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Antibody drug conjugates (ADCs) are a promising method of selective intensification of therapy, offering increased drug concentration to the target with minimal collateral damage to healthy tissue.1   Structurally, ADCs are monoclonal antibodies specific for a tumor antigen connected by a linker molecule to a cytotoxic drug payload.  After endocytotic internalization of the complex, the linker is degraded in a lysosome, releasing the cytotoxic payload.  There are now many FDA approved ADCs, including brentuximab vedotin for anaplastic2 and refractory Hodgkin lymphomas,3 trastuzumab emtansine
One year ago, in this column, I highlighted the non-metastatic (M0) castration-resistant prostate cancer (CRPC) disease state as a fruitful area for clinical trial exploration.1  As part of that article, I emphasized the concept of testing low toxicity, high efficacy agents from metastatic CRPC in earlier disease states.  Two of the randomized, phase 3 trials have just came out and the results are quite impressive.
Immune checkpoint inhibitors (e.g. anti-PD1/PDL1, anti-CTLA4) have revolutionized the treatment of multiple tumor types, including urothelial and renal cell carcinomas.1, 2 Unfortunately, response rates to anti-PD1/PDL1 therapy are still generally low, although those who do respond or who have stable disease may have long-term durable clinical benefit.  It is likely that combination immunotherapy strategies targeting multiple negative regulators of tumor immune responses will be more effective than anti-PD1/PDL1 monotherapy.
PD-1/PD-L1 antibodies are being studied in every disease state imaginable for patients with urothelial carcinoma.  Atezolizumab, nivolumab, durvalumab and avelumab are all regulatory approved for patients with metastatic disease in the post-platinum chemotherapy setting.1-4  Pembrolizumab is also approved and is the only agent to have demonstrated an overall survival benefit to date when compared to taxane chemotherapy in the post-platinum setting.5  Additionally, atezolizumab and pembrolizumab are approved for patients who are ineligible for cisplatin chemotherapy in the 1st-line. 6,7 
The fibroblast growth factor receptor (FGFR) family has functional roles in regulation of cell proliferation, differentiation, migration, angiogenesis and tumorigenesis.  Activating point mutations of FGFR3 are common (~86%) in low grade and stage bladder tumors.1  However, The Cancer Genome Atlas Research Network identified only 12% of muscle invasive bladder cancers with FGFR3 mutations.2  FGFR3 mutations are also very common in upper tract urothelial tumors, especially of the ureter.3  FGFR1 has been less intensively studied, but increased expression at both the mRNA and protein level is present in a large proportion of bladder tumors.4 
Radium-223 is actually quite capable of dancing on its own without a partner.  It offers an overall survival, symptomatic skeletal events and multiple pain and quality of life benefits for patients with bone metastatic castration-resistant prostate cancer and symptoms.1  Yet, the ALSYMPCA trial, which established the beneficial effects of radium-223, did not mandate regular imaging, so image surveillance expectations are uncertain.  Additionally, prostate-specific antigen (PSA) level does not always associate with clinical outcomes with Radium-223.  Given the mechanism of action of Radium-223, as an alpha-particle emitting radiopharmaceutical that incorporates into areas of osteoblastic activity, it is not surprising that alkaline phosphatase serves as not only a good baseline prognostic marker2 but also a good treatment response biomarker.3
Neoadjuvant chemotherapy use has been on the rise in the last 15 years for patients with high-risk localized urothelial carcinoma.  This is obviously due to randomized control data supporting an overall survival benefit.1,2  However, it has taken significant time for the field to embrace and adopt widespread use of cisplatin-based combination chemotherapy regimens in this setting.  Early reports showed neoadjuvant chemotherapy utilization rates to be 7.6% in 2006, 3 years after the original randomized control trial was published supporting the use of methotrexate, vinblastine, adriamcyin and cisplatin.3 

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