Nerve-sparing radical cystectomy in the era of perioperative enfortumab vedotin plus pembrolizumab: reappraising the value of functional preservation

Radical cystectomy (RC) with pelvic lymph node dissection remains a central treatment for muscle-invasive bladder cancer (MIBC) and selected high-risk non-muscle-invasive disease, but the operation can have lasting effects on sexual and urinary function. Long et al. describe an anterograde approach to neurovascular bundle (NVB) release during robot-assisted radical cystectomy (RARC) in five preoperatively potent men (1). Using the posterior prostatic capsule as a landmark, they developed an avascular plane between the capsule and Denonvilliers’ fascia and released the NVB from the prostatic base to the apex. Four patients were classified as having recovered potency, no positive surgical margin was reported, and no radiographic recurrence was observed during a median follow-up of 11 months.

The conceptual link with intrafascial robot-assisted radical prostatectomy is appropriate. The posterior approach described by Galfano and colleagues showed the feasibility of working close to the prostatic capsule to preserve periprostatic structures (2). Long et al. adapt this principle by changing the landmark from the prostatic vasculature to the posterior capsule. This is technically plausible, but transfer to cystectomy is not automatic: the operative field is broader, the bladder and prostate are removed en bloc, and tumor location or prior treatment may alter the intended plane. A five-patient series cannot establish how often the plane can be developed safely, when a wider plane is required, or whether the result is reproducible across surgeons and institutions.

Interpretation of the functional result requires particular care. An estimate of 4 of 5 has an exact 95% confidence interval of approximately 28.4% to 99.5% and should not be compared directly with the 55% 12-month erectile function rate reported in a larger multicenter RARC-neobladder cohort (3). In addition, the source report defines potency as a Sexual Health Inventory for Men (SHIM) score ≥17 in the abstract but >17 in the Methods; one patient had a final score of exactly 17 (1). The reported recovery proportion is therefore 80% under the first definition and 60% under the second. Assessments were performed by a physician who did not participate in surgery, which reduces one potential source of bias, but follow-up timing and questionnaire administration by clinic visit or telephone were not uniform. The very early recoveries reported in several patients are encouraging, yet they require confirmation using a consistent SHIM threshold, a uniform assessment schedule, and a consistent mode of questionnaire administration.

The clinical heterogeneity of the cohort also limits inference. Four patients had clinical T2 disease and one had multifocal T1 disease; one tumor included adenocarcinoma and micropapillary components, and three patients received 2–4 cycles of neoadjuvant chemotherapy whereas two did not (1). These differences are understandable in an initial technical report, but future studies should define patient selection more clearly and report outcomes by disease characteristics and perioperative treatment.

Since these operations were performed in 2024, the perioperative treatment landscape has changed. NIAGARA showed improved event-free and overall survival with perioperative durvalumab added to neoadjuvant gemcitabine-cisplatin in cisplatin-eligible MIBC (4). In KEYNOTE-905/EV-303, 344 patients who were ineligible for or declined cisplatin were randomized to perioperative enfortumab vedotin plus pembrolizumab (EV + P) with surgery or surgery alone. EV + P improved event-free survival [hazard ratio (HR), 0.40] and overall survival (HR, 0.50), and increased the pathological complete response (pCR) rate from 8.6% to 57.1% (5). Preliminary phase 3 results reported in the KEYNOTE-B15/EV-304 meeting abstract in 808 cisplatin-eligible patients showed improvements in event-free survival (HR, 0.53), overall survival (HR, 0.65), and pCR (55.8% vs. 32.5%) compared with neoadjuvant gemcitabine-cisplatin (6). On July 10, 2026, the US Food and Drug Administration extended the perioperative EV + P indication to adults with MIBC who are candidates for cystectomy regardless of cisplatin eligibility (7). These developments establish a non-platinum perioperative option across cisplatin-eligibility groups in the United States; they do not remove platinum-based treatment from consideration.

These high pCR rates may increase interest in function-preserving surgery, but they do not establish the oncological safety of an intrafascial plane for an individual patient. pCR is determined after cystectomy and does not provide site-specific assurance at the prostatic interface. A lower population-level prevalence of residual disease should therefore not be translated into broader nerve-sparing without careful assessment of tumor location, local extent, and the ability to obtain an adequate margin. The relevant implication is not that the oncological cost of intrafascial dissection has been shown to fall, but that better response assessment and patient selection have become increasingly important.

Bladder preservation should also be considered separately. Trimodal therapy is an established bladder-preserving option for selected patients, with long-term outcomes reported from experienced centers (8). A different strategy is response-adapted omission of immediate cystectomy after systemic therapy. In the phase 2 HCRN GU16-257 study, 33 of 76 patients achieved a clinical complete response after gemcitabine, cisplatin, and nivolumab; 32 of the 33 chose to forgo immediate cystectomy, supporting further study of this approach rather than establishing it as interchangeable with cystectomy (9). These strategies may overlap with nerve-sparing RARC in a subset of patients, but they address different clinical choices. The role of intrafascial RARC is likely to be clearest among carefully selected patients who require or prefer cystectomy and for whom both oncological clearance and functional preservation appear feasible.

A practical question is whether the described plane remains reproducible after contemporary systemic therapy. In EV-303, receipt of surgery was similar in the EV + P and control groups, which is reassuring for overall surgical feasibility (5). However, the trial did not evaluate the specific intrafascial plane between the prostatic capsule and Denonvilliers’ fascia. The report by Long et al. states only that three patients received neoadjuvant chemotherapy; the regimens were not specified (1). Feasibility after EV + P is therefore uncharacterized. Future cohorts should record the ability to maintain the intended plane, the need to convert to a wider dissection, margin status, perioperative complications, and functional recovery according to the preceding regimen.

Two additional issues merit attention. All five patients underwent ileal conduit diversion, so the series cannot assess whether the technique contributes to continence after orthotopic neobladder, which would be an additional clinically relevant potential benefit (1). One patient also had incidental Gleason score 3+3 prostate cancer. Contemporary complete-sampling data confirm that occult prostate cancer is common in cystoprostatectomy specimens and that a substantial proportion has clinically significant features (10). Careful preoperative prostate assessment, including multiparametric magnetic resonance imaging where appropriate, is therefore reasonable before intrafascial dissection is considered.

Long and colleagues present a reasonable technical solution to a genuine anatomical challenge, and the early functional signal is worthy of further study. The current report does not establish comparative functional benefit or oncological equivalence. Further evaluation would benefit from a comparator, a consistent potency definition and assessment schedule, longer oncological follow-up, clear selection criteria, and explicit reporting of feasibility after modern perioperative regimens. In the EV + P era, the most defensible interpretation is that function-preserving cystectomy may become relevant to more treatment discussions, while the threshold for careful individual selection remains high.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was a standard submission to the journal. The article did not undergo external peer review.

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-2026-0681/coif). The authors have no conflicts of interest to declare.

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