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SIUJSociété Internationale d’Urologie Journal
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  • Conference Report
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9 February 2026

19 Pages

B2B: Bladder Cancer Summary

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1
Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
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Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
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Edinburgh Bladder Cancer Surgery (EBCS), The University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
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Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
Soc. Int. Urol. J.2026, 7(1), 5;https://doi.org/10.3390/siuj7010005
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The 7th Bench-to-Bedside Uro-Oncology: GU Cancers Triad Meeting, organized in conjunction with the 45th Annual Congress of the Société Internationale d’Urologie, was held on 31 October 2025, in Edinburgh, Scotland, and transmitted live on the SIU@U Congress app. The first session, on bladder cancer (BCa), took place in the morning and was moderated by Dr. Peter C. Black (Canada). This session included 2 debates, the first on whether immune checkpoint blockade plus bacillus Calmette-Guérin (BCG) is the new standard first-line therapy for high-risk non–muscle-invasive BCa (NMIBC); and the second on whether en bloc is superior to conventional transurethral resection of bladder tumour (TURBT) for initial management of NMIBC. The session continued with a lecture dedicated to advances in perioperative therapy for muscle-invasive BCa (MIBC) and a panel discussion on metastatic BCa. The B2B programme features a luncheon symposium dedicated to key advances in the management of GU cancers. This year, the symposium was dedicated to human epidermal growth factor receptor 2 (HER2)-targeted antibody–drug conjugates in metastatic BCa.
Dr. Black introduced the first speaker, Dr. Kilian M. Gust (Austria), who argued in favour of immune checkpoint blockade plus BCG as the new standard first-line therapy for high-risk NMIBC. Dr. Gust started his talk by pointing out that 5-year oncologic outcomes for this condition include a 50% recurrence and 20% progression rate [1]. Thus, key treatment goals are to eradicate the existing tumours and prevent recurrence and progression, but this must be balanced against maintaining a reasonable quality of life for patients, which typically requires an intact bladder.
Since it received FDA approval in 1990, BCG has become the standard of care for high- and intermediate-risk NMIBC. While progression is a problem in high-risk disease, it is not a major issue in intermediate-risk NMIBC [2]. Treatment strategies include intravesical therapy with BCG, as well as immune checkpoint inhibitor (ICI)-based systemic therapy in the BCG-unresponsive setting [3,4].
While it is unlikely that ICIs will replace BCG as a treatment strategy, there is great potential for combining the 2, with 4 large phase 3 randomized controlled trials (RCTs) exploring this possibility: CREST (BCG induction and maintenance for 2 years vs. BCG induction and maintenance for 2 years plus sasanlimab vs. BCG induction plus sasanlimab) [5], ALBAN (BCG induction and maintenance for 1 year with or without the addition of atezolizumab) [6], POTOMAC (BCG induction and maintenance for 2 years vs. BCG induction and maintenance for 2 years plus durvalumab vs. BCG induction plus durvalumab) [7], and KEYNOTE-676 (BCG induction and maintenance for 3 years with or without the addition of pembrolizumab) [8]. Results of all these trials except KEYNOTE-676 are available.
There are some key differences in the design of these trials. Both CREST and POTOMAC included a BCG induction alone arm with an ongoing ICI arm, while the induction alone arm was skipped in the ALBAN trial and KEYNOTE-676 trial. There are also some differences in the disease characteristics included for each trial, with the highest proportion of patients with carcinoma in situ (CIS) in the ALBAN trial, but the highest proportion of pure CIS in the CREST trial. In addition, ALBAN includes maintenance therapy for only up to 1 year, while CREST and POTOMAC have maintenance up to 2 years. The duration of ICI therapy is 1 year in POTOMAC and ALBAN but 2 years in CREST. Finally, the event-free survival (EFS) endpoints have different definitions across the trials. In POTOMAC and CREST, it is defined as high-grade recurrence, CIS at 6 months, or death. In ALBAN, any recurrence (not just high-grade) was part of the EFS definition. Median follow-up is longest for POTOMAC, at 60 months, versus 36 months for CREST and 35 months for ALBAN [9]. All these differences will make head-to-head comparisons of each regimen difficult.
Only CREST and POTOMAC yielded positive findings. Both trials revealed a 32% reduction in recurrence or death with the addition of ICIs [5,7]. Nevertheless, it is important to consider that European Association of Urology guidelines, as well as American Urology Association and Society of Urologic Oncology guidelines, still recommend radical cystectomy (RC) in patients with high-risk NMIBC as the standard of care, unless patients are treated in the setting of a clinical trial [10].
The trials have shown different outcomes based on subgroups, with conflicting findings across the 2 trials. Notably, in POTOMAC, patients with higher risk papillary disease and high PD-L1 expression appeared to benefit more from the addition of an ICI, while those with CIS benefitted less [7]. Conversely, in CREST, patients with CIS and T1 disease benefitted more from the addition of an ICI [5].
Regarding safety, both trials revealed the difficulty of keeping patients on BCG for 2 or 3 years because of emerging toxicity, and the addition of ICIs can also contribute to life-changing complications [5,7].
Dr. Paramananthan Mariappan (United Kingdom) presented the counterpoint to Dr. Gust’s position. He started his talk by pointing out that level 1 evidence is frequently not employed systematically in the clinical setting. For instance, it has been shown that systemic therapy improves outcomes in MIBC, but its use in the real world remains sparse and inconsistent [11]. Similarly, the use of intravesical treatment following TURBT differs considerably from what is recommended by evidence-based guidelines [12].
Level 1 evidence for the management of high-risk NMIBC is available to guide therapy. A meta-analysis revealed a 75–80% recurrence-free survival (RFS) with maintenance BCG [13]. In the real world, the treatment offers at least a 75% RFS and a 3-year progression-free survival (PFS) > 90% [2]. More importantly, in very high-risk NMIBC, use of maintenance BCG and adequate BCG yields outcomes approaching that of RC, with an overall survival (OS) of 80.2% with BCG vs. 88.1% with RC [14].
Currently, the best way for clinicians to optimize their outcomes, rather than adding ICIs, is to adhere to level 1 evidence. This includes use of adequate BCG, defined as at least 5–6 doses of induction BCG plus 2 further doses as either maintenance therapy or a second induction [15]. A real-world study published in 2013 revealed that approximately only 50% of patients receive adequate BCG, based on this definition [16]. In a 2025 analysis that comprised 8 studies and 17,007 patients, as many as 59.5% (10,122) did not receive adequate BCG treatment [17].
