analyses, which are subject to selection bias, confounding by indication, and heterogeneity in treatment techniques and patient populations (12,13).

This narrative review addresses the following key questions: (I) What is the comparative effectiveness of RP, EBRT, and RT + ADT for overall survival (OS) and prostate cancer-specific survival (PCSS) in high-risk and very high-risk PCa? (II) What is the optimal duration of ADT when combined with radiotherapy? (III) What are the modality-specific toxicity and quality-of-life profiles? (IV) What are the evidence gaps and future research priorities? We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0553/rc).

Methods

Search strategy

A literature search was conducted across PubMed, Cochrane Library (CENTRAL), and ClinicalTrials.gov through May 2026. The search strategy combined terms related to prostate cancer, prostatic neoplasms, high-risk, very high-risk, radical prostatectomy, prostatectomy, radiotherapy, radiation therapy, external beam radiotherapy, brachytherapy, ADT and androgen deprivation therapy. Reference lists of included studies and relevant reviews were hand-searched for additional eligible studies. No restrictions on language of publication were applied. The search strategy is summarized in Table 1. This narrative review was not pre-registered in a prospective registry.

Eligibility criteria

Studies comparing RP, EBRT, and/or RT + ADT in patients with high-risk PCa (PSA ≥20 ng/mL, Gleason score 8–10, or clinical stage ≥T3a) were included. Primary outcomes were OS, PCSS, and biochemical recurrence-free survival (bRFS). Secondary outcomes included metastasis-free survival (MFS), toxicity, and quality of life. RCTs, prospective cohort studies, and retrospective cohort studies were eligible. Case reports, editorials, and studies with fewer than 50 patients per treatment arm were excluded. Biochemical recurrence definitions differ between RP (PSA ≥0.2 ng/mL) and RT (nadir + 2 ng/mL), limiting direct comparisons. Therefore, bRFS results are not presented as a primary comparative outcome.

Data extraction and synthesis

Data were extracted on study characteristics, patient demographics, treatment details, and outcomes. Because of substantial heterogeneity in RT-based interventions and the observational nature of most RP versus RT comparisons, a narrative synthesis was conducted. For RCTs comparing ADT durations, a meta-analysis was performed.

Results

Study selection

Database searches identified 1,159 records. After removal of duplicates and screening, 30 studies met inclusion criteria: 5 RCTs, 12 prospective cohort studies, and 13 retrospective cohort studies. Sample sizes ranged from 62 matched pairs to population-based cohorts exceeding 16,000 patients. Median follow-up ranged from 5.0 to 10.2 years.

OS: RP vs. RT (observational studies)

Observational studies comparing RP and RT-based strategies have reported conflicting results for OS.

Studies reporting more favorable outcomes with RP: Boorjian et al. [2011] reported higher all-cause mortality with EBRT + ADT versus RP after multivariable adjustment [hazard ratio (HR) 1.60, 95% confidence interval (CI): 1.25–2.05] (14).

Studies reporting more favorable outcomes with RT-based strategies: Berg et al. [2019] found that RP was associated with higher mortality compared with EBRT plus brachytherapy boost (HR 1.22, 95% CI: 1.05–1.43) (15). Jayadevappa et al. [2019] reported that EBRT with brachytherapy boost (± ADT) was associated with lower 10-year overall mortality compared with RP (HR 0.47, 95% CI: 0.31–0.73) (16).

For patients with Gleason score 9–10 disease: Kishan et al. [2018] reported that EBRT with brachytherapy boost was associated with lower all-cause mortality compared with RP (HR 0.66, 95% CI: 0.46–0.96) (17).

Studies showing no significant difference: Jayadevappa et al. [2019] found no significant difference in 10-year overall mortality between EBRT + ADT and RP (HR 1.09, 95% CI: 0.72–1.66) (16). Reichard et al. [2019] reported no difference in OS between RP and RT + ADT (HR 1.35, 95% CI: 0.4–4.8, P=0.6) (18).

