Bladder cancer is one of the most prevalent cancers worldwide, accounting for approximately 3.0% of all cancer cases and 2.1% of cancer-related deaths globally (Compérat et al., 2022). While early-stage bladder cancer typically responds well to treatment, the prognosis for advanced or metastatic disease remains poor, with a 5-year survival rate of only 5%–7%. First-line treatments for advanced bladder cancer generally involve cisplatin- or carboplatin-based chemotherapy, which often yields suboptimal results. Despite initial responses, many patients experience relapse, with overall survival usually less than 9 months (Galsky et al., 2012). This underscores the urgent need for novel therapeutic strategies to enhance outcomes for patients with advanced bladder cancer. Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) that targets nectin-4, a protein expressed on the surface of advanced bladder cancer cells. It has received approval from both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of adults with advanced bladder cancer who have previously undergone platinum-based chemotherapy and PD(L)-1 inhibitors (Talukder et al., 2023). Furthermore, EV is FDA-approved for patients who are ineligible for cisplatin, regardless of prior treatments, and can also be combined with pembrolizumab (Hoffman-Censits and Maldonado, 2022). The safety and efficacy of EV were validated in the phase III open-label, randomized, multicenter EV-301 study, which included patients with advanced bladder cancer who had previously been treated with platinum-based chemotherapy and PD(L)-1 inhibitors. Compared to chemotherapy (e.g., docetaxel, paclitaxel, or vinflunine), EV significantly prolonged overall survival (OS, HR = 0.70, 95% CI: 0.56–0.89) and progression-free survival (PFS, HR = 0.62, 95% CI: 0.51–0.75) after a median follow-up of 11.1 months (Powles et al., 2021a). A survey indicated that the incidence of adverse events (AEs) in the EV group was comparable to that in the chemotherapy group, recorded at 93.9% and 91.8%, respectively. Furthermore, the incidence of grade ≥3 AEs was 51.4% in the EV group, compared to 49.8% in the chemotherapy group (Powles et al., 2021b). Among the EV group, grade ≥3 serious AEs occurring in more than 5% of patients included maculopapular rash (7.4%), fatigue (6.4%), and neutropenia (6.1%). Conversely, the chemotherapy group exhibited higher incidences of neutropenia (13.4%), anemia (7.6%), leukopenia (6.9%), neutropenic fever (6.2%), and febrile neutropenia (5.5%) (Rosenberg et al., 2023).

Erdafitinib is an oral fibroblast growth factor receptor (FGFR) kinase inhibitor that has been approved by the FDA for the treatment of adults with advanced bladder cancer harboring susceptible FGFR3 genetic alterations, particularly in patients who have progressed after at least one line of systemic therapy, including PD-1 or PD-L1 inhibitors (Ascione et al., 2023). In a phase III randomized controlled trial, Erdafitinib significantly improved overall survival (OS) (HR 0.64; 95% CI: 0.47–0.88) and progression-free survival (PFS) (HR 0.58; 95% CI: 0.44–0.78) compared to chemotherapy (e.g., docetaxel or vinflunine), demonstrating superior clinical efficacy (Franza et al., 2022). Furthermore, Erdafitinib’s established safety profile includes grade 3 or 4 AEs, such as dermatologic conditions (11.9%), nail disorders (11.1%), central serous chorioretinopathy (2.2%), and other ocular diseases (2.2%) (Loriot et al., 2023).

Both EV and Erdafitinib have demonstrated promising efficacy in the treatment of advanced bladder cancer. A critical aspect of their clinical application is the understanding of their distinct safety profiles. Recent studies have identified common adverse drug reactions (ADRs) associated with each treatment. EV is frequently linked to peripheral neuropathy, skin reactions, fatigue, and neutropenia (Hanna, 2019), whereas ADRs of Erdafitinib are primarily related to its inhibition of FGFR, manifesting as dermatologic and nail disorders, central serous chorioretinopathy, and hyperphosphatemia (Van Sanden et al., 2024). A narrative review has highlighted the rapid advancements in genitourinary cancer treatments, emphasizing the significant progress in therapeutic options alongside the concurrent challenges posed by the adverse effects of commonly used drugs, including EV and Erdafitinib. Among these challenges, dermatologic toxicity, encompassing changes to the skin, nails, and hair, emerges as one of the most prevalent side effects. Notably, the incidence and types of skin-related toxicities differ between EV and Erdafitinib. EV is often associated with severe skin reactions, such as maculopapular rash and toxic epidermal necrolysis, whereas Erdafitinib more commonly causes dermatologic and nail disorders, as well as central serous chorioretinopathy (Daher et al., 2024). Furthermore, a matching-adjusted indirect treatment comparison has revealed that while EV and Erdafitinib demonstrate comparable efficacy in overall survival and progression-free survival, Erdafitinib appears to provide a higher probability of achieving a deeper response. However, this benefit comes with a slightly higher incidence of ADRs compared to EV, although the severity of these events is generally low (Van Sanden et al., 2024). These findings underscore the importance of comparing the safety profiles of EV and Erdafitinib, as understanding the specific ADRs associated with each drug is crucial for optimizing treatment strategies.

