Patients with advanced UC represent a clinical population in which polypharmacy is highly prevalent, driven both by the advanced age at diagnosis and by the burden of chronic comorbidities such as cardiovascular disease, diabetes, and metabolic disorders. In this context, maintenance immunotherapy with avelumab is frequently administered alongside multiple concomitant medications, raising clinically relevant questions regarding the potential impact of DDIs on treatment efficacy and safety [18]. The present analysis provides a real-world evaluation of DDI burden in patients receiving avelumab maintenance therapy, using the Drug-PIN® system within the multicenter MALVA study.

The clinical effectiveness of avelumab maintenance in advanced UC has been firmly established by the JAVELIN Bladder 100 trial and further supported by real-world evidence. Recently, the Italian multicenter MALVA study confirmed the effectiveness of avelumab maintenance in routine clinical practice, demonstrating survival outcomes comparable to those observed in the pivotal randomized trial, despite a broader and more heterogeneous patient population. These real-world data underline the robustness of avelumab efficacy across different clinical settings and patient profiles, including older and more comorbid individuals. The clinical relevance of our findings lies in the fact that avelumab does not appear to increase the overall drug interaction burden, supporting its integration into treatment strategies in patients with complex pharmacological profiles. In this setting, Drug-PIN® may still represent a potentially useful tool for structured assessment of baseline polypharmacy, although its prognostic utility was not supported in the present study.

Against this background, our analysis focused on whether the burden of concomitant medications, as captured by the Drug-PIN® score, could influence clinical outcomes during avelumab maintenance therapy. Drug-PIN® is designed to integrate information on polypharmacy into a composite score reflecting the overall risk of DDIs. In our cohort, Drug-PIN® scores showed wide inter-patient variability, reflecting the heterogeneity of concomitant medication use observed in everyday practice. However, stratification of patients according to Drug-PIN® score did not reveal any significant differences in OS or PFS.

These findings are consistent with the pharmacological characteristics of ICIs. Unlike cytotoxic agents and most targeted therapies, anti-PD-L1 monoclonal antibodies such as avelumab are not metabolized by cytochrome P450 enzymes and are not eliminated through hepatic, biliary, or renal pathways. Their clearance relies predominantly on target-mediated and non-target-mediated proteolytic catabolism within the reticuloendothelial system, resulting in classical pharmacokinetics. DDIs are unlikely to occur, even in the presence of extensive polypharmacy. This pharmacological profile likely explains why inclusion of avelumab in the Drug-PIN® computation did not meaningfully increase interaction scores in our analysis.

Nevertheless, growing evidence suggests that interactions involving ICIs may occur at a pharmacodynamic or immunological level rather than through traditional pharmacokinetic mechanisms. Recent studies have highlighted that several commonly prescribed drug classes, including corticosteroids, antibiotics, proton pump inhibitors, opioids, and other immunomodulatory agents, may influence antitumor immune responses by altering immune cell function, cytokine signaling, or the gut microbiota. These so-called immunological DDIs have been associated with altered efficacy and toxicity of ICIs across different tumor types [19]. In this context, the absence of an association between Drug-PIN® score and survival outcomes in our study deserves careful interpretation. Drug-PIN® is primarily designed to capture pharmacokinetic and clinically actionable DDIs, and although it integrates multiple patient-related variables, it does not specifically quantify immunological interactions that may subtly modulate ICI activity. Therefore, it is possible that certain immunologically relevant interactions are not fully reflected in the Drug-PIN® score, particularly when they do not translate into overt clinical toxicity or measurable differences in survival within the available follow-up period.

Importantly, our findings do not suggest that concomitant medications are clinically irrelevant in patients receiving avelumab maintenance therapy. Rather, they indicate that, within the limits of our analysis, the overall burden of DDIs as measured by Drug-PIN® does not appear to compromise the survival benefit of avelumab. This observation is reassuring for clinicians managing older and comorbid patients, in whom discontinuation or modification of chronic therapies may not always be feasible.

Another relevant aspect emerging from our study is that the variability in Drug-PIN® scores was largely driven by background comorbidities and non-oncological treatments rather than by avelumab itself. This finding reinforces the concept that ICIs can be safely integrated into complex therapeutic regimens without substantially increasing interaction burden. From a practical standpoint, this supports the continued use of avelumab maintenance therapy in real-world populations characterized by polypharmacy, as also reflected in the MALVA effectiveness study.