Prostate cancer-specific mortality

For patients with Gleason score 9–10 disease, Kishan et al. [2018] reported that EBRT with brachytherapy boost was associated with lower prostate cancer-specific mortality than RP (HR 0.38, 95% CI: 0.21–0.68) and lower than EBRT alone (HR 0.41, 95% CI: 0.24–0.71) (17). Boorjian et al. [2011] found no significant difference in PCSM between EBRT + ADT and RP (HR 1.14, 95% CI: 0.68–1.91) (14).

Optimal ADT duration in RT-treated patients (RCT evidence)

DART 01/05 trial: at 5-year follow-up, long-term ADT (28 months) produced significant improvements in OS compared with short-term ADT (4 months) (HR 2.48, 95% CI: 1.31–4.68, P=0.009) (19). At 10-year follow-up, the benefit was no longer statistically significant in the overall population (HR 0.84, 95% CI: 0.55–1.27, P=0.40) (20). In the high-risk subgroup, a trend persisted (HR 0.58, 95% CI: 0.33–1.01, P=0.054) (21).

PCS IV trial: there was no significant difference in 10-year OS between 36 months and 18 months of ADT (HR 1.02, 95% CI: 0.81–1.29, P=0.84). Quality of life was significantly better in the 18-month group (P<0.001) (21).

Synthesis: current evidence suggests that 18–24 months of ADT is a reasonable standard for many patients with high-risk disease. The benefit of extending ADT beyond 18–24 months remains uncertain.

Emerging RCT data: STAMPEDE and ENZARAD

Recent data from the STAMPEDE trial have demonstrated that adding abiraterone to ADT improves outcomes in patients with extremely high-risk localized PCa. Leone et al. [2025] reported that plasma AR alterations may predict response to intensified hormone treatment, suggesting a biomarker-driven approach for patient selection (22). At the 2025 ESMO meeting, updated results showed a significant OS benefit for abiraterone in this subgroup (22).

The ENZARAD trial evaluated enzalutamide in regular high-risk PCa. Nguyen et al. [2025] reported that at 8 years, MFS was 74% with enzalutamide vs. 72% with non-steroidal antiandrogen (HR 0.88; 95% CI: 0.67–1.15; P=0.34), and OS was 83% vs. 80% (HR 0.87; 95% CI: 0.63–1.20) (23). These results suggest that intensification with enzalutamide did not translate into significant benefit, unlike abiraterone in STAMPEDE, highlighting the need for careful patient selection.

Toxicity and quality of life

Quality-of-life outcomes demonstrated consistent modality-specific patterns.

Urinary function and incontinence

RP was associated with significantly worse urinary incontinence. Barocas et al. [2017] reported that at 3 years, RP patients had worse urinary incontinence than EBRT patients (adjusted mean difference −18.0 points, 95% CI: −20.5 to −15.4) (24). A difference of −16 points on the EPIC urinary domain represents a clinically meaningful deterioration in urinary continence, corresponding to approximately 1–2 additional pads per day. Sanda et al. [2008] found that 79% of RP patients experienced clinically relevant sexual deterioration compared with 34% after EBRT and 33% after brachytherapy (P<0.001) (25). Updated data from more recent cohorts [2020–2025] suggest that erectile function recovery rates have improved with nerve-sparing surgical techniques, though long-term dysfunction remains a significant concern (26).

Sexual function

Sexual dysfunction was more pronounced after RP. Donovan et al. [2016] reported that 95% of men reported erectile dysfunction at 6 months after RP, persisting for 85% at 6 years (27). However, these data are nearly 10 years old. More contemporary series suggest that with nerve-sparing techniques, recovery rates at 2 years may be higher, though long-term data remain limited (26). The impact of ADT on sexual function is substantial, with studies reporting that ADT reduces libido and erectile function in 50–80% of men. This effect is additive to the effects of radiotherapy itself (28).

Bowel function

Bowel toxicity was more common after radiotherapy. Barocas et al. [2017] found that EBRT was associated with worse bowel function (EPIC bowel domain beta coefficient −0.46, 95% CI: −1.20 to −0.28, P<0.001) (24).

Radiation-related complications

Urethral strictures occur in approximately 2–5% of patients after EBRT, while radiation cystitis affects 5–10% and is typically self-limiting but can be chronic in 1–2%. Secondary malignancies are a rare but recognized long-term risk after prostate radiotherapy, particularly involving the bladder and colorectal/rectal sites, although reported absolute rates are low and vary across studies (29,30).

