In the last decade, molecular characterization of bladder cancer (BC) has been performed and new treatment options with immune checkpoint inhibitors (ICIs) have become available (EAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer 2018; bit.ly/2Hh4GOP). However, only a subset of patients responds to ICIs, thus more knowledge on bladder cancer oncogenesis is needed to develop novel therapies to reduce deaths from muscle-invasive bladder cancer (MIBC) and metastatic bladder cancer (mBC) (Urol Oncol 2018;36:43-53, J Clin Oncol 2005;23(21):4602-4608).
Improvements in omics technologies have led to distinction of BC into molecular subtypes predictive of response to treatment and clinical outcome (Cell 2017;171:540-556.e525, Eur Urol 2017;72(4):544-554). While promising, these advances have not led to novel therapies yet, but ongoing preclinical research and multiple clinical trials based on this data show promise for the future. Here, we provide an overview of promising druggable targets based on preclinical research and clinical trials and we discuss their potential use in the current BC treatment paradigms.
Non-Muscle Invasive Bladder Cancer
Non-muscle invasive bladder cancer (NMIBC) is divided in low-, intermediate-, and high-risk disease. This classification is based on multiple clinicopathological parameters and functions as a risk stratifier for recurrent and progressive disease (progression: MIBC, lymph node disease, or mBC) (J Urol 2016;196(4):1021-1029). Treatment of NMIBC consists of a transurethral resection of the bladder tumor (TURBT), followed by adjuvant intravesical chemotherapy (mitomycin C) for intermediate-risk disease and Bacillus Calmette-Guerin immunotherapy (BCG) for high-risk disease (J Urol 2016;196(4):1021-1029).
Despite all NMIBC patients having frequent tumor recurrences, only 1-6 percent of low- to intermediate-risk patients develop progression (EAU Guidelines on Non-Muscle-Invasive Bladder Cancer (TaT1 and CIS) 2018; bit.ly/2Q1adMe). In contrary, 17-45 percent of high-risk NMIBC (HR-NMIBC) patients treated with BCG develop progressive disease. In case of progression, radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) is the only oncologically safe treatment option (EAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer 2018; bit.ly/2Hh4GOP).
A recent study showed that, despite extensive treatment with NAC followed by a RC, patients with progression have a poor clinical outcome (Eur Urol 2019;75(2):231-239). The data showed that patients with progressive disease (secondary MIBC) had a reduced clinical benefit of NAC and worse clinical outcome compared to patients having primary MIBC (Eur Urol 2019;75(2):231-239). Sequencing analysis of both groups showed that somatic genomic alterations in ERCC2, which is known to be implicated in response to platinum-based chemotherapy in MIBC, account for the difference in clinical outcome and chemosensitivity between primary and secondary MIBC (Eur Urol 2019;75(2):231-239).
To prevent progression to MIBC, patients are treated with BCG and patients failing BCG have been defined as “BCG-unresponsive” based on their clinical outcome (Bladder Cancer 2016;2(2):215-224). Until now, only few attempts have been made to molecularly characterize these patients (Eur Urol 2017;72(6):952-959). However, thus far, how and why these BCG-unresponsive patients fail treatment and why some BCG-unresponsive patients progress to MIBC remains unclear, hence these patients are a major focus of the BC research community.
One important reason why BCG-unresponsive patients are a difficult-to-treat group of patients in the urological clinical practice is the lack of treatment options. To stimulate development of novel therapeutics, the FDA recently approved single-arm trials for the assessment of therapies in BCG-unresponsive disease (BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment: Guidance for Industry. 2018; bit.ly/2W1OoSa). Moreover, finding alternatives for BCG has become a pressing subject because of existing BCG shortages (Curr Opin Urol 2018;28(6):570-576).
Since BCG immunotherapy in HR-NMIBC and ICIs in MIBC are effective, BC is considered an immunogenic tumor and these findings present a rationale for ICI treatment in NMIBC. As a result, multiple phase II/III trials are currently investigating the efficacy of different ICIs in patients with BCG-unresponsive NMIBC.