While it is true that adding systemic sasanlimab ICI therapy to BCG does improve outcomes, the improvement is marginal, with a 36-month absolute difference in EFS of 7.3%, and a number needed to treat of approximately 14 patients for only 1 to experience an EFS benefit [5]. Dr. Mariappan also questioned whether EFS is even the best endpoint to consider in this setting, noting that the addition of sasanlimab did not improve OS [5].
Notably, in this setting, sasanlimab is used to augment both induction and maintenance BCG, which means there is no scope to reduce the amount of BCG used, resulting in additive toxicity. Importantly, 1 in 4 patients treated with sasanlimab plus BCG may experience grade ≥ 3 toxicity. Immune-related adverse events are unfamiliar to most urologists, whereas many urologists may be comfortable managing of the adverse events related to BCG [18]. Therefore, adding an ICI to BCG creates a need to recruit oncologists to support the management of treatment-related toxicities with combination therapy.
Beyond sasanlimab, durvalumab [7] and atezolizumab [6] have also been investigated as add-on therapy to BCG in high-risk NMIBC. The benefit of durvalumab was marginal, with a 5% additional EFS and no OS benefit [7]. There was no EFS benefit with the addition of atezolizumab, all the while exposing patients to significant toxicity [6].
When it comes to the addition of systemic agents to BCG, several questions remain unanswered, such as which definition of BCG failure (relapse, refractory, BCG-unresponsive) should be used and whether re-challenging with BCG following BCG-relapse can still be considered. It is also unknown what the role of intravesical chemotherapy (e.g., using TAR-200) will be in BCG-unresponsive disease and whether ICIs could still be used in BCG-unresponsive disease, as well as after progression to MIBC or metastatic disease.
During the Q&A session following the talks, Dr. Black asked Dr. Gust whether he felt that sasanlimab and durvalumab will receive regulatory approval for use in this setting. Dr. Gust believes they will. Nevertheless, the question of which patients to treat with an ICI plus BCG combination remains open because it is unclear which specific patient populations are likely to benefit most, especially since the subgroup analyses of CREST and POTOMAC yielded somewhat contradictory findings.
A medical oncologist in the audience echoed concerns that EFS is not the appropriate endpoint for these trials. Given the cost and toxicity of these agents, more pragmatic endpoints, such as avoidance of RC and progression to MIBC or OS may be more useful. In addition, patients treated upfront with an ICI plus BCG who progress to MIBC may not respond to ICI monotherapy, potentially depriving them of life-saving treatment later on. Dr. Black replied that progression events in CREST were very minimal, around 7 patients out of 340. Over time, additional progression and RC data will add clarity. Dr. Gust agreed that EFS is not a very clinically relevant endpoint, particularly given the small absolute difference between the groups, and noted that the BCG monotherapy arm in the trials performed so well that it is difficult to measure the incremental improvement offered by the ICI.
A discussion among medical oncologists in the audience ensued, with some disagreement regarding whether immune-related adverse events from ICIs are worth the incremental benefits seen in these trials, especially given that they can, on rare occasions, be long-lasting and even fatal, not to mention very uncomfortable for patients. Nevertheless, the addition of ICIs may reduce the need for RC, which also carries a rare risk of mortality and is unpleasant for patients. Dr. Black emphasized the need to make such clinical decisions in collaboration with patients.
The next debate centred on whether en bloc resection of bladder tumour (ERBT) is superior to conventional TURBT for initial management of NMIBC. The position in favour of ERBT was presented by Dr. Jeremy Y. C. Teoh (Hong Kong). He pointed out the well-known problems with conventional resection, including the subjective nature of what constitutes complete resection (risking residual disease) and the risk of leaving behind floating tumour cells following piecemeal resection (risking tumour re-implantation). En bloc resection was proposed about 40 years ago as a superior approach, through which the tumour is removed in one piece, with margins clearly assessed. Dr. Teoh noted that clear surgical margins can be achieved in about 98.6% of cases if a 5 mm surgical resection margin is used. The goal is to achieve a uniform resection along the entire detrusor muscle layer.
Last year, Dr. Teoh and colleagues published an RCT comparing 350 patients with bladder tumours ≤ 3 cm who underwent ERBT or standard resection. The 1-year recurrence rate was 28.5% with ERBT vs. 38.1% with standard resection (p = 0.007). Subgroup analyses revealed that patients with tumours 1–3 cm in size, single tumours, Ta disease, or intermediate-risk NMIBC benefitted the most from ERBT [19].
Notably, in patients with high-risk tumours, ERBT alone was not sufficient to improve outcomes significantly. In subgroup analyses of this trial, among patients with high-risk tumours who also received BCG, ERBT resulted in a 1-year recurrence rate of 5%, compared with 26% using standard resection [19].
A challenge to ERBT is how to deal with larger tumours, which can be resected en bloc but cannot be removed in one piece. Dr. Teoh said he knows of cases of NMIBC where the technique was still beneficial in terms of ensuring complete resection. As a result, investigation is ongoing into how to modify ERBT to address larger tumours. This could involve, for example, debulking the tumour and then using ERBT to remove the tumour base or simply following the basic principles of ERBT of defining the margins and systematically removing each layer while still performing a conventional resection.
Dr. Teoh and collaborators designed a phase 2 trial of modified ERBT in tumours ≥ 3 cm (NCT04081246). Overall, 27 patients underwent ERBT as part of the trial. Following surgery, those with NMIBC underwent magnetic resonance imaging (MRI), followed by second-look TURBT, to ensure the tumour was completely resected. Those with MIBC underwent MRI or contrast computed tomography (CT) after ERBT, followed by RC if there were no distant metastases or second-look TURBT if RC was not performed.
The trial included 15 patients with NMIBC, 14 of whom achieved complete resection with ERBT (93.3%). The remaining 12 patients had MIBC, and 11 had proper staging of MIBC at the first surgery (91.7%). Eight of these patients underwent RC. Among the 4 patients with final T2 disease, 3 patients had T0 upon RC (75%). The remaining 4 patients had T3 disease upon RC.