Compound toxicity

When RP was followed by adjuvant or salvage RT, toxicity was compounded. Haisraely et al. [2021] found that primary radiotherapy was associated with significantly better urinary continence [odds ratio (OR) 2.67, 95% CI: 1.7–4.1] and lower odds of combined poor urinary and sexual outcomes (OR 0.29, 95% CI: 0.14–0.58) compared with surgery followed by radiotherapy (31).

ADT side effects and their clinical impact

ADT is associated with a range of side effects that significantly impact quality of life (32,33):

• Hot flashes: occur in 50–80% of men on ADT and can be severe in 10–20%.
• Metabolic effects: ADT is associated with weight gain, insulin resistance, and increased risk of metabolic syndrome. Long-term use (≥6 months) is associated with a 20–30% increase in cardiovascular event risk (28). Drudge-Coates et al. [2025] provide practical recommendations for assessment and management of these risks (28).
• Bone health: ADT reduces bone mineral density by 3–5% annually, increasing fracture risk by 1.5–2 folds (28). Bone-protecting agents are effective but underutilized in clinical practice (28).
• Sexual dysfunction: ADT causes loss of libido (90–100%), erectile dysfunction (70–80%), and reduced penile length and testicular volume. These effects are often partially reversible after ADT cessation but may be permanent in some men (28).
• Fatigue: moderate-to-severe fatigue affects 40–60% of men on ADT and can persist for months after treatment completion (28).
• Cognitive effects: some men report subtle cognitive changes, though the clinical significance remains debated. Cui et al. [2024] systematically reviewed the risks associated with cognitive function and management strategies in the clinical use of ADT (32).

Discussion

Summary and interpretation of key findings

This narrative review synthesized comparative evidence from 30 studies evaluating RP versus radiotherapy-based strategies for high-risk and very high-risk PCa. The key finding is that high-quality, randomized evidence directly comparing these two modalities is lacking, and the existing observational data are conflicting. This is not a failure of the review but rather a reflection of the evidence base. The clinical community has long debated the optimal local treatment for high-risk disease, and our review confirms that this debate remains unresolved due to significant methodological limitations in the available literature.

Several factors explain the conflicting survival findings. First, patient selection is a major confounder: younger, healthier men are preferentially selected for surgery, whereas older men with comorbidities are directed toward RT (14). Second, RT techniques have evolved substantially over time, with dose-escalated RT, ADT use, and brachytherapy boost not uniformly represented in older cohorts (15). Third, the definition of “RT-based strategy” varies widely across studies, encompassing EBRT alone, EBRT with brachytherapy boost, and EBRT with varying ADT durations. Fourth, the differential use of ADT between treatment arms—with nearly all RT patients receiving ADT while only a minority of RP patients receive adjuvant ADT—substantially confounds comparisons.

Despite these limitations, our review provides clinically useful insights. For patients who choose RT, the randomized evidence supports 18–24 months of ADT compared with RT alone. For patients who choose RP, the quality-of-life trade-offs are predictable: worse urinary incontinence and sexual dysfunction compared with RT. Importantly, approximately 50% of RP patients may be spared from ADT and its associated side effects, which is a significant consideration for patients concerned about the metabolic, sexual, and cardiovascular effects of long-term androgen suppression (26). This advantage must be weighed against the potential need for adjuvant or salvage RT in a subset of RP patients, which compounds toxicity (31).

The value of this review lies not in providing a definitive answer—which is impossible given the current evidence—but in synthesizing the existing data to inform clinical decision-making. We have systematically cataloged the methodological reasons for conflicting results, provided a detailed analysis of modality-specific toxicity profiles, and articulated a clear research agenda. For clinicians, this review offers a comprehensive resource for discussing treatment options with patients in a shared decision-making framework.

