Results from the PRESERVE trial: an editorial commentary

Focal therapy represents a hybrid treatment of prostate cancer (PCa), involving ablative treatment of the index lesion whilst maintaining close surveillance of the untreated gland. Irreversible electroporation (IRE) was first described as a focal treatment modality for PCa in 2010 by Onik et al. (1) and shown to be safe and clinically feasible by Valerio et al. in 2014 (2). Since then, there has been growing evidence supporting favourable functional outcomes compared to traditional whole-gland treatment, and promising short-to-medium term oncological outcomes.

In the January 2026 issue of European Urology, George et al. present the results from the PRESERVE trial, having previously published preliminary safety outcomes in June 2024 (3,4). This was a prospective, single-cohort trial conducted across 17 centres in the United States, reporting 12-month oncological and functional outcomes of 121 men with intermediate-risk International Society of Urological Pathology (ISUP) grade group (GG) 2/3 PCa treated with focal IRE using the Nanoknife System (AngioDynamics, Latham, NY, USA).

The primary endpoint, 12-month negative in-field biopsy (positive biopsies defined as any amount of any PCa), was met in 71% of patients. This rate increased to 84% when using the Delphi consensus criterion for clinically insignificant PCa (≤3 mm ISUP GG 1). This 16% rate of in-field recurrence is comparable to other studies using similar definitions: 16% recurrence reported by van den Bos et al. (5) and 9% by Miñana López et al. (6). The rate of negative out-of-field biopsy was 64%, although half of the patients with positive out-of-field biopsies had ISUP GG 1 disease only; this equates to an 18% rate of out-of-field clinically significant PCa (csPCa). Overall, csPCa anywhere was observed in 26% of patients at 12 months. This is by far the most clinically relevant finding, yet is not clearly highlighted in the results section, nor is it addressed in the remainder of the paper. This is a relatively high overall 12-month failure rate when compared to similar cohorts, which will only increase over time as new disease arises in the untreated gland and in-field recurrences develop (7). Although there is no existing consensus, based on existing literature we believe that a lower overall failure rate needs to be achieved at such an early timepoint as the initial 12-month post-treatment biopsy for any form of focal therapy to gain widespread acceptance as a genuine option for highly selected patients. Factors that may help achieve this target are discussed later in this commentary.

Retreatment rates were low, with one patient undergoing repeat IRE due to a persistent magnetic resonance imaging (MRI) lesion at 3 months, and another who underwent salvage robotic prostatectomy 11 months post-IRE due to persistent ISUP GG 2 disease. However, given the follow-up duration was only 12 months, it is expected that retreatment rates would increase significantly with longer follow-up; it will be important to await the longer-term clinical outcomes of this relatively high failure rate.

Both the Expanded Prostate Cancer Index Composite (EPIC) urinary domain and International Prostate Symptom Score (IPSS) improved from baseline at 3, 6, 9 and 12 months. This is consistent with findings from a recent systematic review of focal IRE, where there was an improvement in urinary patient-reported outcome measures (PROMs) in half of studies and no change in the other half (7). After 12 months, 96% of patients in the PRESERVE trial who were continent at baseline remained pad-free. Again, this is similar to other studies, with an overall decrease in the percentage of pad-free patients in 4/15 studies, no change in 10/15 studies, and an increase in 1/15 (7). In those with functional baseline erections, 15-question International Index of Erectile Function (IIEF-15) scores worsened 1-month post-IRE but approached baseline by 12 months. Mean erectile function in these patients was 23 at baseline and 19 at 12 months. This deterioration in erectile function is consistent with existing literature, with deterioration in sexual PROMs reported in 8/15 studies, with gradual improvement towards baseline also noted (7). Overall, functional outcomes from the PRESERVE trial and existing studies are comparable even despite variations in operative technique, treatment parameters, extent of ablation and patient selection. This reproducibility supports the key concept of focal IRE and focal therapy in general: favourable preservation of urinary and sexual function.

Adverse events were common (86%) but predominantly low-grade, with only three procedure-related grade 3 events and one unrelated death. Notably, there was one case of rectourethral fistula 6 weeks after treatment that resolved with prolonged suprapubic catheterisation. There are only two other reported cases of post-focal IRE rectourethral fistula in the literature (8,9).