The group of patients who benefitted the most from ERBT were those with large T1 NMIBC. These patients were able to have their tumours completely resected. Patients with T2 disease, who would have formerly undergone transurethral resection for staging and then possible RC, might be able to achieve T0 disease with ERBT alone. ERBT alone is unlikely to help patients with more advanced disease (T3 or above). These patients will still require RC as definitive management.
Dr. Teoh concluded that conventional TURBT is associated with many limitations, but ERBT, using the same instruments, allows for a systematic approach to tumour resection, improving surgical quality. This in turn may improve surgical and oncological outcomes with no disadvantages beyond a slightly increased operative time.
Dr. Stephen B. Williams (United States) argued the contrary position to Dr. Teoh. He pointed out that TURBT is the gold standard that should not be neglected, critical for both diagnosis and treatment, with complete resection being paramount [20]. Various improvements in technique and adjuncts to conventional TURBT improve its performance, such as the use of blue light technology to aid in the identification of tumours [21]. With the rate of innovation in this field, there is also a possibility that the ultimate goal of reducing the frequency of the procedure is on the horizon.
While he agreed with Dr. Teoh that results of the phase 3 trial of ERBT were impressive, it was conducted only in tumours ≤ 3 cm and on the basis of the surgeon’s endoscopic judgment, which may vary from surgeon to surgeon [19]. Other key exclusions were bladder tumour detected during intravesical BCG therapy, histological diagnosis other than NMIBC, presence or prior history of upper urinary tract malignancy, ECOG score ≥ 3, ASA > 3, history of bleeding disorder or use of anticoagulants, pregnancy, presence of other active malignancy, and life expectancy < 1 year [19]. Dr. Williams acknowledged that ERBT does indeed appear to be the superior approach among those specific patients who were eligible for the trial, but that patient group is limited. There is also some evidence it may be more cost effective in these patients [22].
He concluded that while ERBT certainly challenges conventional TURBT, TURBT remains the gold standard. In expert hands, it has a low risk of perforation (<5% with TURBT but not always mentioned in ERBT trials), suggesting that new trainees should learn TURBT before moving on to the more challenging ERBT. There also remains a lack of long-term follow-up of oncologic outcomes and safety data with ERBT, the latter with or without the addition of intravesical chemotherapy. Ultimately, he said, the size of the tumour is a key consideration, with the feasibility of conducting ERBT in larger tumours still unclear. In the meantime, TURBT remains effective for all sizes of tumours.
During a Q&A period, Dr. Williams acknowledged that he does perform ERBT, but only in smaller tumours, noting that training surgeons to perform ERBT helps improve their skills in conventional TURBT at the same time. Nevertheless, trainees start with performing TURBT and then move up to ERBT. Dr. Black, conversely, felt it was easier to train ERBT than TURBT. His challenge is finding patients who are good candidates for ERBT. Dr. Teoh, however, said that he routinely performs ERBT in his patients. In Dr. Teoh’s view, many surgeons may prefer to perform conventional TURBT because that is the technique they are most used to rather than because of challenges in identifying patients eligible for ERBT.
Dr. Black next asked how blue light cystoscopy and single dose chemotherapy play into the benefits of ERBT. Dr. Teoh replied that about 60% of patients in the ERBT trial also received mitomycin C (MMC) installations, but blue light cystoscopy was not used in the trial.
Discussion next centred on how the outcomes of surgery, whether TURBT or ERBT, are highly dependent on surgeon skill level, with Dr. Teoh reiterating that ERBT is relatively easy to teach. Ultimately, the panelists and audience agreed that good surgical training is the cornerstone of good outcomes, whether TURBT or ERBT is used, and that surgeons should be able to perform both competently. There was also agreement that pathology findings are important for guiding care.
The next presentation was a state-of-the-art talk by Dr. Karima Oualla (Morocco) on advances in perioperative treatment for MIBC. The current standard of care in this patient population, she explained, is neoadjuvant cisplatin-based chemotherapy, with a strong rationale for this approach derived from phase 3 RCTs demonstrating improvement in OS [23]. The aim of neoadjuvant treatment is to eradicate micro-metastasis early on, to maximize outcomes. In addition, paired tumour tissue obtained from TURBT and RC/pelvic lymph node dissection (PLND) offer an opportunity to evaluate tissue for biomarkers and response to neoadjuvant therapy, helping with risk stratification and prediction of sensitivity to adjuvant therapy [24].
The VESPER trial compared gemcitabine plus cisplatin (GC) with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) in the neoadjuvant or adjuvant setting. Five-year OS was superior with ddMVAC in the neoadjuvant setting (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.52–0.97), with a trend toward improvement in OS in the entire patient population (HR 0.77, 95% CI 0.58–1.03). These findings cemented cisplatin-based therapy as the standard of care in the neoadjuvant setting for MIBC [25].
The addition of ICIs was evaluated in the NIAGARA trial, which compared GC with or without durvalumab in the neoadjuvant setting. Those in the durvalumab arm continued this therapy into the adjuvant setting for 8 cycles. This trial included patients with divergent differentiation or histologic subtypes as well as a creatinine clearance ≥ 40 mL/min. The pathological complete response (pCR) was greater with the addition of durvalumab (odds ratio 1.60, 95% CI 1.23–2.08), and the curves continue to separate over time [26]. Among patients with a pCR, EFS was superior (HR 0.69, 95% CI 0.56–0.86). Nevertheless, patients who did not achieve pCR still benefitted from durvalumab, with an EFS of 53.3%, compared with 49.5% among those who did not receive an ICI [27]. Similarly, patients benefitted from durvalumab regardless of whether they were positive or negative for circulating tumour DNA (ctDNA), with a better prognosis observed, as expected, for those who were ctDNA negative [27].
A challenge in the clinical setting is the fact that not all MIBC patients are eligible for cisplatin chemotherapy. To address the unmet needs of this patient population, the KEYNOTE-905/EV-303 study was conducted, assessing enfortumab vedotin (EV) with or without pembrolizumab in the neoadjuvant and adjuvant settings. Patients in this trial were ineligible for cisplatin-based chemotherapy or declined to use it. The EFS was superior with the addition of pembrolizumab (HR 0.40, 95% CI 0.28–0.57) as was OS (HR 0.50, 95% CI 0.33–0.74), with subgroup analyses revealing benefits in almost all patients. There was a high pCR rate, at 48.3% in the group receiving EV plus pembrolizumab, with benefits observed regardless of pCR [28].
