# Targeted Therapy in Metastatic Bladder Cancer: Present Status and Future Directions
## 1 Introduction  
Bladder cancer (BC) is a major source of morbidity and mortality, with an estimated 430,000 new cases and 165,000 deaths in 2012 [1]. Tobacco smoke is the single most important risk factor associated with BC [2]. Bladder cancer is almost always of urothelial origin, referred to as urothelial carcinoma of the bladder. Three-quarters of BC patients have non-muscle invasive disease, which is treated by transurethral tumor resection (TUR) followed by adjuvant intravesical instillations. Muscle-invasivebladder cancer (MIBC) is a life-threatening disease requiring aggressive treatment due to occult micrometastasis. The recommended treatment option for non-metastatic MIBC is cisplatin-based neoadjuvant chemotherapy (NAC) followed by surgical removal of the bladder (radical cystectomy). In patients who want to keep their bladder, external beam radiotherapy together with concurrent chemotherapy is a feasible alternative. Despite this extensive treatment, approximately half of the MIBC patients who are treated with curative intent will progress to metastatic urothelial carcinoma (mUC). The first-line treatment option in mUC is cisplatin-based chemotherapy, which includes combinations of gemcitabine + cisplatin (gem/cis) or (dose-dense) methotrexate + vinblastine + doxorubicin + cisplatin (ddMVAC), with associated objective response rates (ORRs) of 46% and 49%, respectively [3]. The long-term survival benefits of gem/cis and ddMVAC regimens are equal, with a median survival of 14 months [3]. Nonetheless, 30% of mUC patients are cisplatin-ineligible due to having a poor performance status, renal dysfunction, or other comorbidities. Cisplatin-ineligible patients are treated with carboplatin-containing chemotherapy, which has a lower anti-cancer effect but a more favorable toxicity profile than cisplatin [4]. In recent years, immune checkpoint inhibition (ICI) has shown its superior efficacy in mUC patients that relapsed after platinum-based therapy (platinum-relapsed) compared to second-line chemotherapy [5]. The U.S. Food and Drug Administration (FDA)-approved second-line treatment options pembrolizumab or atezolizumab, for treatment of mUC patients, which were associated with ORRs of ~20% [5,6]. Although the response rates to ICI are low and the median overall survival benefit for all-comers is limited, it is important to emphasize that the majority of responses to ICI are durable, with a median duration of response to atezolizumab of 16 months, while 68% of responses to pembrolizumab lasted over 12 months [5,6]. For mUC patients that experience a relapse after ICI, no standard treatment options are available. Recent gene expression studies of MIBC identified six molecular subtypes but novel candidates for targeted therapies were not found. These MIBC molecular subtypes are luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuro-endocrine-like (3%) [7]. The Cancer Genome Atlas (TCGA) project showed that approximately 69% of MIBC patients harbored molecular alterations that could be targeted for therapy [8, 9, 10]. The multiomics approach of TCGA combined gene-expression profiling with whole-exome sequencing, RPPA protein expression, and DNA methylation that culminated into a snapshot of the molecular landscape of MIBC [8, 9, 10]. Frequently occurring alterations were identified in the receptor tyrosine kinase (RTK)/MAPK pathway, (RTK)/PI3K/AKT/mTOR pathway, and chromatin-modifying genes. Identification of BC driver genes provides an opportunity to develop and investigate personalized treatment options for UC, and as a result, the study of mUC is rapidly evolving. Recently, the FDA has granted accelerated approval for endafitinib, a first-in-class pan-FGFR (fibroblast growth factor receptor inhibitor, and enfortumab vedotin, a first-in-class antibody-drug conjugate (ADC). The aim of this review was to provide a contemporary overview of targeted therapy in mUC.