Spontaneous Reporting Systems (SRS) provide invaluable real-world safety data on drugs and vaccines, enabling the early detection of previously unrecognized ADRs, facilitating treatment comparisons, and offering insights into ADRs mechanisms (Noguchi et al., 2019). The World Health Organization (WHO)-VigiAccess, launched by the WHO in 2015, grants public access to VigiBase, a global repository of reported drug side effects. By analyzing data from this database, researchers can identify new associations between drugs and AEs and further confirm existing clinical links (Zhou et al., 2024). This study uniquely leverages the WHO-VigiAccess database to compare the incidence of ADRs between EV and Erdafitinib, with a focus on differences in reporting rates between the two treatments. By highlighting these novel findings, we aim to enhance clinical decision-making, enabling better personalized treatment strategies that optimize both efficacy and quality of life for patients with advanced bladder cancer.

This study elucidates the safety profiles of EV and Erdafitinib, two novel drugs for the treatment of bladder cancer, through an analysis of post-market ADR reports from the WHO-VigiAccess database.

Geographically, the majority of ADR reports originate from the Americas and Europe, consistent with previous studies on ADR associated with other drugs. For instance, Varallo and Forgerini noted that developed countries typically possess more advanced pharmacovigilance systems, resulting in a higher volume of ADR reports (Varallo et al., 2019). Conversely, the lower reporting rates from Asia, Africa, and Oceania may indirectly reflect inadequacies in pharmacovigilance systems and reporting mechanisms in these regions, or potentially a lower usage of these drugs. Kiguba et al. emphasized the challenges faced by developing countries in establishing effective pharmacovigilance systems, including resource constraints and a lack of trained personnel (Kiguba et al., 2023). This finding underscores the necessity of strengthening global pharmacovigilance systems, particularly in developing countries.

The analysis of gender distribution indicates that EV and Erdafitinib exhibit a higher reporting rate in males. Smoking is a well-established risk factor for bladder cancer (Strope and Montie, 2008). Studies suggest that women may be more susceptible to bladder cancer than men (Scosyrev et al., 2009). Interestingly, the incidence of bladder cancer is approximately three to four times higher in men than in women (Krabbe et al., 2015; Dobruch et al., 2016). Several studies have explored the potential molecular mechanisms underlying this disparity. Zhang proposes that this difference may be linked to variations in liver metabolism and the detoxification of carcinogens. Specifically, uridine 5′-diphospho-glucuronosyltransferase (UGT), which is involved in the metabolism of aromatic amines, can reduce the harmful components found in tobacco smoke, while androgen receptor (AR) signaling may suppress this detoxification pathway (Zhang, 2013). Additionally, microbial differences in the urinary tract have been implicated in this gender disparity. Lactobacillus predominating in women, whereas Corynebacterium is more common in men (Xu et al., 2014). A previous clinical trial demonstrated a protective effect of oral Lactobacillus supplementation against bladder cancer recurrence, however further clinical data are required to substantiate this finding (Aso et al., 1995). Other studies suggest that the combination of estrogen and progesterone may reduce the risk of bladder cancer (McGrath et al., 2006; Davis-Dao et al., 2011; Cantwell et al., 2006). Jubber et al. reported that this variability may be related to drug use patterns, but further research and discussion are needed (Jubber et al., 2023). In terms of age distribution, EV and Erdafitinib show a higher reporting rate among elderly patients aged 65–74 years. As physiological functions gradually decline with age, the likelihood of elderly individuals developing various complications increases. This decline also impacts drug metabolism within the body, significantly elevating the risk of AEs (Budnitz et al., 2011; Budnitz et al., 2006).