Preliminary data from Keynote-057, a single-arm phase II trial in which BCG-unresponsive patients receive pembrolizumab, showed a 3-month complete response (CR) rate of 40 percent (Ann Oncol 2018;29(suppl8):viii303-viii331). Interestingly, patients with a CR seemed to have a durable response (53% ≥9 months). The S1605 study investigates the efficacy of atezolizumab in BCG-unresponsive patients and additionally investigates the usefulness of multiple biomarkers for response to treatment, such as PD-L1 expression and immune expression signatures (J Clin Oncol 2018;36:TPS527-TPS527).
Furthermore, a global phase III trial (POTOMAC) is randomizing ±1,300 HR-NMIBC patients and assigning patients to: 1) BCG-induction plus BCG-maintenance; 2) durvalumab plus BCG-induction alone; and 3) durvalumab plus BCG-induction and BCG-maintenance. Results of this study are highly anticipated as outcomes may also present opportunities for a new treatment schedule in all HR-NMIBC patients (J Clin Oncol 2019;37:TPS500-TPS500).
Another randomized phase III study investigates if pre-BCG treatment intradermal BCG-priming may decrease the number of high-grade recurrences in HR-NMIBC patients (Eur Urol Focus 2018;4(4):522-524.) Previous studies showed that interferon stimulates a local immune reaction with antitumor effects (Eur Urol 2012;61(1):128-145).
A phase III study now investigates the effectivity of nadofaragene firadenovec in BCG-unresponsive patients after a recently successful phase II trial showing safety and clinical activity in BCG-unresponsive patients (J Clin Oncol 2017;35(30):3410-3416, https://clinicaltrials.gov/ct2/show/NCT02773849. Nadofaragene firadenovec, which is a recombinant adenovirus used as gene vector for interferon-α with Syn3, integrates rAd-INFα/Syn3 into the bladder wall.
Vesigenurtacel-I (HS-410) is a bladder cancer vaccine with a variety of bladder tumor antigens, thereby stimulating the immune system by specifically effectuating a CD8+ cytotoxic T-cell influx (J Clin Oncol 2017;35(6):319-319). Interim results were encouraging and HS-410 was well-tolerated, but final conclusions have yet to be published.
Finally, FGFR3 mutations are frequently found in NMIBC (Cancer Med 2014;3:835-844). After initial disappointing results of a phase II study investigating dovitinib (FGFR1/3 inhibitor) in 44 patients, FGFR inhibition has now regained momentum after positive preliminary results of the novel drug erdafitinib (FGFR inhibitor) in metastatic BC (J Clin Oncol 2018;36(6):411-411). It is expected that erdafitinib will also be explored in HR-NMIBC. Table 1 provides an overview of discussed treatments in HR-NMIBC.
Localized Muscle-Invasive Bladder Cancer
Treatment of MIBC consists of NAC followed by an RC (EAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer 2018; bit.ly/2Hh4GOP). Response to NAC is limited to a subset of patients and currently there are no prospectively validated biomarkers of response available for implementation in the clinical setting (Cancer Treat Rev 2017;54:1-9, J Clin Oncol 2011;29(16):2171-2177). Molecular subtyping of BC patients revealed that basal tumors were more likely to respond to NAC than other molecular subclasses, but results have not been validated (Eur Urol 2017;72(4):544-554).
One prospective trial, entitled “Co-expression Extrapolation (COXEN) Program to Predict Chemotherapy Response in Patients with Bladder Cancer (COXEN),” determines whether expression profiles of the NCI-60 cell lines and sensitivity of these lines to GC or MVAC can be extrapolated to a patient's response to these drugs in the neoadjuvant setting (Cancer Res 2010;70:1753-1758, https://clinicaltrials.gov/ct2/show/NCT02177695).
Recent TCGA analyses revealed that retinoblastoma (RB) pathway defects are frequently found in MIBC patients (Cell 2017;171(3):540-556.e525). RB is involved in cell growth and proliferation and CDK4/6 regulates the cell cycle by phosphorylation of RB. Inhibitors of CDK4/6 have the potential to inhibit RB, which in turn could lead to cycle arrest and antitumor effects (Clin Cancer Res 2019;25:390-402). Hence, a phase I trial is currently investigating the efficacy of neoadjuvant CDK4/6 inhibitors in cisplatin-ineligible patients (Clin Cancer Res 2019;25:390-402). Similarly, EGFR is a growth factor that is frequently mutated in BC and the subject of clinical trials using erlotinib, which is an EGFR inhibitor. Results of this trials are eagerly anticipated and will probably follow shortly (Cell 2017;171(3):540-556.e525, https://clinicaltrials.gov/ct2/show/NCT00380029).
