Emerging Perioperative Strategies for Muscle-Invasive Bladder Cancer

Nearly 25% of patients diagnosed with urothelial cancer will have muscle- invasive bladder cancer (MIBC) at initial presentation.¹ Due to tumor invasion into the muscularis propria layer, MIBC notably has a high risk of micrometastatic disease with nearly 50% of patients having metastatic recurrence following definitive treatment.² Thus, the treatment of MIBC requires a multimodal approach with a multidisciplinary care team. Radical cystectomy is considered to be the gold standard for MIBC; however, bladder-sparing approaches (eg, chemoradiation) remain appropriate for patients who are not candidates for or prefer to avoid surgery. For patients pursuing radical cystectomy, the addition of neoadjuvant cisplatin-based chemotherapy increases overall survival (OS) compared with surgery alone.^3,4 However, patients with MIBC still have a poor prognosis, although recent paradigm shifts in perioperative approaches may further maximize outcomes.

Adjuvant Immunotherapy in MIBC

For patients with MIBC who have or have not received neoadjuvant platinum-based chemotherapy, immune checkpoint inhibitors (ICIs) can be given as adjuvant therapy depending on the pathologic risk category. The role of adjuvant nivolumab (Opdivo) in MIBC was evaluated in the CheckMate 274 study (NCT02632409).⁵ In this phase 3 study, patients with MIBC who underwent cystectomy were included if they were at high risk of recurrence, defined as disease with a tumor stage above pT3 or as pN disease (if the patient did not receive neoadjuvant chemotherapy) on surgical pathology or above ypT3+ or pN+ disease (if received neoadjuvant chemotherapy). Patients were randomly assigned to 1 year of adjuvant nivolumab vs placebo. The study demonstrated an improvement in the primary end point of disease-free survival (DFS) (20.8 months vs 10.8 months; HR, 0.70; 95% CI, 0.55-0.90), regardless of PD-L1 status.

In recently updated results from extended follow-up, adjuvant nivolumab exhibited sustained DFS benefit and improved OS (69.5 months vs 50.1 months; HR, 0.76; 95% CI, 0.61-0.96).⁶ Adjuvant pembrolizumab (Keytruda) for MIBC was recently evaluated in the AMBASSADOR study (NCT03244384). This was similar to CheckMate 274, with disease with a tumor stage above pT3 or as N disease (if the patient did not receive neoadjuvant chemotherapy) or disease with a tumor stage above ypT2 or as ypN disease (if the patient received neoadjuvant chemotherapy) after radical cystectomy, but also included positive surgical margins. Patients were randomly assigned to 1 year of adjuvant pembrolizumab vs observation. The study met one of the coprimary end points of DFS with a median DFS of 29.6 months with pembrolizumab compared with 14.2 months with placebo (HR 0.73; 95% CI, 0.59-0.90), regardless of PD-L1 status. There were no differences in the other coprimary end point of OS, likely from a lack of extended follow-up and a high proportion of patients in the control arm receiving postprotocol ICI. Currently, both nivolumab (Opdivo) and pembrolizumab (Keytruda) are listed in the NCCN guidelines as adjuvant therapy options for patients with MIBC.

NIAGARA Trial Implications

More recently, the role of ICIs has moved from the adjuvant setting to the perioperative setting. The NIAGARA study (NCT03732677) was a recent phase 3 study evaluating perioperative durvalumab (Imfinzi) in combination with neoadjuvant cisplatin-based chemotherapy.8 In this study, eligible patients had stage cT2 to T4 and/or N1 disease. Patients were also cisplatin-eligible, but the study included patients with a creatinine clearance of 40 mL/min or higher, allowing the use of split-dose cisplatin. Patients were randomly assigned to 4 cycles of neoadjuvant gemcitabine/ cisplatin plus durvalumab vs gemcitabine/ cisplatin alone (control). The patients who received durvalumab prior to surgery also received 8 cycles of adjuvant durvalumab monotherapy, regardless of surgical pathology findings. In contrast, the patients in the control arm did not receive any adjuvant treatment. The co–primary end points of this study were pathologic complete response (pCR) rate and event-free survival (EFS). In the recently published report,⁸ the study demonstrated an improvement in EFS with the durvalumab arm (not reached vs 46.1 months; HR, 0.68; 95% CI, 0.56-0.82). During the initial analysis for pCR, 33.8% of patients in the durvalumab group had a pCR vs 25.8% of patients in the control group. However, this did not meet the prespecified threshold for significance initially. At a median follow-up of 46.3 months, patients in the durvalumab arm also had an improvement in the key secondary end point of OS (HR, 0.75; 95% CI, 0.59-0.93). In March 2025, the NIAGARA regimen of perioperative durvalumab with neoadjuvant chemotherapy received FDA approval for MIBC. A key criticism of this study is that all patients received adjuvant durvalumab, which could have led to overtreatment in some patients. Additionally, it is unknown how much of the benefit in NIAGARA was due to the neoadjuvant vs adjuvant portions of the regimen.