There are notable differences in the common types of ADRs associated with the two medications. EV is primarily linked to skin and subcutaneous tissue disorders and nervous system disorders, while Erdafitinib is chiefly associated with eye disorders, metabolic disturbances and skin and subcutaneous tissue disorders. These differences may arise from the distinct mechanisms of action of the two drugs.

EV has demonstrated remarkable efficacy in the treatment of blaader cancer. Due to its mechanism of targeting nectin-4, EV is also being investigated for the treatment of other nectin-4-expressing malignancies, including gastrointestinal tumors, small cell lung cancer, and breast cancer (Chatterjee et al., 2021; Challita-Eid et al., 2016). EV targets nectin-4 to deliver the cytotoxic agent MMAE into cancer cells, where MMAE disrupts microtubule polymerization in keratinocytes, inducing apoptosis or necrosis and achieving a tumor-specific antitumor effect. In the EV-201 trial, Rosenberg et al. reported skin toxicity and peripheral neuropathy as notable adverse effects of EV, with skin toxicity typically emerging within the first or second cycle (Rosenberg et al., 2023). Severe reactions, such as SJS and TEN, have also been observed (Nguyen et al., 2021). These findings underscore the necessity of closely monitoring skin reactions during EV therapy. The mechanisms underlying these adverse reactions may be associated with the physiological expression of nectin-4 in keratinocytes and sweat glands. Under normal skin conditions, the targeting of nectin-4 by EV could result in skin-related AEs. But in pathological skin conditions, EV may represent a potential therapeutic option. For instance, increased nectin-4 expression has been noted in a subset of cutaneous adnexal carcinomas, particularly sebaceous carcinomas, indicating that EV may be a promising treatment for these tumors (Ingen-Housz-Oro et al., 2024; Cho et al., 2024). Alternatively, it has been suggested that these adverse effects may be mediated by a Type IV hypersensitivity reaction. Actively dividing epidermal keratinocytes are particularly vulnerable to the anti-mitotic effects of MMAE (Doronina et al., 2003). Damaged keratinocytes release antigens that activate dendritic cells, leading to antigen presentation to T cells. These T cells subsequently activate other immune cells, such as effector T cells, and secrete cytokines and chemokines, including tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2). The release of cytokines and chemokines triggers an inflammatory response and tissue damage, which manifests in the skin as erythema, edema, rash, and pain. In severe cases, this may progress to SJS or TEN (Phillips et al., 2019; Duong et al., 2017; Tan and Tan, 2011; Bellón, 2019). Additionally, the bystander effect induced by EV may provoke immune responses in adjacent healthy tissue, further exacerbating the damage (Liu et al., 2020). Furthermore, Ingen-Housz-Oro et al. provided detailed insights into EV-related skin toxicity in the EV-301 trial, proposing various management strategies to mitigate these adverse effects (Ingen-Housz-Oro et al., 2024). Peripheral neuropathy, in contrast, tends to appear later in treatment cycles (Zschäbitz et al., 2023). Research by Taoka et al. demonstrated that EV significantly impacts sensory nerves, especially in the lower limbs, with the sural nerve being particularly susceptible (Taoka et al., 2024). This neurotoxicity may correlate with the amount of MMAE released following EV uptake by cancer cells, suggesting a positive relationship between therapeutic efficacy and the incidence of peripheral neuropathy.