Among patients who received surgery upfront, adjuvant chemotherapy options are available. While the rationale for using adjuvant treatment is not as strong as for neoadjuvant, it is still offered for patients who are pT3/4 and/or pN+ [29]. The CheckMate 274 trial was designed to determine whether ICIs could also be of benefit in this setting, comparing nivolumab against placebo in patients with high-risk muscle-invasive urothelial carcinoma (MIUC) who underwent RC. Patients may or may not have also received cisplatin-based chemotherapy in the neoadjuvant setting.
The 5-year disease-free survival (DFS) was superior with active therapy (HR 0.74, 95% CI 0.61–0.91), with particular benefits in patients who were PD-L1 ≥ 1% (HR 0.58, 95% CI 0.42–0.79). In addition, OS benefits were observed in the PD-L1 ≥ 1% population (HR 0.58, 95% CI 0.42–0.79). Patients who were ctDNA positive had a worse prognosis but still benefitted from nivolumab. Patients with undetectable ctDNA had a greater than 10-fold longer median DFS (HR 0.30, 95% CI 0.18–0.48), as well as an improved OS (HR 0.44, 95% CI 0.25–0.76), compared with those with detectable ctDNA [30]. This approach is rapidly becoming the standard of care worldwide in this patient population.
The IMvigor010 study compared atezolizumab with placebo in the adjuvant setting for patients with high-risk MIBC who were ctDNA positive. While this was a negative trial [31], it did provide insight on the importance of ctDNA for prognostication as well as for predicting response to atezolizumab [32,33]. The TOMBOLA trial also demonstrated that serial measurements of ctDNA following adjuvant treatment and RC is a highly specific method for identifying patients who might benefit from early immunotherapy (IO) at a time of minimal metastatic disease [34].
For the IMvigor011 trial, patients with high-risk MIBC who were ctDNA positive following RC were randomized to adjuvant atezolizumab or placebo. Among these patients, DFS was significantly improved with active therapy (stratified HR 0.64, 95% CI 0.47–0.87), as was OS (stratified HR 0.59, 95% CI 0.39–0.90), with clinical benefit observed even in patients who were pT2N0. Similar efficacy was observed in patients with ctDNA positive status at baseline and those who converted to ctDNA positive status at repeated testing [35]. These practice-changing findings again highlight the importance of ctDNA in BCa for both prognostication and treatment selection. The expectation is that ctDNA stratification will soon be included in treatment guidelines.
The A031501 AMBASSADOR trial evaluated the benefits of pembrolizumab vs. observation in the adjuvant setting for patients with MIUC who had undergone neoadjuvant therapy or who were cisplatin-ineligible (or refused it). Notably, 34% in the observation arm vs. 20% in the active therapy arm received a non-protocol ICI or withdrew consent. The DFS clearly favoured pembrolizumab (HR 0.73, 95% CI 0.59–0.90), with benefits observed regardless of PD-L1 status. Unfortunately, significant OS benefits were not observed, making the role of pembrolizumab in this setting uncertain [36].
Dr. Oualla concluded that while cisplatin-based chemotherapy in combination with durvalumab in the perioperative setting is the gold standard treatment for MIBC, improvements in outcomes are possible among those who are cisplatin-ineligible, with the combination of EV plus pembrolizumab.
In the adjuvant setting, ICI treatment options include nivolumab, and ctDNA is a key biomarker for prognostication and treatment selection, specifically for atezolizumab. There is a need to focus more on tumour variant subtypes that do not respond well to current therapeutic options.
The next session was a case-based panel discussion on systemic therapy for metastatic urothelial cancer (mUC) moderated by Dr. Gust, with Dr. Robert Jones (United Kingdom), Dr. Oualla, and Dr. Daniele Raggi (United Kingdom) as panelists. Dr. Gust began the session by pointing out that treatment selection for mUC used to be quite simple, but the recent approval of new agents makes the situation more complex. It is important to determine, for instance, whether patients are eligible for EV, ICIs, and platinum-based chemotherapy. Typically, about 70–75% of all new cases of bladder cancer present with NMIBC, 20–25% with MIBC, and 5–10% with mUC. In clinical trials of mUC, typically around half of patients have already undergone RC.
The first case discussed was of a 78-year-old female who presented with recurrent urinary tract infections (UTIs), residual voiding urine, and intermittent gross hematuria. Cystoscopy revealed a 4 cm papillary lesion with a wide base. She underwent TURBT, with macroscopic complete resection. Histology revealed MIUC. PD-L1 status was combined positive score (CPS) 5, and she had no FGFR3 alterations. A CT scan revealed stage cT2 cN2 cM1a disease. She had no history of malignancy but did have diabetes mellitus, with an HbA1c of 6.9% on dual therapy. She also had hypertension, treated with double therapy, and a glomerular filtration rate (GFR) of 66 mL/min.
Dr. Gust asked the panelists what staging modality would be used in this patient. They agreed that CT scanning is the most widely used method. Some patients may undergo FDG positron emission tomography (PET), but this modality is usually reserved for patients about to undergo RC with the purpose of excluding metastatic disease. In cases like this of de novo disease, biopsy testing of the primary site is usually sufficient. In the case of relapsed disease, biopsy of the metastatic sites may also be required, particularly where there is significant latency of relapse. Biopsy of the metastatic sites might also be performed if there is uncertainty about the origin of the metastatic disease.
Next, the panelists discussed first-line treatment options, including eligibility criteria for various available therapies. Dr. Oualla said it would be important to evaluate the patient’s eligibility for platinum-based chemotherapy as well as IO and EV. From a safety perspective, this patient is eligible for all of these therapies, although the level of control of her diabetes would need to be considered. Dr. Raggi noted that virtually all patients are eligible for EV plus pembrolizumab, making it a good upfront option, particularly given the high rate of complete response with this combination in clinical trials. Dr. Jones agreed, noting that virtually everyone who is eligible for platinum-based chemotherapy would also be eligible for EV plus pembrolizumab, making the latter option the default for many patients. Dr. Oualla added that the best treatment may not be locally available, pointing out that EV is not available in her centre. For this patient, therefore, she would probably offer platinum-based chemotherapy plus gemcitabine, followed by maintenance with avelumab.
