Therapeutic strategies for advanced bladder cancer

Bladder cancer is diagnosed in approximately 540 people in Ireland per year and represents the 14th most common cancer in Ireland.¹ Worldwide it is the 13th leading cause of cancer-related death. It is a diagnosis largely seen in older populations with 75% of those diagnosed over the age of 65 years.¹ There is a male preponderance internationally and this is reflected in Irish data, with men in Ireland at least twice as likely to be affected as women.² In 2021, men comprised more than 70% of patients diagnosed with bladder cancer.³

Localised disease

Bladder cancer most commonly presents as localised disease, with a smaller number of patients presenting with de novo metastatic disease, somewhere in the region of 10-15%.⁴ Localised bladder cancer is classified as non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC) based on invasion of the underlying muscularis propria of the bladder. This is prognostic and also guides treatment strategies. The majority of localised bladder cancer is NMIBC at presentation. NMIBC is treated with local resection and, if warranted, intravesical treatment. The majority of NMIBC cases will recur within six to 12 months at the same disease stage. Of those with NMIBC, 10-15% of patients will recur with muscle-invasive or metastatic disease.⁵ A smaller percentage of patients present with de novo MIBC. Optimal treatment of MIBC includes neo-adjuvant chemotherapy and curative resection, or tri-modality treatment incorporating maximal transurethral resection of bladder tumour (TURBT) followed by radiation therapy (RT) with concurrent radio-sensitising chemotherapy. 

Despite optimal treatment, recurrence post-definitive treatment is in the region of 30-40%, signifying the aggressive nature of bladder cancer.² NMIBC and MIBC will not be addressed further in this article, which will focus on unresectable, locally advanced and metastatic bladder cancer. 

Metastatic disease

When metastatic disease develops, the most common sites of metastasis include lymph nodes, liver, lung and bone. Prior to the widespread use of immune-oncology (IO) agents, treatment options for metastatic disease were limited to cytotoxic chemotherapy regimens with overall survival (OS) for patients diagnosed with metastatic disease in the region of 15 months.⁶ However, in recent years there is cause for optimism with the introduction of new agents into the treatment paradigm, including the widespread use of IO agents, a shift towards personalised medicine and the integration of novel therapeutic agents including antibody drug conjugates. 

We will summarise the recent updates in the management of bladder cancer including practice changing data published as recently as last year. Ongoing translational research and clinical trials into targeted medicine approaches continue to show promise in this dynamic treatment field.

Epidemiology and risk factors

A number of epidemiological risk factors have been identified in relation to the development of bladder cancer. 

Age and sex

Older age and male sex are two key associated risk factors in the development of bladder cancer. Bladder cancer is generally seen as a cancer of older populations and a presentation much more commonly seen in men. In the most recent NCRI report in 2021,³ figures suggest that advanced invasive bladder cancer incidence at presentation was 22.9 per 100,000 population for men and 7.3 per 100,000 population for women, with the average age at diagnosis being 73 years.

Tobacco smoking

Tobacco smoking has been noted to confer risk in the development of bladder malignancy. The incidence of bladder cancer has been shown to be directly related to the duration of smoking and the number of cigarettes smoked per day.⁷

Chronic low grade inflammation 

Long-term catheterisation, urinary stasis and urolithiasis all provide environments which lead to chronic inflammation of the bladder mucosa. This chronic low grade inflammation is felt to be a contributory risk factor for the development of bladder cancer, with higher incidence rate noted in these populations when studied.⁸

Occupational and prior exposure

The risk of bladder cancer due to occupational exposure to carcinogenic aromatic amines such as those found in dyes, paint and oils, is significantly greater after 10 years or more of exposure. Other environmental risk factors for bladder cancer include higher concentrations of arsenic, chlorinated byproducts and other pollutants in drinking water.⁹

Individuals who have undergone previous pelvic radiotherapy have been noted to have increased rates of developing secondary bladder cancer. Relative risk of 2-4 has been reported by studies of patients who have previously received external-beam radiotherapy (EBRT) as part of cancer treatment.¹⁰

Inherited genetic predisposition

It has been found that patients with Lynch syndrome, a condition which arises from the germline mutation in one of the mismatch repair (MMR) genes, have a higher risk of developing urothelial cancer, particularly those with an MSH2 mutation.¹¹ Of note, patients with Lynch syndrome are likely to particularly benefit from immunotherapy treatment approaches. 

