While radical cystectomy remains a primary management strategy for muscle-invasive bladder cancer (MIBC), high rates of recurrence with surgery alone highlight the likelihood of occult micro-metastatic disease at the time of diagnosis. In this review, we discuss two decades of contemporary evidence for the benefit of neoadjuvant chemotherapy-based systemic therapy. We also review the results of ongoing trials evaluating neoadjuvant immunotherapy and other novel targeted therapies. These trials will likely expand neoadjuvant therapy options for cisplatin-ineligible patients. The growing insights into the molecular heterogeneity and biology of MIBC have paved the way for future biomarker-directed treatment selection as well as possible bladder-sparing approaches with systemic therapy.

Unique issues must be considered when selecting agents for use in the neoadjuvant setting. Neoadjuvant treatment should not delay time to radical cystectomy such that patients miss their window for cure. Additionally, side effects from treatment should not be so severe that they limit a patient’s surgical fitness. Adverse effects related to immunotherapy and newer targeted therapies must be recognized and treated expediently in the preoperative setting to reduce the risks of additional surgical and anesthetic complications.

An appraisal of the primary literature was performed to select clinical trials focused on neoadjuvant systemic therapies for bladder cancer. A preliminary search on clinicaltrials.gov using terms “bladder cancer” and “neoadjuvant” was performed, yielding 155 studies. Studies with status of suspended, terminated, unknown or withdrawn were excluded (n=37). Studies limited to non-muscle invasive disease were excluded (n=6), as well as adjuvant or upper tract only studies (n=4). Studies testing intravesical agents, behavioral interventions, surgical technique, imaging, or biomarkers were also beyond the scope of this review and excluded (n=28). In addition, bladder preservation regimens incorporating radiation therapy were excluded (n=14). These clinical trials were then cross-referenced with recently published abstracts or manuscripts with reportable results (preliminary or fully resulted). Select, multi-institutional trials whose trial designs have been presented at national meetings were also included. A list of 29 clinical trials were finalized for this review. Historical clinical trials were incorporated where relevant to provide context to existing studies.

Robust clinical trial data supports the use of neoadjuvant cisplatin-based chemotherapy for patients with nonmetastatic MIBC. Based on Level I evidence, use of preoperative cisplatin-based chemotherapy is now included in the guideline recommendations from the American Urologic Association (AUA), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), and European Association of Urology (EAU) (1).

The pivotal SWOG 8710 randomized clinical trial published nearly two decades ago demonstrated a 33% reduced relative risk of death and improved median survival from 46 months to 77 months in patients receiving 3 cycles of preoperative methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) compared to immediate cystectomy (2). In this trial, pathologic complete response rate (pCR) at cystectomy was associated with an 85% 5-year survival. Overall, 38% of chemotherapy-treated patients demonstrated a pathologic complete response (pCR or pT0N0), compared to 12% in the cystectomy only arm. An additional randomized trial (BA06 30894) of 976 patients with MIBC evaluated neoadjuvant cisplatin, methotrexate, and vinblastine for a median follow up time of 8 years and demonstrated a statistically significant 16% reduction in mortality risk, corresponding to a 10-year survival increase from 30% to 36% in favor of neoadjuvant chemotherapy over local therapy alone (3).

Another commonly used and well-tolerated neoadjuvant regimen is the doublet of gemcitabine and cisplatin (GC). Although this combination has not been directly tested in a prospective randomized fashion, its efficacy is extrapolated from prior randomized trials in the locally advanced and metastatic disease setting showing no differences in survival, but improved toxicity and tolerability (4). A retrospective series of 154 patients with pT2a-T4aN0M0 MIBC demonstrated that neoadjuvant GC achieved a 21% complete pathologic response (ypT0N0) rate and 25% rate of downstaging to ypTa/Tis/T1N0, which in turn was associated with 5-year overall survival rates of 85% and 89% respectively (5). The ongoing French GETUG/AFU VESPER V05 trial (NCT 01812369), comparing 6 cycles of dose-dense (dd)MVAC to 4 cycles of standard dose GC in the perioperative setting (~90% neoadjuvant and ~10% adjuvant), demonstrated higher organ-confined disease (<ypT3N0) rates with ddMVAC (77% vs 63%, p=0.001), although progression free survival results are still pending (6). Dose-dense gemcitabine in combination with cisplatin (ddGC) was explored in a phase II multicenter trial evaluating 6 cycles of ddGC in 49 patients with MIBC and demonstrated pathologic downstaging (<ypT2) in 57% of patients, which was associated with improved recurrence-free survival and overall survival (7). While the primary endpoint was not to compare the pathologic down-staging rates of ddGC with studies of neoadjuvant ddMVAC, the reported pathologic response rates (≤pT2) were similar (57% vs 49-53%).

Despite several clinical trials indicating a survival benefit with cisplatin-based NAC, uptake and utilization remain low nationally, both within academic centers and community-based practices (8, 9). The combination of advanced age, medical comorbidities, obstructive uropathy, and smoking history common among bladder cancer patients limit the use of cisplatin. Significant contraindications include renal, cardiac and neurologic co-morbidities, and studies suggest that only around 60% of patients are cisplatin-eligible (4, 10–12). A minority of cisplatin-eligible patients with MIBC undergo consultation with a medical oncologist to be counseled on the risks and benefits of NAC prior to surgery, and several retrospective studies demonstrated that less than 20% of eligible patients receive neoadjuvant chemotherapy (8, 13). Predictors of health care access including race, insurance status, geographic area and facility type are associated with marked differences in NAC use (13). While more contemporary studies suggest that uptake has been slowly increasing, (14, 15) a persistent need for non-cisplatin-based regimens remains.