The PRESERVE trial has several notable strengths. It represents one of the largest prospective cohorts evaluating focal IRE for PCa and the largest conducted in the United States. Furthermore, the multi-centre nature enhances the generalisability of results. Despite 14 out of 17 sites performing their first focal IRE case during the trial, the outcomes support the notion that this is an accessible technique with reproducible results. The study also incorporated strict protocol-mandated oncological follow-up in the form of prostate-specific antigen (PSA) testing at 3–10 days and 1, 3, 6, 9, 12 months post-IRE, MRI 3 and 12 months post-IRE, and biopsy 12 months post-IRE. Regular PSA testing allows for better understanding of PSA kinetics, both in terms of nadir level (median 1.3 ng/mL) and timing (median 3.5 months), as well as percentage reduction at 6-month (68%) and 12-month (60%). Similarly, per-protocol MRI and repeat biopsy avoids underreporting of residual disease when compared to ad hoc biopsy performed only due to concerns with PSA levels/kinetics; this limitation exists in other focal IRE studies not including per-protocol repeat biopsy in all patients. Finally, functional outcomes were closely followed-up with urinary and sexual PROMs performed at 1, 3, 6, 9, and 12 months. The use of PROMs allows for standardised comparison, whilst frequent follow-up provides increased insight into temporal trends in functional outcomes.

Several limitations must also be acknowledged. Firstly, the PRESERVE trial was a single-arm study. The lack of a comparator arm limits interpretation of oncological outcomes due to potential selection bias and confounders. This, however, is a recurring limitation in the existing literature, with only a single study directly comparing focal IRE to radical prostatectomy (10). Furthermore, 121 out of 128 enrolled patients actually underwent focal IRE. It would be valuable to know what factors contributed to eventual non-treatment in these seven patients, as this may have further contributed to selection bias.

Second, subgroup analysis by baseline tumour grade was not reported. Differences in recurrence rates between the 80% of men with ISUP GG 2 PCa compared to the 20% with ISUP GG 3 disease were not reported. This is vital missing information that could help guide appropriate and safe patient selection, as well as informed patient counselling. Furthermore, there are very limited data and there is no analysis provided on the grading of recurrence; Gleason scores of overall recurrences are only provided in the supplementary data, and 40% of in-field recurrence grading was in fact missing. These data are important to understand the nature and nuances of treatment failure as not all recurrence is equal—was the recurrence the same grade, higher or lower? If the same grade, was the core cancer length shorter and was the proportion of Gleason pattern 4 lower than pre-treatment and low enough to switch to active surveillance?

Next, prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) was not incorporated into the trial protocol. PSMA PET/CT is increasingly utilised in clinical practice not only for clinical staging but also to confirm concordance with MRI and biopsy findings. Although systematic biopsy was performed in all patients, it would be valuable to know what proportion of patients with out-of-field csPCa were harbouring this disease at baseline and may have been detected on PSMA PET/CT. It has been well-established now that PSMA PET and MRI complement each other, whereby each modality can detect a small proportion of significant cancers not visible on the other, reducing the negative predictive value of each (11). The high rate of out-of-field csPCa (18%) indicates a degree of ’selection failure’ in which out-of-field disease is often residual rather than recurrent disease (12,13). Compared to existing literature, we believe that this rate needs to be improved (7). Pre-treatment PSMA PET/CT is an important diagnostic tool to help optimise appropriate patient selection. Where available, we believe it should be utilised as part of patient-selection protocol.

The authors did not provide details of the relationship between technical parameters such as margins, current, number of electrodes, and probe active tip length, with in-field recurrence. Correlative analyses between these variables and outcomes may help identify optimal treatment parameters, thereby improving oncological outcomes within the study, as well as improving overall study reproducibility and generalisability by aiding in standardising treatment protocols. Several studies demonstrated improved in-field recurrence rates after the initial learning curve associated with tailoring optimal parameters and treatment technique (5,14,15). It is likely that with more optimal treatment parameters and technique, in-field recurrence rates may have improved, particularly given that the majority of sites were performing their first focal IRE cases.

Although PSA kinetics were explored in detail as aforementioned, the relationship between PSA and recurrence was not assessed. This could potentially assist in predicting treatment success based on initial PSA nadir, as well as risk-stratifying recurrence based on PSA kinetics, thereby informing when repeat MRI and biopsy should be performed. Finally, despite promising early oncological outcomes at 12 months, this is still short-term follow-up only and much longer-term data are required to adequately assess the durability of oncological control.

Despite these caveats, the PRESERVE trial is a well-conducted study with short oncological and patient-reported functional follow-up. It provides valuable prospective data to the growing evidence that has historically relied on smaller, single-institution series. The favourable functional outcomes and early oncological outcomes reinforce the essence of focal therapy—the potential to preserve urinary and sexual function while providing meaningful oncologic treatment in carefully selected patients. The implementation of PSMA PET/CT and refinement of treatment technique with clear technical parameters will likely decrease overall csPCa failure to a more acceptable rate and should be included in future studies. Ultimately, longer-term oncological follow-up and comparative studies against established whole-gland therapies are essential to define the role of focal IRE, and focal therapy more broadly, within the treatment paradigm for localised PCa.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Andrology and Urology. The article has undergone external peer review.

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0264/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0264/coif). The authors have no conflicts of interest to declare.

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