Limitations and quality of the reviewed evidence

Several limitations of the current evidence warrant acknowledgment:

• The most significant limitation is the absence of large-scale RCTs directly comparing contemporary RP with modern RT + ADT. All comparative survival evidence derives from observational studies, which are subject to selection bias and confounding by indication. Observational methods cannot fully account for unmeasured confounders, and the observed survival differences may reflect patient selection rather than treatment efficacy.
• RT-based strategies are heterogeneous, including EBRT alone, EBRT with brachytherapy boost, and EBRT with varying ADT durations, making comparisons challenging. Differential follow-up also biases comparisons, as long-term data are more mature for older treatment techniques.
• Quality-of-life data were inconsistently reported across studies, with varying instruments and follow-up durations. Very high-risk subgroup data were sparse, limiting conclusions for this patient population. Publication and sponsorship bias are also concerns, as positive trials are more likely to be published and cited than negative or null results.

Clinical implications

For practicing clinicians, this review underscores that treatment selection for high-risk PCa should be individualized according to patient age, comorbidity burden, tumor characteristics, and quality-of-life preferences. Shared decision-making should include explicit discussion of the trade-offs between urinary, sexual, and bowel function, as well as the implications of ADT exposure.

For patients who prioritize avoidance of ADT and its side effects, RP may be preferable, particularly if the patient is a good surgical candidate. For patients who wish to avoid surgical morbidity or who have comorbidities that increase surgical risk, RT + ADT is a reasonable alternative supported by randomized evidence. The choice among RT techniques (EBRT alone, EBRT with brachytherapy boost, or proton therapy) should be guided by institutional expertise and patient factors.

Multidisciplinary care is essential for optimal treatment selection. Patients should be evaluated by both urologists and radiation oncologists to ensure that all treatment options are considered and that the chosen approach aligns with patient goals and preferences.

Future research directions

Several research priorities should guide future investigation. A large-scale RCT directly comparing contemporary RP with modern RT + ADT in high-risk PCa remains urgently needed. Such a trial would ideally stratify by disease volume and incorporate modern imaging (PSMA-PET) and biomarker-driven patient selection. Molecular biomarkers may identify patients who derive differential benefit from surgery versus radiotherapy, enabling precision treatment selection. Parker et al. [2026] demonstrated that a multimodal artificial intelligence model can predict abiraterone efficacy in very high-risk PCa, suggesting a pathway toward biomarker-driven patient selection (33).

Further trials are needed to determine the optimal ADT duration for individual patients, as well as the role of combination therapies (e.g., abiraterone, enzalutamide) in high-risk settings, building on the STAMPEDE and ENZARAD data (22,23). Studies evaluating stereotactic body radiotherapy (SBRT) and proton therapy in high-risk disease are also needed. Standardized quality-of-life assessments should be integrated into all future studies to enable meaningful comparisons across modalities.

Conclusions

For patients with high-risk and very high-risk PCa, radiotherapy combined with 18–24 months of ADT is supported by evidence from randomized trials. Comparative survival evidence between RP and radiotherapy-based strategies remains conflicting and is limited by observational designs and selection bias; therefore, causal inferences cannot be drawn. Quality-of-life outcomes demonstrate consistent modality-specific toxicity profiles.

Clinical implications: treatment selection should be individualized according to patient age, comorbidity burden, tumor characteristics, and quality-of-life preferences. Shared decision-making should include explicit discussion of urinary, sexual, and bowel function trade-offs. The potential to avoid ADT (in approximately 50% of RP patients) is an important consideration that may favor surgery in appropriately selected patients (26).

Policy implications: healthcare systems should ensure access to both surgical and radiotherapy expertise for high-risk PCa patients. Multidisciplinary care is essential for optimal treatment selection.

Future research: randomized trials directly comparing contemporary RP with modern radiotherapy plus ADT are urgently needed. Additional research priorities include biomarker-driven patient selection, optimization of ADT duration, and integration of patient-reported outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0553/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0553/prf

Funding: This work was supported by the National Natural Science Foundation of China (grant Nos. 82372831, 82403963, and 82170785); the Natural Science Foundation of Sichuan, China (grant No. 2025ZNSFSC1892); the National Key Research and Development Program (grant No. 2024YFB3311703-1); and the Postdoctor Research Fund of West China Hospital, Sichuan University (grant No. 2025HXBH134).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0553/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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