Early efforts to develop predictive molecular signatures for chemosensitivity in bladder cancer laid the groundwork for a rapidly expanding interest in predictive biomarkers. (see Section 3) The co-expression extrapolation (COXEN) gene expression model was derived from pre-clinical models of bladder cancer, using cell lines tested against cisplatin to derive a molecular signature for chemosensitivity that was independent from clinical and pathologic features (16). In a subsequent prospective trial (SWOG 1314) evaluating the ability of COXEN to predict cisplatin sensitivity in 167 patients, however, there was no consistent association between the COXEN score and pCR rates in either the ddMVAC or GC arm in the neoadjuvant setting (17). Nevertheless, S1314 provided a platform to develop and validate additional biomarkers in the neoadjuvant setting.

Immune checkpoint inhibitors (ICI) have emerged with broad application in urothelial cancers. These monoclonal antibodies (mAbs) target various immune checkpoint proteins (PD-L1, PD-1, CTLA-4) to inhibit local immune escape of cancer cells and enable T-cell priming in lymphoid tissue. Such agents include atezolizumab, durvalumab, and avelumab (anti-PD-L1); pembrolizumab and nivolumab (anti-PD-1); and ipilimumab and tremelimumab (anti-CTLA-4). Successful application of ICI in patients with metastatic or locally advanced urothelial cancer paved the way for their potential use in early stage disease (18–21 Phase Ib Study (22). Multiple ICIs are currently being evaluated in ongoing clinical trials in the neoadjuvant setting for patients with MIBC in both cisplatin eligible and ineligible populations ( Table 1 ). Pooled complete response rates of published studies vary from 30-50% with 60-70% rates of pathological downstaging. Single agent and combination ICI trials are outlined below.

Antibody-drug conjugates are a novel class of biologic drugs that are likely to play a role the perioperative setting. Enfortumab vedotin (EV) is an ADC targeting Nectin-4, a surface antigen highly expressed in urothelial carcinoma, to deliver the microtubule destabilizing agent monomethyl auristatin E (MMAE). A phase II clinical trial of EV monotherapy (EV-201) demonstrated a high overall response rate in patients with heavily pretreated, metastatic, or locally advanced urothelial carcinoma, leading to expedited FDA approval (53). Due to its activity in advanced and metastatic disease, EV is now being tested in earlier disease states: EV-103 is a phase 1b/2 multi-cohort trial that is exploring enfortumab vedotin (EV) as monotherapy or in combination with various systemic therapies in both the metastatic and perioperative settings in patients with bladder cancer (54). At ASCO GU 2022, preliminary results reported from Cohort H included 22 cisplatin-ineligible patients with cT2-T4aN0M0 MIBC who received neoadjuvant EV followed by RC-PLND. The pCR rate, the primary endpoint of the trial, was 36%, while pathologic downstaging was observed in 50% of patients (43). No delays to cystectomy were seen, but three peri-operative deaths were reported. Although these deaths were not directly related to EV, the high mortality seen in this trial highlights the importance of both careful patient selection and the maintenance of perioperative surgical fitness with novel agents.

Sacituzumab govitecan (SG) is an ADC that targets TROP-2 to deliver SN-38, the active metabolite of the topoisomerase inhibitor irinotecan. SG is currently being tested in monotherapy in cis-ineligible patients (NCT05226117) as well as with or without pembrolizumab (55). Ongoing clinical trials exploring the role of ADCs with or without ICI in the perioperative setting are listed in Table 1 .

Growing insight into tumor heterogeneity and the role of the tumor microenvironment have spurred an explosion of research in the correlative analysis of pre- and post-treatment tissue in neoadjuvant studies. Emerging biomarkers include molecular subtype, DNA damage response (DDR) genes, tumor mutation burden (TMB), and gene expression signatures.

The landscape of neoadjuvant therapy in MIBC is rapidly evolving as novel agents previously approved in the metastatic setting are being used and tested in earlier disease states. While cisplatin based neoadjuvant chemotherapy remains an important backbone, either alone or in combination with other agents, ICI and ADCs have shown significant activity in patients who are cisplatin ineligible or intolerant. Indeed, cisplatin-ineligible patients with MIBC have the greatest unmet need for novel neoadjuvant regimens. Ongoing correlative studies enabled by pre- and post-treatment molecular analyses may one day give rise to predictive biomarkers than can not only personalize treatment for patients, but also identify patients for bladder-sparing strategies.

CC, GI, and BB contributed to conception, design, writing, revision, and approval of this manuscript.

GI, Consulting/Advisory Board, Janssen, Mirati Therapeutics, Basilea, Flare Therapeutics, LOXO. Speaker’s fees, Gilead Sciences, The Lynx Group Research. Funding, Mirati Therapeutics, Novartis, Debiopharm Group, Bayer, Janssen, Seagen.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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