Over the last years, ICIs have showed a significant efficacy in mBC. As a result, multiple studies are now investigating the role of ICIs in the neoadjuvant setting. In a single-arm phase II trial, patients are currently being recruited for neoadjuvant pembrolizumab combined with gemcitabine/cisplatin (https://clinicaltrials.gov/ct2/show/NCT02690558). The BLASST-1 phase II study recruits MIBC patients with localized disease and investigates nivolumab combined with gemcitabine and cisplatin in the neoadjuvant setting before a cystectomy (https://clinicaltrials.gov/ct2/show/NCT03294304). ICIs are also explored in the bladder-sparing strategy where the additional value of durvalumab to trimodal therapy (radical TURBT with adjuvant chemoradiation) is investigated in a phase II trial (https://clinicaltrials.gov/ct2/show/NCT03768570).
Chemoradiation is still frequently used for the treatment of MIBC patients who are unwilling or unfit to have a cystectomy. Chemoradiation causes DNA damage and selecting patients with mutated DNA damage response (DDR) genes may intensify chemoradiation effects, and it seems mutated DDR genes are also a marker for response to chemotherapy (Cancer Discov 2014;4(10):1140-1153, Clin Cancer Res 2019;25(3):977-988, Eur Urol 2016;69(3):384-388). As molecular changes in DDR genes are now identified as a marker for chemotherapeutic response, a phase II study performs mutation analyses on all patients before receiving NAC (https://clinicaltrials.gov/ct2/show/NCT03609216).
Next, NAC-treated patients are stratified for bladder-sparing treatment in case of a <cT1 response to NAC and the presence of DDR alterations. Such a study design could indicate whether preselection of patients with molecular changes in DDR genes can be used to improve stratification for NAC. Patients without DDR alterations may also be targeted for DDR inhibition/knockdown, thereby increasing chemotherapeutic response but also boosting immunogenicity and an elevated response to ICI (Sci Adv 2019;5(2):eaav2437).
One recently started and noteworthy phase III study investigates concurrent chemoradiation therapy with or without atezolizumab in localized MIBC (https://clinicaltrials.gov/ct2/show/NCT03775265). A second study investigates if avelumab can be combined with chemoradiation in MIBC patients (https://clinicaltrials.gov/ct2/show/NCT03617913). A third phase II study investigates cisplatin-ineligible patients with nivolumab and radiotherapy (https://clinicaltrials.gov/ct2/show/NCT03421652). Several other studies use pembrolizumab or atezolizumab as an adjunct to NAC (https://clinicaltrials.gov/ct2/show/NCT02690558, https://clinicaltrials.gov/ct2/show/NCT02989584). Table 1 provides an overview of discussed promising novel treatments in localized MIBC.
Locally Advanced, Unresectable or mBC
In the past, the only suitable treatment for patients diagnosed with locally advanced, unresectable, or mBC was platinum-based chemotherapy, which is not a curative option (J Clin Oncol 2005;23(21):4602-4608). Recently, ICIs have been added to the clinical guidelines, either in the first-line treatment for cisplatin-ineligible patients or as a second-line treatment for metastatic bladder cancer (mBC) (EAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer 2018; bit.ly/2Hh4GOP). Ongoing studies are now investigating whether a combination of ICIs with chemotherapy in the first-line setting is feasible, while others are studying the role of ICI maintenance therapy after initial chemotherapy in mBC (https://clinicaltrials.gov/ct2/show/NCT02500121).
Despite the clear effectiveness of ICIs, we are unable to identify which patients will respond to treatment (Nat Rev Cancer 2019;19(3):133-150, Lancet 2018;391:748-757). Multiple biomarkers are currently being investigated for their predictive accuracy of response to ICIs.
As a result of KEYNOTE-361 and IMvigor130 comparing ICI with chemotherapy, we have recently learned that patients with low expression levels of PD-1/PD-L1 are unlikely to benefit from ICI monotherapy (J Clin Oncol 2017;35:TPS4590-TPS4590, J Clin Oncol 2018;36:TPS4589-TPS4589). Patients are only eligible to receive ICIs if they are unfit for chemotherapy or if the tumor and/or tumor-infiltrating lymphocytes express high levels of PD-1/PD-L1.