Dr. Gust continued to describe the case, noting that the patient had metastasis only to her lymph nodes, and such patients tend to have the best outcomes from systemic therapy [37,38,39]. He asked whether this would influence treatment selection. Dr. Jones replied that while lymph node-only metastasis is a good prognostic factor, subgroup analyses of clinical trials reveal that HRs with these patients are similar to the other groups, and therefore, it would not influence his therapy selection. Most of these patients will ultimately die of metastatic BCa, so it is important to give them the best possible upfront treatment.
The panelists agreed that the patient would be best treated with EV plus pembrolizumab, pending availability, which is indeed what she was given. After 7 cycles, CT revealed progression of lymph node metastases and a new liver lesion. Dr. Oualla and Dr. Raggi agreed that a second biopsy would be warranted, in case the biology of the cancer had evolved. However, Dr. Jones pointed out that this would take time, and the likelihood the metastasized tumour would represent a new pathology is low, given FGFR mutations are quite stable over time. Dr. Raggi agreed but added that biopsy could provide insight into HER2 status, helpful where access to anti-HER2 approved treatments or clinical trials are available.
Dr. Gust proceeded to explain that the patient did receive a biopsy of the tumour in the liver, and no FGFR3 alteration was noted. He asked whether platinum-based chemotherapy would be the only second-line option for this patient. Dr. Oualla said it would be a good option, given the lack of FGFR3 alteration, but she would also like to now examine the HER2 status. Dr. Jones said there is a paucity of evidence to answer the question of optimum therapy after failure of EV plus pembrolizumab, but several ongoing clinical trials are exploring this exact circumstance. He said he would discuss treatment options with the patient, given that her prognosis is poor, and chemotherapy may not prolong her life. Best supportive care may be a better choice. Dr. Raggi was more optimistic that chemotherapy might be effective, based on the few real-world data recently collected and presented. Dr. Gust asked whether it would be appropriate to extrapolate the findings from the JAVELIN Bladder 100 trial and offer subsequent avelumab to the patient, assuming she did respond to chemotherapy. Dr. Jones replied that since the patient already progressed on an ICI, it was unlikely that avelumab would be effective.
Next, Dr. Gust presented the case of a 71-year-old male who received TURBT plus double J stenting consisting of a 5 cm lesion with unilateral hydronephrosis. Pathological findings were at least pT2 UC with broad muscle invasion, stage cT3 cN1 cM0. The patient was a smoker, with coronary heart disease, for which he had received 2 stents, and he had a GFR of 81 mL/min. Dr. Gust asked what the panelists would choose as first-line therapy. Dr. Oualla replied that, given the lack of contraindications, she would start with cisplatin-based chemotherapy, with the possible addition of durvalumab. Dr. Jones expressed concern about the cardiovascular risk of using cisplatin, but Dr. Oualla felt it would be appropriate with close monitoring.
Dr. Gust explained that the patient received neoadjuvant GC, followed by RC. At RC, the stage was ypT2 ypN1 (1/32) cM0 LVI-positive R0. The patient’s prostate was without malignancy, and his PD-L1 status was CPS 10. He was treated with adjuvant nivolumab, intended to continue for 12 months, but after 6 months he developed positive retroperitoneal lymph nodes and liver metastases. Given early progression, he was not considered suitable for further platinum-based chemotherapy. Should this patient receive EV monotherapy or EV plus pembrolizumab? Dr. Oualla and Dr. Raggi replied that he did not appear to be a good candidate for a re-challenge with IO. Dr. Jones agreed that the evidence-based choice is EV monotherapy but nevertheless pointed out that there might be a benefit in combining EV with IO, and he would be tempted to use the combination if it were accessible (which is unlikely).
If the patient had an FGFR3 mutation, asked Dr. Gust, how would that modify treatment selection? Dr. Oualla and Dr. Jones would consider erdafitinib, even though it is not yet approved in this indication, but it remains unknown if it is a better option than EV monotherapy or EV plus pembrolizumab. There is a paucity of evidence on the activity of EV in the FGFR3 population, but Dr. Raggi pointed out that, very recently, the UNITE consortium did report EV activity in patients with FGFR3 alterations [40]. Nevertheless, he would preferentially choose erdafitinib given the state of the evidence.
The next case presented by Dr. Gust was of a 74-year-old male who presented febrile, with a UTI. He had infected bilateral hydronephrosis and acute-on-chronic kidney failure. Non-contrast CT revealed a massive thickening of the bladder wall. He was treated with bilateral nephrostomy and intravenous antibiotics. Cystoscopy revealed an ulcerous, papillary surface of nearly the entire bladder lining. He underwent TURBT with antegrade double J stenting, and histopathology revealed MIUC. His kidney function improved. Ultrasound revealed no hydronephrosis, with the bilateral double J stent in place. Contrast-enhanced CT revealed cT3 cN1 cM0 stage disease. His GFR was 49 mL/min.
Renal function made the patient only borderline eligible for platinum-based chemotherapy, but Dr. Oualla pointed out that it appeared to be improving, making him eligible for the NIAGARA regimen of split dose GC, with the possible addition of durvalumab [27]. Another option, given the very recent findings from EV-303/KEYNOTE-905, is EV plus pembrolizumab in the perioperative setting [28]. He was also eligible for the CheckMate 274 regimen of adjuvant nivolumab following RC, provided he was found to be PD-L1-positive [30].
The patient was treated with EV plus pembrolizumab. Dr. Gust asked what the next line of therapy should be if he progressed on this regimen. Since he has received all the best options already, there is no evidence-based option left. Dr. Jones highlighted that this is a quandary that comes up time and again—if patients are given the best treatments upfront, then there will be very limited options available should they progress. Dr. Raggi and Dr. Jones emphasized that patients should nevertheless receive the best available treatments upfront because that offers the greatest hope for the most positive outcomes, based on clinical trial findings. In addition, by the time that patients treated today have progressed, new therapeutic options may be available, even if they are accessible only via clinical trials.