ctDNA Testing in MIBC

There are growing data on the role of circulating tumor DNA (ctDNA) in MIBC for disease recurrence monitoring and providing prognostic and potentially predictive insights. The IMvigor010 study (NCT02450331) was a randomized phase 3 trial of adjuvant atezolizumab (Tecentriq) vs observation for patients with MIBC following radical cystectomy. Although the study was negative, recent post hoc analyses from IMvigor010 demonstrated that patients with a positive ctDNA at the start of treatment with atezolizumab or observation had worse outcomes, including an increased risk of disease recurrence compared with patients with a negative ctDNA (HR for DFS, 6.3; 95% CI, 4.45-8.92; P <.0001).⁹ Furthermore, patients with a positive ctDNA had improved OS with atezolizumab compared with observation (median OS, 29.8 months vs 14.1 months; HR, 0.59; 95% CI, 0.42-0.83).¹⁰ Overall, these findings suggest that ctDNA may be a useful risk stratification tool that can potentially guide therapy in MIBC. However, prospective studies in MIBC are needed to validate these findings.

IMvigor011 (NCT04660344) is an ongoing phase 3 study of adjuvant atezolizumab in patients with MIBC who have a positive ctDNA after cystectomy. The MODERN study (NCT05987241) is another ongoing study where patients with MIBC and positive ctDNA after cystectomy are randomly assigned to adjuvant nivolumab vs nivolumab plus relatlimab; in contrast, patients with a negative ctDNA will be randomly assigned to upfront vs delayed (upon conversion to positive ctDNA on serial testing) adjuvant nivolumab.

Future Directions

The treatment landscape of MIBC is rapidly evolving with several ongoing clinical trials that all have the potential to drive further paradigm shifts in the management of this disease.

The combination of the antibody-drug conjugate (ADC) enfortumab vedotin-ejfv (Padcev) and pembrolizumab (EV/P) has recently revolutionized the treatment of metastatic bladder cancer based on the pivotal EV-302 trial (NCT04223856), which showed improved objective response rates and survival compared with chemotherapy.¹¹ The highly anticipated ongoing EV-303 and EV-304 trials (NCT03924895 and NCT04700124, respectively) will evaluate the efficacy of perioperative EV/P in cisplatin-ineligible and -eligible patients with MIBC, respectively. Similarly, the ongoing VOLGA trial (NCT04960709) will investigate the role of perioperative EV plus durvalumab (with or without tremelimumab) in MIBC. For HER2-positive MIBC, HER2-targeted ADC combinations, such as disitamab vedotin (Aidixi) plus the novel anti-PD1 agent toripalimab-tpzi (Loqtorzi), are also promising in this subset.¹²

Novel intravesical therapies such as TAR200 are also being investigated in MIBC. SunRISe-4 (NCT04919512) is an ongoing trial of neoadjuvant TAR-200 in combination with the anti–PD-1 inhibitor cetrelimab. Beyond perioperative approaches, there is also mounting interest in bladder preservation strategies that potentially offer patients the opportunity to avoid cystectomy and maintain their quality of life. Overall, partnerships with community oncologists to accrue patients to clinical trials are critical to advancing treatment approaches in MIBC.

Charles B. Nguyen, MD, is a genitourinary medical oncolgoist at City of Hope Orange County in Irvine, California.

REFERENCES:

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