In comparison, the BLC2001 study conducted by Zheng et al. identified ocular toxicity and metabolic disturbances associated with Erdafitinib (Zheng et al., 2022). Ocular adverse reactions linked to Erdafitinib, including corneal thinning, retinal disorders, and macular degeneration, likely a consequence of its FGFR inhibitory action, as FGFRs play a critical role in the cell growth and maintenance of retinal cells. The inhibition of FGFRs may disrupt normal retinal and corneal functions, potentially leading to retinal detachment and changes in the corneal epithelium (Ouwerkerk and Boers-Doets, 2010). One study suggests that this inhibition can block the activation of the mitogen-activated protein kinase (MAPK/MEK) signaling cascade, resulting in MEK-related retinal disorders (Sassine et al., 2024). This finding aligns with the safety profiles observed for other FGFR inhibitors and underscores the importance of conducting routine ophthalmologic assessments during Erdafitinib therapy (Borkar et al., 2013). Hsu et al. have proposed management strategies to address FGFR inhibitor-induced ocular toxicity, which may help mitigate the ocular adverse effects associated with Erdafitinib treatment (Hsu et al., 2024). Concerning metabolic disturbances, the underlying machanism is primarily linked to FGFR signaling in phosphate metabolism. FGFR1, which plays a critical role in the skeletal system, regulates the secretion of fibroblast growth factor 23 (FGF23), a hormone produced by osteocytes that reduces serum phosphate levels by decreasing renal phosphate reabsorption and lowering 1,25-dihydroxyvitamin D synthesis. By inhibiting FGFR1, Erdafitinib reduces FGF23 levels, which diminishes the inhibition of sodium-phosphate co-transporters in renal proximal tubules, thereby increasing renal phosphate reabsorption and resulting in hyperphosphatemia (Kommalapati et al., 2021). Additionally, FGFR inhibitors may impact other metabolic pathways. For example, FGFRs are involved in insulin signaling, and their inhibition could lead to insulin resistance, affecting blood glucose levels (Wöhrle et al., 2011). However, further research is required to clarify the specific mechanisms of other metabolic abnormalities. In clinical practice, monitoring serum phosphate levels during Erdafitinib therapy is essential. For patients experiencing hyperphosphatemia, dose adjustments or other interventions may be necessary to manage metabolic disturbances, ensuring both the safety and the efficacy of the treatment. Moreover, although both EV and Erdafitinib are associated with notable skin adverse reactions, their mechanisms are differ. FGFR is expressed in skin cells and various other tissues, playing a crucial role in cell proliferation, differentiation, and repair. Erdafitinib may induce dermatological adverse effects by inhibiting FGFR, which disrupts the normal growth and repair processes of skin cells. Similar dermatologic events are also observed with other targeted anticancer therapies and immunotherapies (Lacouture et al., 2021; Schneider et al., 2021; Lacouture and Sibaud, 2018).

In our study, it is noteworthy that the number of ADR reports associated with EV is significantly higher than that for Erdafitinib, yet the mortality rate linked to EV is markedly lower (EV 1.22%, Erdafitinib 8.34%). This discrepancy may be attributed to the distinct nature of the adverse reactions associated with each drug. The primary side effects of EV include skin reactions and peripheral neuropathy, which can be severe but are not necessarily fatal. In contrast, the adverse effects of Erdafitinib, such as ocular disorders and metabolic abnormalities like hyperphosphatemia, may lead to more serious complications that could impact patient survival. Additionally, our study indicate there is no significant difference between the two drugs in terms of hospitalization, the possible reason is the side effects of both drugs can often be managed through outpatient care or short-term hospitalization.

While this study offers valuable insights, it is not without limitations. Firstly, SRS data may be subject to reporting biases, including notoriety bias and selective reporting. Hauben and Aronson discussed the implications of these biases for the interpretation of pharmacovigilance data (Hauben and Aronson, 2009). Secondly, the lack of accurate exposure population information renders the calculation of true ADRs incidence rates unfeasible. Bate and Evans highlighted this limitation and proposed potential remedies (Bate and Evans, 2009). Furthermore, as the WHO-VigiAccess database comprises cumulative data, it lacks annual ADRs data, which restricts the analysis of ADR trends.