The final case was that of a 73-year-old male who, following cystoscopy and TURBT, was found to have metastatic MIUC with lymph node and liver metastases. His PD-L1 status was CPS 10, and he was HER2 2+. He was eligible for an early access program of disitamab vedotin (DV) plus toripalimab, recently found to be effective in this setting [41]. However, this regimen was studied in a Chinese-only population. It remains unclear whether DV plus toripalimab will be approved for use in Europe without an additional trial. The findings also give rise to the question of how best to sequence antibody–drug conjugates (ADCs) and ADC plus IO combinations. Will new biomarkers and imaging methods be needed? A disappointing finding from the DV plus toripalimab trial was that HER1 vs. HER2/3 status did not appear to be predictive of response. What is sorely needed is a test predictive of which patients will best respond to specific ADCs targeting individual proteins, such as HER2 or NECTIN4. The best sequence remains unknown, but the biggest concern with EV and DV, said Dr. Jones, is toxicity, particularly neurotoxicity, which is largely a function of the vedotin, present in both ADCs.
The BCa session concluded with a luncheon symposium on HER2-targeted ADCs in metastatic BCa, which was chaired by Dr. Oualla, with Dr. Gust, Dr. Raggi, and Dr. Viktor Grünwald (Germany) as faculty. The session began with a presentation from Dr. Raggi on the role of ERBB2 as an oncogene in BCa. HER2 (encoded by ERBB2) is a pivotal member of the EGFR receptor family, acting as the preferred dimerization partner, he explained. Furthermore, the HER2-HER3 heterodimer is the most potent activator of downstream signalling (PI3K/AKT), as HER3 lacks intrinsic kinase activity [42]. Heterodimers activate key signalling pathways, including PI3K/AKT/mTOR (driving cell survival and growth), RAS/RAF/MEK/ERK (driving cell proliferation), and crosstalk with Wnt/β-catenin, NF-κB, and ER [43].
HER2 regulates cell growth and differentiation as well as tissue repair. Oncogenic dysregulation of HER2 can include mutations leading to constitutive dimerization, amplification leading potent HER2-HER3 heterodimer signalling, and overexpression/isoforms leading to persistent signalling, invasion, and resistance to treatment [44,45,46]. In the context of UC, HER2 expression is frequent, seen in nearly 70% of samples, including those labeled HER2 low or 1+, although worldwide prevalence varies across cohorts from about 50% to 70% [46]. HER2 positivity varies by anatomical site [47], stage [48,49], histology [50], and molecular class [51,52], with high expression more likely to appear in the upper tract as well as with more advanced disease, micropapillary disease, and luminal subtype [47,48,49,50,51,52].
Discordance in HER2 expression between primary and metastatic tumour sites is common, with loss of HER2 expression in up to 55% of metastases [53]. Importantly, this dynamic biomarker requires repeat testing, and clinicians should interpret single-site results with caution [54].
In UC, ERBB2 alterations are common, with ECD S310F/Y mutations present in about 65% of samples, leading to constitutive dimerization [55]. A minority of samples also reveal amplification, which often requires in situ hybridization (ISH) for confirmation [56]. Overexpression is another possibly, and it can be variable and heterogeneous. It is not always linked to mutation/amplification, and it remains relevant for ADC targeting [57]. In the context of UC, HER2 activation drives growth, invasion, and drug resistance, especially via the PI3K-AKT/MAPK pathway. It modulates anti-tumour immunity, which may affect ICI response.
There are 2 paradigms to consider with respect to ERBB2 alterations. The classic paradigm, “oncogene addiction”, is seen in breast cancer and refers to situations where tumour growth depends directly on ERBB2 signalling, thus representing HER2-driven disease. The new paradigm of “docking biomarkers” indicates that even when expression of HER2 is low the ADC payload can still be delivered, independent of oncogenic signalling. This latter paradigm appears to apply largely to UC.
A composite HER2 biomarker in UC includes NECTIN4, and both are often seen in luminal disease, which predicts EV response, risk of clonal selection, and HER2 loss. Another, EGFR, is also commonly co-expressed and predicts early tumourigenesis, with bispecific ADCs a promising treatment in this context. More rarely co-expressed is FGFR3, and this biomarker has distinct biological subsets and therapeutic targets. Another biomarker, KRAS, may drive anti-HER2 resistance. The immune context is more complex and appears to have a stage-dependent effect. HER2 crosstalk with other pathways may guide sequential or combination strategies and refine patient selection in advanced UC [58,59,60,61,62,63,64,65,66].
When it comes to testing for HER2, specific definitions of what constitutes positivity matter. Intra-tumour variability is a possibility, with up to 20% of HER2-positive samples containing negative foci [46]. In cases of discordance, additional testing includes immunohistochemistry (ICH) testing for the protein, ISH for the gene, or next generation sequencing (NGS) to identify mutations. Results of these tests may diverge [67], and the specific role of NGS for UC remains unclear in terms of ERBB2 testing, as compared with protein-based tests. As mentioned, discordance between primary and metastatic sites is common [53,68].
Within clinical trials, the scoring rules for HER2 positivity were often derived from breast or upper gastrointestinal cancers. Thus, there is a need for standardization, with a universally accepted HER2 IHC testing framework. This will ensure reliable and reproducible results.
Next steps, said Dr. Raggi are to refine composite biomarkers (e.g., NECTIN4, PD-L1, and FGFR3), integrate spatial pathology and liquid assays to capture tumour heterogeneity, and move toward consensus-based reporting frameworks.
The next presentation was by Dr. Grünwald, on the targeting of HER2 in BCa treatment. He started by pointing out the wide array of ADCs currently available in oncology, with those targeting HER2, NECTIN4, and Trop2 of particular interest in UC [69]. The ADCs targeting HER2 bind to the cell surface, become incorporated into the cell, and release their payload (typically chemotherapy) [54]. Their potential is being explored in breast cancer and other malignancies, with trastuzumab deruxtecan (T-DXd) and ado-trastuzumab-emtansine (T-DM1) being studied most often [46].
In the context of UC, the main focus is on DV and T-DXd [70]. In the case of DV, the payload is monomethyl auristatin E (MMAE). Two trials explored the benefits of DV in UC, with stratification by HER2 expression level. The first trial showed efficacy in HER2 2+ or 3+ patients, with a median PFS of 5.88 months [71]. In addition, objective response rate (ORR) was less among those with lower HER2 expression, which was further characterized by the addition of HER2 gene amplification status for a more detailed analysis [71]. In a trial of patients with UC that was HER2-negative or HER2 1+, response to DV was still in evidence among those with low HER2 expression, with a median PFS of 5.5 months in the overall population [72]. These findings raise questions as to how helpful HER2 expression is as a predictive biomarker for patients receiving DV.