Furthermore, high tumor mutational burden has been identified as a promising predictive marker of response to ICI (Mol Cancer Ther 2017;16(11):2598-2608). Whole transcriptome sequencing of 298 tumor samples in the IMvigor210 study recently revealed a TGFβ signature holds promise as a marker for ICI, which may also be a potential new “druggable” pathway in BC (Nature 2018;554:544-548). In addition, T-cell receptor clonal expansion shows promise as a predictive marker but needs further validation (PLoS Med 2017;14(5):e1002309).
Besides ICIs, multiple trials using precision medicine are presently recruiting or ongoing. PARP inhibitors are successful against ovarian and breast cancer with BRCA1/2 mutations and PARP inhibitors might also show efficacy in other cancer types (Clin Cancer Res 2018;24:3163-3175). BRCA1/2 mutations cause double strand breaks and PARP inhibition prevents double strand repair, leading to cell death. The BAYOU phase II randomized trial investigates safety and efficacy of olaparib (PARP inhibitor) combined with durvalumab or durvalumab alone as first-line treatment of mBC (https://clinicaltrials.gov/ct2/show/NCT03459846).
Another phase II trial studies afatinib, a protein kinase inhibitor of HER2 and EGFR, after first-line chemotherapeutic failure (https://clinicaltrials.gov/ct2/show/NCT02122172). Afatinib is a drug used successfully as a treatment in non-small cell lung carcinoma.
Sapanisertib is an experimental drug that inhibits mTOR, which is needed for cell growth, proliferation, and survival (Nat Rev Cancer 2018;18:744-757). TSC1/2 negatively regulates mTOR and a phase II trial is recruiting patients with TSC1/2 mutations, for which sapanisertib may be an interesting drug (https://clinicaltrials.gov/ct2/show/NCT03047213).
Cabozantinib is a fourth precision drug that is currently approved for kidney cancer but is now also investigated for mBC in conjunction with nivolumab (PD-1) and ipilimumab (CTLA-4). Cabozantinib blocks c-Met and VEGFR2 protein production, both involved in cell proliferation (https://clinicaltrials.gov/ct2/show/NCT03866382).
Finally, FGFR inhibition is an exciting topic of interest for the BC community, as FGFR3 mutations (10%) or overexpression of FGFR3 (40%) are frequent events in MIBC (Clin Cancer Res 2018;24:1586-1593). Moreover, FGFR3-TACC3 fusions are also found in MIBC (1-3%) (Oncotarget 2017;8:16052-16074). Erdafinitib (FGFR inhibitor) showed a 42 percent CR in patients with chemo-refractory or chemo-ineligible FGFR-altered mBC. In fact, in April 2019, the FDA granted accelerated approval to erdafitinib for patients with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 or FGFR2 genetic alterations that showed progression during or following platinum-containing chemotherapy. Further phase III studies will hopefully show beneficial long-term effects of erdafitinib. Table 1 provides an overview of discussed promising novel treatments for locally advanced, unresectable or mBC.
Upcoming BC research will be defined by new biomarker-driven trials for BC patients. Well-designed illustrations of these trials are the NCI-MATCH, NCI-MPACT, and BISCAY trials (Curr Probl Cancer 2017;41(3):182-193, J Clin Oncol 2016;34:TPS4577-TPS4577). In these trials, biomarker analysis precedes and pre-selects actual patients and drugs before treatment commences and, therefore, these studies are excellent examples of precision medicine.
Many new precision drugs are imminent for BC. Some are very promising (erdafitinib), whilst others still need further validation. One new molecular therapy definitively gained momentum: PD-1/PD-L1 ICI. For ICIs, one of the future challenges is to develop biomarker-driven patient selection. Eventually, precision medicine will allow us to treat BC patients with the customized therapies they need.
FLORUS C. DE JONG, MD, and TAHLITA C.M. ZUIVERLOON, MSC, MD-PHD, are in the Department of Urology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands. DAN THEODORESCU, MD, PHD, is at Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles.
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