Several limitations of this analysis should be acknowledged. First, the retrospective nature of the study limits causal inference and exposes the analysis to potential selection bias and missing data. Second, the relatively limited sample size, particularly within the higher Drug-PIN® risk categories and among patients with greater levels of polypharmacy, may have reduced the statistical power to detect modest but clinically meaningful differences in survival outcomes. Therefore, the absence of statistically significant associations should be interpreted with caution. In addition, given the exploratory nature of the analysis and the limited sample size, survival analyses were intentionally restricted to descriptive comparisons across pre-defined Drug-PIN® categories and should not be interpreted as inferential evidence of prognostic effects.

An important methodological limitation relates to the ascertainment of concomitant medications. Baseline pharmacological data were retrospectively collected from routine clinical records, and no standardized medication reconciliation process was prospectively implemented. Consequently, incomplete capture of concomitant therapies cannot be excluded, potentially leading to underascertainment of polypharmacy and systematic underestimation of Drug-PIN® scores. This limitation is particularly relevant considering the age and comorbidity profile of the study population and may partly explain the relatively low prevalence of polypharmacy observed in our cohort. The unexpectedly low prevalence of concomitant medications observed in this older metastatic population further supports the possibility of underascertainment in routine clinical records. Therefore, the reliability of the primary exposure variable may have been affected, and the present findings should be regarded as exploratory and hypothesis-generating. Therefore, the reliability of the primary exposure variable may have been affected, and the present findings should be regarded as exploratory and hypothesis-generating.

Another limitation is that the present analysis was specifically designed to explore the potential impact of polypharmacy and DDIs on survival outcomes and was not intended to systematically assess clinically meaningful DDI-related outcomes, including treatment-related toxicities, treatment modifications, discontinuation, or immune-related adverse events. Moreover, as a result of the limited sample size and exploratory design, multivariable analyses adjusting for key confounding factors such as ECOG performance status and comorbidity burden were not performed, and residual confounding related to frailty and baseline clinical characteristics cannot be excluded. Consequently, although no association between Drug-PIN® score and survival outcomes was observed, we cannot exclude that higher DDI burden may still influence toxicity risk or treatment adherence, even in the absence of measurable survival differences.

Finally, an additional limitation concerns the proprietary nature of the Drug-PIN® algorithm. Although previous studies have supported its clinical utility in oncology and pharmacogenomics settings, the exact weighting system and mathematical calculations underlying the software are not publicly accessible, limiting independent reproducibility and external verification of the generated scores. Furthermore, the present study was not designed to externally validate Drug-PIN® performance or compare it with alternative DDI assessment approaches. For these reasons, our findings warrant confirmation in future prospective studies incorporating standardized medication reconciliation, systematic toxicity assessment, and independently verifiable methodologies.

Finally, another important limitation of this study is the absence of sex- and gender-stratified analyses. This was primarily due to the limited sample size and the marked imbalance between male and female patients, which would have reduced the statistical robustness and interpretability of subgroup analyses. As a result, potential differences related to sex or gender in terms of DDI burden, immune response, and clinical outcomes could not be explored. This limitation may affect the interpretation and generalizability of our findings, particularly for female patients and underrepresented gender groups. Future studies with larger and more balanced populations are needed to better elucidate the role of sex and gender in patients receiving avelumab maintenance therapy.

Despite these limitations, this study represents, to our knowledge, one of the first real-world analyses specifically evaluating DDI burden in patients receiving avelumab maintenance therapy for advanced UC. By integrating Drug-PIN® assessment within a well-characterized multicenter cohort, our findings provide exploratory real-world data regarding the feasibility of evaluating DDI burden in patients receiving avelumab maintenance therapy.

Future prospective studies are warranted to further elucidate the clinical relevance of DDIs in the context of immune checkpoint inhibition. In particular, studies incorporating systematic toxicity assessment, immune-related adverse event profiling, microbiome analyses, and dedicated evaluation of immunological DDIs may help clarify whether specific concomitant medications influence the efficacy or safety of avelumab beyond what is captured by current interaction scoring systems.