In a recent Asian study, PFS was 9.3 months among patients with mUC who were treated with DV plus toripalimab [73]. Once again, response rates and PFS were superior with greater HER2 expression [73]. In the Western world, DV plus pembrolizumab was investigated among patients with HER2-positive mUC [74]. No major difference in response was observed based on degree of HER2 expression, but this study comprised only 20 patients [73].
Also of interest is T-Dxd. In the DESTINY-PanTumor02 phase 2 study, patients with a variety of HER2-positive tumours were treated with this agent. Response was observed in the BCa cohort, again with greater responses with higher HER2 expression [75]. When T-Dxd was combined with nivolumab in a phase 1b study of previously treated patients with mUC, activity was also greater with higher HER2 expression, with a median PFS of 6.9 months among those with high HER2 expression [76].
The phase 2 KAMELEON trial demonstrated that TDM1 also has clinical activity in HER2-positive mUC, with a PFS of 2.2 months and OS of 7.0 months [77]. Again, greater response was observed with higher HER2 expression.
While these studies suggest that HER2 expression can help determine which patients may benefit from specific ADCs, Dr. Grünwald warned that each study used different tools to assess HER2 expression. These differences complicate interpretation of the role of HER2 expression in identifying which patients may benefit from treatment.
Treatment with ADCs is superior to infusions of chemotherapy because it delivers the payload directly into the cells. In addition, the carrier system can take many forms, such as a large monoclonal antibody, nanoparticle, peptide, or affibody. Each of these has different characteristics, including tumour penetration, tumour uptake, and clearance [78]. This is why different ADCs using the same chemotherapy agent can have different effects. For instance, DV, EV, and zelenectide pevedotin all have MMAE as their chemotherapy agent, but their efficacy and toxicity profiles remain quite distinct [71,79,80].
Another important characteristic of ADCs is how the antibody and the drug are linked. For instance, sacituzumab govitecan does not have a stable linkage, which means some free drug is released into the circulation instead of being incorporated into tumour cells [81]. As a result, toxicity levels were higher than anticipated with this ADC and included deaths.
Looking to the future, the ongoing phase 3 SGNDV-001 trial is comparing DV plus pembrolizumab with platinum-containing chemotherapy plus gemcitabine plus avelumab maintenance among patients with HER2-positive locally advanced or mUC [82]. As mentioned, an Asian trial examining DV plus toripalimab vs. chemotherapy in a similar population revealed superior outcomes with the ADC [41]. Notably, response is very similar to that obtained with EV plus pembrolizumab, which is unsurprising because HER2 and NECTIN4 are within the same molecular subgroup and are often co-expressed.
During a Q&A session, Dr. Black asked which ADCs are eliciting the most excitement from the medical oncology community. Dr. Grünwald replied that they all have promise, and their real potential can only be determined in larger trials.
Next, Dr. Black asked whether more than one vedotin-containing ADC can be given to patients sequentially. Dr. Grünwald replied that this is an apt question because vedotin has considerable toxicity, as does MMAE, so caution must be used when considering repeated use. Another concern is development of resistance, and Dr. Raggi said that will be the focus of the next round of research. Resistance can occur both at the cell receptor and to the payload. As a result, there is a need for new ADCs with different payloads as well as different anti-HER2 properties. Dr. Gust pointed out that there is research showing that with EV treatment NECTIN4 expression diminishes. Thus, treatment with EV could potentially eliminate the subpopulation of tumour cells susceptible to EV. Dr. Raggi replied that mechanisms of resistance vary. The most common pathway is direct resistance to the payload, but another avenue is NECTIN4 loss with disease progression. Nevertheless, research into the amplification of the NECTIN4 gene indicates that up to 20% of patients maintain NECTIN4 expression after progression. This might represent a subpopulation to target with anti-HER2 therapy.
Dr. Grünwald added that in academic cohorts, 20–30% are NECTIN4 negative or have low expression, but there is about a 20% discordance between biopsies of the primary sites vs. the metastatic sites, highlighting the need for repeat testing. Also, the patients who completely lose NECTIN4 positivity are unlikely to be those who started with NECTIN4 amplification, so amplification might be a useful biomarker.
Dr. Gust asked why NECTIN4 amplification is used as a biomarker rather than the actual level of the protein produced. Dr. Grünwald replied that, in the EV-302 trial, it was never disclosed how testing for NECTIN4 was accomplished, but it likely involved staining both plasma and membranous expression of NECTIN4. Considering how the ADC binds to the tumour cell, it is unlikely that the plasmatic expression level is clinically relevant. Nevertheless, among patients treated with EV plus pembrolizumab, NECTIN4 expression level has been found to be a predictor of response [83].
Dr. Oualla asked the panelists if they have found that anti-HER2 ADCs have greater potency in patients with greater HER2 expression, unlike anti-Trop2 or anti-NECTIN4 ADCs, which work regardless of biomarker findings. Dr. Gust replied that it is difficult to answer this question because testing for HER2 has yet to be standardized, and targeted therapies are still being tested in unselected patients. Dr. Oualla added that this highlights the need for expertise from uro-pathologists. Dr. Raggi agreed, noting that IHC is important in UC.
Next, Dr. Oualla asked what is likely to be the best treatment sequence, given the current limited state of knowledge. Dr. Grünwald said he would use biomarkers to drive therapeutic decisions, using EV plus pembrolizumab in patients with NECTIN4 amplification and DV for HER2-positive tumours. Dr. Raggi would start with EV plus pembrolizumab because this combination has the most data to support it, using an anti-HER2 ADC for salvage. Dr. Grünwald asked the other panelists how they would treat a patient who, on IHC, was found to be HER2 1+ and NECTIN4 amplified. The others agreed there is no clear answer, and Dr. Grünwald added that, while giving all-comers EV plus pembrolizumab is easy, using biomarkers is needed to better individualize therapy.
Finally, Dr. Raggi asked panelists’ opinion on use of ctDNA to measure HER2 expression. The panelists agreed it could be helpful, but it remains a much more expensive option than IHC.

Author Contributions

Conceptualization, P.C.B.; writing—review and editing, P.C.B., K.M.G., P.M., J.Y.C.T., S.B.W., K.O., R.J., D.R. and V.G.; supervision, P.C.B. All authors have read and agreed to the published version of the manuscript.