Obesity 

Studies have suggested a correlation between higher body mass index (BMI) and the development of bladder cancer.¹²

Schistosoma haematobium 

Human schistosomiasis a tropical disease which is endemic in 78 countries across the world. Chronic urinary schistosomiasis is a risk factor for the development of squamous cell carcinoma in countries where the parasite is endemic.¹³

Histology and staging 

Histology

95% of bladder cancers are urothelial cell cancers in origin, which was previously known as transition cell carcinoma. It is worth mentioning that while most urothelial cancer is found in the bladder, a smaller proportion of urothelial cancers are of the upper urinary tract, including renal pelvis and ureter, and these may co-exist with bladder urothelial cancer. 

Urothelial cancers may have evidence of variant histology such as squamous or sarcomatoid differentiation, which can have implications for prognosis.¹⁴ Non-urothelial cancers of the bladder include pure squamous cell carcinoma, adenocarcinoma and small cell carcinoma  and represent a much smaller proportion of bladder malignancies overall. These non-urothelial cancers tend to be more advanced at presentation, less responsive to conventional treatments and have a poorer prognosis.¹⁴

Staging

Bladder cancer is staged, as many cancers, with the tumour, node, metastasis (TNM) staging system. At diagnosis, disease can be classified as:

• Non-muscle invasive bladder cancer – carcinoma in situ (CIS)/TA/T1
• Muscle invasive bladder cancer – T2/ T3/T4 Nx M0
• Locally advanced unresectable or metastatic.

Management of locally advanced unresectable and metastatic bladder cancer

The therapeutic agents used for the treatment of metastatic bladder cancer are discussed below, with a focus on the newer drugs that will transition into clinical practice over the course of the coming years.

Cytotoxic chemotherapy with platinum-based regimens 

Platinum-based regimens for metastatic bladder include:

• MVAC (methotrexate, vinblastine, doxorubicin and cisplatin)
• Cisplatin and gemcitabine 
• Carboplatin and gemcitabine. 

The backbone of treatment of advanced metastatic bladder cancer has long been cytotoxic platinum based chemotherapy. The choice of regimen is ordinarily based on a patient’s co-morbidities, preference and performance status. 

The platinum-based regimens used are listed above. Since the 1980s, methotrexate, vinblastine, adriamycin and cisplatin (MVAC) had been a standard chemotherapy regimen, however treatment related toxicities were challenging for patients to tolerate.^15,16 In an attempt to combat these toxicities as well as improve outcomes, ‘dose-dense’ MVAC regimens (ddMVAC) were developed. These included escalated doses of chemotherapy agents delivered alongside haematologic growth factor support in an attempt to mitigate myelosuppression. Granulate colony stimulating factor (GCSF) was prescribed alongside escalated chemotherapy doses. When compared to standard MVAC, ddMVAC demonstrated comparable efficacy and encouragingly a reduction in treatment-related adverse events and improvement in tolerability for patients, but did not lead to an improvement in overall survival for patients.¹⁷

While MVAC and ddMVAC represent a valid therapeutic option for patients with metastatic bladder cancer, the use of a triplet chemotherapy regimen in the metastatic setting can be challenging to deliver due to toxicity, particularly in older or frailer patients. Clinical practice has mostly moved to the delivery of a doublet regimen, cisplatin and gemcitabine (Cis-Gem) in the metastatic setting. Cis-Gem has demonstrated similar efficacy to MVAC regimens, with less toxicity.¹⁸ Although Cis-Gem has been found to have a reduced toxicity profile when compared to MVAC and ddMVAC, the use of Cis-Gem is still limited in patients whose frequent co-morbid conditions limit their ability to tolerate aggressive therapy.¹⁹ Traditionally, ineligibility for cisplatin therapy has required the presence of one of the following factors:

• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≥ 2 
• Creatinine clearance (Cr Cl) < 60mL/min 
• Peripheral neuropathy ≥ grade 2 
• Hearing impairment ≥ grade 2 
• New York Heart Association (NYHA) Heart Failure > 2.¹⁹

In the setting of patients who are ineligible for cisplatin but otherwise fit for chemotherapy, the regimen of carboplatin and gemcitabine may be used. While there are direct comparison trials with cisplatin based regimens, the small patient numbers studied limits the interpretation of the relative efficacy of the regimens.^20,21 It is generally accepted however, that carboplatin is inferior in terms of efficacy but a valid option for those not fit for cisplatin.²²

Toxicity

Toxicities associated with cytotoxic chemotherapy include: myelosuppression, alopecia, mucositis, gastrointestinal, cardiac and renal toxicities, as well as emetogenic effects of the treatment, with platinum being a highly emetogenic chemotherapeutic in doublet or triplet combinations. Particular to cisplatin is the risk of nephrotoxicity, neuropathy and hearing loss, which should be carefully assessed prior to the delivery of each cycle of treatment.^16,23,24 As with most chemotherapeutic regimens, cumulative doses can increase the risk of side effects, including treatment-related fatigue, which can necessitate dose reductions or delays in treatment. 