This study provides valuable insights into the post-marketing safety of EV and Erdafitinib through an analysis of the WHO-VigiAccess database. The results underscore the distinct safety profiles of these two drugs, providing crucial information for clinical practice. However, given the inherent limitations of SRS data, these findings should be interpreted in conjunction with evidence from other sources. Based on these considerations, we propose several potential directions for future research as useful references. First of all, global pharmacovigilance systems need to be strengthened. Despite the ongoing introduction of new drugs, pharmacovigilance systems in various countries continue to face significant challenges. To more comprehensively assess the post-marketing safety of drugs, enhancements to global pharmacovigilance systems are essential particularly in developing countries. Improvements in drug monitoring systems in these regions will enhance the efficiency and accuracy of safety monitoring (Conn and Ruppar, 2017). Furthermore, stricter drug safety monitoring is necessary: big data and artificial intelligence technologies can be employed to analyze large datasets from multiple sources, including clinical trials, electronic health records, and patient feedback, thereby improving the accuracy and efficiency of drug safety monitoring (Ajlan et al., 2019). Patient adherence is a key factor influencing the incidence of ADRs, and there exists a complex interplay between the two (Conn and Ruppar, 2017). Studies indicate that the average adherence rate in developed countries is approximately 50% (Brown and Bussell, 2011). Patients with poor adherence are more likely to experience or exacerbate ADRs, while the occurrence of ADRs further diminishes adherence (Ho et al., 2009). Therefore, improving patient adherence not only enhances therapeutic efficacy but also reduces ADRs and complications, lowers healthcare costs, and improves the overall quality of life for patients. Current strategies for improving patient adherence primarily focus on the patient level and include individualized treatment, supervision and management, patient education, medication reminder systems, behavioral incentives, adherence assessment tools, and psychological interventions (Morisky et al., 1986; Madhombiro et al., 2019). Among these strategies, individualized treatment and supervision are crucial. Future drug therapies will increasingly be personalized, with treatment plans tailored to the genetic of patients, environmental, and health status. Research indicates that EV is more suitable for patients with healthy skin and neurological systems, a robust immune status, and no significant comorbidities, while Erdafitinib is best suited for patients with FGFR gene mutations, no severe ocular or metabolic diseases, and those willing to undergo regular monitoring. Additionally, strengthening supervision and management is key to preventing ADRs and reducing associated risks. For EV, it is recommended to regularly assess skin and neurological health, alongside the preventive use of zinc-based moisturizers to protect the skin from UV-induced damage. In cases of severe ADRs (such as SJS or TEN), treatment should be discontinued immediately, and patients should be transferred to intensive care for supportive therapy (Yu et al., 2020; Salzmann et al., 2019; Chen et al., 2018). For Erdafitinib, patients should undergo baseline ocular and metabolic screening prior to treatment and be monitored regularly throughout therapy, particularly in elderly patients. In cases of severe retinal disease, hyperphosphatemia, or other life-threatening ADRs, treatment should be discontinued, and appropriate interventions initiated. In conclusion, a patient-centered approach involving enhanced pre-treatment education, individualized treatment plans, strengthened monitoring during therapy, and collaborative rehabilitation post-treatment can effectively improve patient adherence, reduce ADR incidence, maximize therapeutic efficacy, and ultimately improve patient outcomes.

Developing new drugs or repurposing existing ones offers great potential. Current treatments for bladder cancer primarily consist of immunotherapy and targeted therapies, often used in combination to achieve better outcomes (Bader et al., 2020; Meric-Bernstam et al., 2021). However, these methods carry safety concerns due to adverse reactions (Galon and Bruni, 2019). Future research should validate the efficacy and safety of combination therapies through larger clinical trials. Targeting specific tumor molecular drivers also represents a promising avenue for exploration (Shariati and Meric-Bernstam, 2019; Li D. X. et al., 2023; Shen et al., 2024). Moreover, exploring the molecular mechanisms of ADRs is vital. Understanding drug interactions with immune systems, metabolic pathways, or cytotoxic responses, and validating findings through cohort studies or randomized trials, is crucial for identifying the causes of side effects. This will pave the way for improved prevention and treatment strategies.

EV and Erdafitinib are essential drugs in the treatment of bladder cancer, making their safety and toxicity management crucial. According to data from the WHO-VigiAccess database, these two drugs have a substantial number of ADR reports, with EV reporting 2,257 cases and Erdafitinib reporting 1,181 cases. The ADRs primarily involve skin and subcutaneous tissue disorders, general disorders, nervous system disorders, and gastrointestinal issues. Specifically, EV is more likely to cause skin and nervous system-related adverse reactions, whereas Erdafitinib is closely associated with eye disorders and metabolic disturbances. Notably, the mortality rate for Erdafitinib is 8.34%, significantly higher than the 1.22% associated with EV. Although most ADRs are relatively mild, some severe reactions may necessitate hospitalization or even result in death. Therefore, countries should actively conduct safety studies on biologic agents, with a particular focus on monitoring ADRs in real-world applications to better understand the risk-benefit profile of these therapies. Establishing robust monitoring systems and data collection mechanisms, especially for analyzing impacts across diverse populations and patients with specific diseases, is essential for elucidating the causal relationship between ADRs and individual drugs. Furthermore, personalized strategies should be developed based on ADR characteristics; for instance, EV may be more appropriate for patients at risk of ocular issues or metabolic disturbances, whereas Erdafitinib might be a more suitable choice for those with potential risks related to skin or nervous system complications. This approach aims to reduce ADR risk in specific patient populations, enhance overall therapeutic outcomes, and provide more effective, targeted treatment options for bladder cancer patients.