Funding

The Proceedings From the 7th B2B Uro-Oncology: GU Cancers Triad Meeting received no external funding. The 7th B2B Uro-Oncology: GU Cancers Triad Meeting was supported by independent medical education grants from Daiichi Sankyo|AstraZeneca, Johnson & Johnson, Bristol Myers Squibb, CG Oncology, Ferring Pharmaceuticals, Merck Sharp & Dohme, and Novartis Pharma AG.

Data Availability Statement

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

Conflicts of Interest

P.C.B., consultant (AbbVie, Astellas, AstraZeneca, Aura, Bayer, BMS, CG Oncology, Combat, EMD-Serono, Ferring, Johnson & Johnson, Merck, Nonagen, Nanobot, NanOlogy, Photocure, Prokarium, Sumitomo, TerSera, Tolmar, Verity), speaker (Bayer, TerSera), clinical trial (Sustained Therapeutics, J&J, enGene, CG Oncology, Pfizer); K.M.G., grants (BMS), consulting (Astellas, AstraZeneca, BMS, Cepheid, Ferring, Ipsen, Johnson & Johnson, Merck, MSD, Pfizer, Roche), speaker (Astellas, AstraZeneca, BMS, Cepheid, Ferring, Ipsen, Johnson & Johnson, Merck, MSD, Pfizer, Roche), meeting/travel (Allergan, Astellas, AstraZeneca, Bayer, BMS, Johnson & Johnson, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche), advisory board (Astellas, AstraZeneca, BMS, Cepheid, Ferring, Ipsen, Johnson & Johnson, Merck, MSD, Pfizer, Roche), membership (ESMO, ÖGU, DGU, ASCO, SIU), leadership (Austrian Uro-Oncology Working Group [AUO] of the Austrian Urological Society [ÖGU]); P.M., honoraria and advisory/sponsorships (Baxter, BMS, Coloplast, Ethicon, Ferring, Janssen, Medac Pharma, Nucleix, Pfizer, Photocure, Storz), design and development (Scot BC Quality OPS), guidelines panel member (EAU Guidelines on NMIBC, UTUC and MIBC), core committee (International Bladder Cancer Group [IBCG]), CI (INTERMEDIATE, Epicheck in haematuria), TSC (RESECT, YORKSURe), medical advisor (Fight Bladder Cancer charity); J.Y.C.T., honorarium/lecture (Astellas, Boston Scientific, Combat Medical, Ferring, Ipsen, Janssen, Olympus, Sanofi), consultancy/advisory board (Astellas, Aulea Medical, CMR Robotics, Combat Medical, EQT, Ferring, Illumicell AI, Janssen, MRI PRO, Phase Scientific, Procept BioRobotics), research grant (Baxter, Bristol Myers Squibb, Ferring, Janssen, Merck Sharp & Dohme, Storz, Olympus); S.B.W., advisory board (Janssen, Photocure, Valar Labs), consultant (Janssen, Merck, Photocure, Valar Labs), section editor (BJUI); K.O., investigator (Roche), advisory board (Janssen, Astellas, Roche, Bayer, MSD, Sothema, Merck, AstraZeneca, Cipla); speaker honoraria (Janssen, Astellas, Pfizer, Novartis, Roche, MSD, Mylan, Sothema, Pierre Fabre, Axess Pharma, Bayer, Merck, AstraZeneca, Hikma, Servier); R.J., advisory board (AstraZeneca, Astellas, Bayer, BMS, Janssen, Merck KGaA, MSD, Novartis, Pfizer), speaker honoraria (Astellas, Bayer, BMS, Janssen, Merck KGaA, MSD, Pfizer), research funding (Astellas), travel support (Bayer, MSD), grant funding (Bayer), manuscript support (Janssen, Pfizer); V.G., invited speaker (Amgen, AstraZeneca, Astellas, BMS, EISAI, Ipsen, Johnson & Johnson, Merck, MSD, Pfizer, Novartis/AAA, Telix Pharmaceutical, Roche), advisory board (BMS, EISAI, Ipsen, Debiopharm, Gilead, Johnson & Johnson, Merck, MSD, Novartis, Oncorena, Recordati, Synthekine), steering committee member (Amgen, BMS, EISAI, Ipsen), research grant/financial interest/institutional (AstraZeneca, BMS, MSD, Ipsen, Pfizer), travel support (Ipsen, Johnson & Johnson, Merck, Pfizer), stocks/shares (Amgen, AstraZeneca, BMS, Bicycle Therapeutics, MSD, Genmab), membership (ASCO, ESMO, German medical Oncology and Hematology Society), advisory role (German Cancer Society), leadership role (Working Group medical oncology [AIO]); D.R. declared no conflict of interest.

Abbreviations

ADCantibody–drug conjugate
BCabladder cancer
BCGbacillus Calmette-Guérin
CIScarcinoma in situ
CPScombined positive score
CTcomputed tomography
ctDNAcirculating tumour DNA
dd-MVACdose-dense methotrexate, vinblastine, doxorubicin, and cisplatin
DFSdisease-free survival
DVdisitamab vedotin
EFSevent-free survival
ERBTen bloc resection of bladder tumour
EVenfortumab vedotin
GCgemcitabine and cisplatin
GFRglomerular filtration rate
HER2human epidermal growth factor receptor 2
HRhazard ratio
ICIimmune checkpoint inhibitor
IHCimmunohistochemistry
ISHin situ hybridization
IOimmunotherapy
MIBCmuscle-invasive bladder cancer
MIUCmuscle-invasive urothelial carcinoma
MMAEmonomethyl auristatin E
MMCmitomycin C
MRImagnetic resonance imaging
mUCmetastatic urothelial carcinoma
NGSnext generation sequencing
NMIBCnon–muscle-invasive bladder cancer
OSoverall survival
pCRpathologic complete response
PFSprogression-free survival
PLNDpelvic lymph node dissection
RCradical cystectomy
RCTrandomized controlled trial
RFSrecurrence-free survival
T-DM1ado-trastuzumab emtansine
T-DXdtrastuzumab deruxtecan
TURBTtransurethral resection of bladder tumour
UCurothelial carcinoma
UTIurinary tract infection

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