As outlined above, both ddMVAC and Cis-Gem have less toxicity than standard dose MVAC. A randomised control trial (RCT) comparing MVAC and Cis-Gem in patients with advanced bladder cancer demonstrated an improved safety profile with reduced rates of neutropenia, neutropenic sepsis, toxic death and mucositis with Cis-Gem as compared with MVAC. Additionally, less dose reductions were required and improved quality of life were recorded for patients on the Cis-Gem treatment arm.¹⁸

Setting and efficacy 

Currently, cytotoxic chemotherapy with platinum-based regimens remains a first-line treatment option for eligible patients with metastatic bladder cancer in Ireland with disappointing median survival for patients. The first RCT comparing the efficacy of Cis-Gem versus MVAC back in 2000, recruited treatment-naive patients with stage four disease, who were then randomised to Cis-Gem or MVAC. OS was similar on both arms at 14 and 15 months respectively (hazards ratio [HR], 1.04; 95% CI, 0.82 to 1.32; p = 0.75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% confidence interval [CI] 0.72 to 1.10), and response rate (Cis-Gem, 49%; MVAC, 46%). Given the improved toxicity as outlined above, Cis-Gem tends to be preferred in the metastatic setting.¹⁸

Platinum-based regimens have been the first-line standard of care for bladder cancer up until last year when practice changing data has demonstrated the superiority of IO combination regimens which we will discuss in further detail later in the article. It is worth noting that these novel combinations are not yet reimbursed for use in Ireland at the time of writing this article.

Cytotoxic chemotherapy with taxane regimens

Taxane agents, including docetaxel and paclitaxel, have been studied as second-line monotherapy options for patients with advanced bladder cancer, who have progressed through first-line platinum based treatments. 

Toxicity

Haematologic toxicity including anaemia, thrombocytopenia, neutropenia and febrile neutropenia have been associated with the use of taxanes. Additionally non-haematologic toxicities include alopecia, fatigue, mucositis, gastrointestinal effects and neuropathy, among others.²⁵

Setting and efficacy

Both docetaxel and paclitaxel have been explored as monotherapy second-line options in phase II trials to date.^25,26,27 In this second-line setting, outcomes are generally poor with a short time of treatment benefit and survival measured in less than a year. As an illustration, this study in patients who had progressed on a cisplatin-containing regimen examined outcomes for patients receiving weekly paclitaxel. The median progression free survival (PFS) of second-line chemotherapy was three months and the median OS following the start of second-line therapy was 6.4 months. As it stands, paclitaxel is licensed in Ireland for the second-line treatment of patients with advanced urothelial cancer who have progressed following first-line platinum based treatment. 

Immune-oncology agents

Harnessing and activating the body’s immune response to cancer has led to vast advances in the treatment of a number of cancers, including bladder cancer. Immune cell surface receptors known as ‘immune checkpoints’ ultimately control the activation or inhibition of the body’s immune response. An inhibitory mechanism used by tumour cells to ‘turn off’ the immune response to cancer occurs through the binding of PD-1 (programmed death-1) proteins on T cells with PD-L1 (programmed death-ligand 1) proteins on tumour cells. A type of immunotherapy known as immune checkpoint inhibitors (CPIs) can block receptors for these proteins, ultimately allowing the immune system to stay activated and engage its anti-cancer response. This class of immunotherapy is considered the most thoroughly investigated to date and plays an important role in the treatment of multiple malignancies. Two of the most promising checkpoint inhibition approaches that have been widely used in the past decade are the blockade of PD-1/PD-L1 and CTLA-4 (cytotoxic t-lymphocyte associated protein-4) molecules. Below we will discuss some of the immunotherapy agents most utilised in metastatic bladder cancer in Ireland. As a guide, we have included a table to give an overview of how an IO agent can be selected for an individual patient in particular settings.

Regimens

CPIs reimbursed for use in Ireland for locally advanced unresectable and metastatic bladder urothelial cancer include:

• Atezolizumab
• Pembrolizumab
• Avelumab.

In some settings, their use is dependent on the presence of a biomarker PD-L1 which is tested with immunohistochemistry and tumour specimens. These are used in different stages of disease depending on the agent. 

Toxicity

A number of toxicities arising from CPIs have been reported which can range from mild to rare life-threatening side effects. Immune related adverse events (irAEs) arise from the inhibition of normal immune homeostasis, resulting in the migration of immune cells into normal cells and leading to inflammation.²⁸ IrAEs can occur at any time during treatment and even up to 12 months post-treatment. Once an irAE arises, the clinical decision regarding rechallenging a patient depends on the severity of the toxicity and patient factors.

IrAEs are classified according to the system affected; the following is a non-exhaustive list of documented toxicities: 

• Endocrine irAEs, including thyroid dysfunction (primarily hypothyroidism), adrenal insufficiency and hypophysitis
• Lung irAEs, including pneumonitis
• Gastrointestinal irAEs, including enteritis and colitis 
• Skin irAEs, including dermatitis 
• Liver irAEs, including hepatitis
• Rheumatological irAEs, including arthralgia and myalgia, inflammatory arthritis and myositis 
• Kidney irAEs, including nephritis
• Neurological irAEs, including myasthenia gravis-like syndrome, peripheral neuropathy, Guillain Barré-like syndrome
• Cardiovascular irAEs, including myositis and peri-carditis.²⁹

Generally speaking, immunosuppression with corticosteroids is the first step in the management of irAEs (aside from endocrinopathies which involve replacing deficient hormones), with escalation to other immunosuppressive agents if the toxicity is not responsive to corticosteroids.²⁹

First-line setting: platinum ineligible

First-line IO has not been demonstrated to be superior to platinum-based chemotherapy in all instances, although data supports its use in patients ineligible for platinum-based treatment and have a high PD-L1 score, which is an imperfect biomarker which may guide the use of immunotherapy. 

Atezolizumab was tested in this setting in  IMvigor 210.³⁰ This phase II single arm study of atezolizumab in patients with locally advanced or metastatic urothelial cancer who were ineligible for platinum treatments, demonstrated a reassuring median OS of 16 months for the group and a higher overall response rate in those with PD-L1 of > 5%.³⁰

Pembrolizumab was also tested in this setting in Keynote-052,³¹ a phase II single arm study. A total of 35 patients (9.5%) achieved a complete response (CR) and 72 patients (19.5%) achieved a partial response (PR). The median OS was 11.3 months (95% CI 9.7 to 13.1 months) overall. The response rate was most pronounced in those with a high PD-L1 score (defined as a combined positivity score of ≥ 10) with an impressive 20% of these patients achieving a complete response. 

First-line setting: maintenance

Avelumab is an anti-PD-L1 antibody that is reimbursed in Ireland for maintenance treatment following completion of platinum-based chemotherapy, which is usually given for between four and eight cycles. In the JAVELIN Bladder 100 trial³² investigators enrolled patients with unresectable locally advanced or metastatic urothelial carcinoma with stable disease or a response following first-line platinum-based chemotherapy. In those who received maintenance treatment with avelumab, the median OS was 21.4 months (95% CI, 18.9 to 26.1) versus 14.3 months (95% CI, 12.9 to 17.9) in those who did not (hazard ratio [HR] for death, 0.69; 95% CI, 0.56 to 0.86; CI, 0.54 to 0.92; p = 0.001). With long-term follow-up (data cut-off June 4, 2021), median OS was 23.8 versus 15 months (HR, 0.76; 95% CI, 0.63 to 0.91).³³ Avelumab has become a standard of care for those who are suitable for immunotherapy and have stability or response post-platinum-based chemotherapy in the first-line setting. 

Second-line setting: post-progression on platinum-based chemotherapy

Pembrolizumab was studied in this setting in Keynote-045,³⁴ a phase III trial that compared pembrolizumab with a second-line chemotherapy agent. OS was longer for pembrolizumab than for chemotherapy at 10.1 months versus 7.2 months (HR 0.71; 95% CI 0.59 to 0.86). The 36 and 48 month OS rates were 20.7% and 16.7% respectively for pembrolizumab and 11.0% and 10.1% respectively for chemotherapy. Importantly, for patients in the second-line treatment setting with advanced disease, the incidence of severe toxicity with pembrolizumab was much reduced compared to chemotherapy. 

Atezolizumab was studied in this setting in a phase III trial IMvigor  211 but failed to show a survival advantage compared to chemotherapy.³⁵ It did however, have less toxicity than chemotherapy as per the Keynote-045 study, which makes it a reasonable choice in this setting.

Antibody drug conjugate – enfortumab vedotin

Enfortumab vedotin (EV) is an antibody drug conjugate (ADC). ADCs typically consist of an antibody (which targets a tumour protein) attached to a cytotoxic chemotherapy payload, often referred to as ‘targeted chemotherapy’. Once the antibody attaches to the tumour protein or antigen, the ADC is internalised and the cytotoxic drug is eventually released in the cell, resulting in cell death. EV is directed against Nectin-4, a cell-adhesion molecule that is highly expressed in urothelial carcinoma.³⁶ The protein is physiologically expressed on tissues such as skin, bladder and lung at weak to moderate levels, but is highly expressed in a number of cancers, including urothelial cancer. Its use in bladder cancer, first in the heavily pretreated population and more recently in combination in the first-line setting, has led to significant improvements in outcomes for patients with metastatic urothelial bladder cancer.^37,38

Toxicity

Important treatment-related side effects from EV include: 

• Dermatological reactions, such Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) 
• Hyperglycaemia, 
• Pneumonitis/interstitial lung disease (ILD)
• Peripheral neuropathy.

Setting and efficacy

EV is licensed for use as a single agent in patients with locally-advanced or metastatic urothelial cancer previously treated with both platinum-based chemotherapy and immunotherapy. 

EV-301³⁷ was an international phase III trial that assessed the effects of EV versus chemotherapy in patients previously treated with both platinum-based chemotherapy and immunotherapy for locally advanced or metastatic urothelial carcinoma. OS was longer in the EV group than in the chemotherapy group with a median OS of 12.88 versus 8.97 months respectively (HR for death, 0.70; 95% CI, 0.56 to 0.89; p = 0.001). PFS was also longer in the EV group than in the chemotherapy group (median progression-free survival, 5.55 versus. 3.71 months; HR for progression or death, 0.62; 95% CI, 0.51 to 0.75; p < 0.001). The results of this study demonstrated promising outcomes in the heavily pre-treated advanced bladder setting and consequently EV emerged as a key treatment option for this cohort of patients.

Molecularly targeted agents – erdafitinib

Alterations in fibroblast growth factor receptor (FGFR) have been demonstrated as a molecular driver of urothelial bladder cancer, particularly FGFR3 mutations. Approximately 20% of bladder urothelial cancers  have an FGFR3 mutation or rearrangement. Erdafitinib is a pan-FGFR tyrosine kinase inhibitor licensed for the treatment of patients with cisplatin refractory FGFR2/FGFR3-altered bladder cancer.³⁸

Toxicity

Key toxicities include:

• Dermatological (stomatitis, mucositis, hand and foot syndrome and nail toxicities)
• Ocular disorders 
• Gastrointestinal (diarrhoea)
• Electrolyte disorders (hyperphosphatasemia).³⁹

Setting and efficacy

Patients with locally advanced or metastatic urothelial cancer harbouring susceptible FGFR3 genetic alterations who have previously received at least one line of therapy containing a PD-1 or PD-L1 inhibitor in the unresectable or metastatic treatment setting.

The phase III Thor trial⁴⁰ randomised patients with locally advanced or metastatic urothelial cancer and select FGFR2/3 alterations to either erdafitinib or single agent chemotherapy (docetaxel or vinflunine). All patients had received previous immunotherapy and the majority had also received prior chemotherapy regimens. Erdafitinib significantly increased overall survival and reduced the risk of death versus chemotherapy with a median OS of 12.1 months versus 7.8 months respectively (HR 0.64, 95% CI 0.47 to 0.88). These findings demonstrate the need for molecular testing in patents with bladder cancer, which is usually achieved with targeted next generation sequencing panels on tissue specimens. 

Combination strategies

Recently published data has dramatically changed the treatment landscape for metastatic urothelial bladder cancer given the superior efficacy of combination strategies over traditional first-line chemotherapeutic strategies. The two new first-line options for metastatic bladder cancer are: 

• Enfortumab vedotin plus pembrolizumab
• Nivolumab plus cisplatin and gemcitabine.

Toxicity

The toxicities of individual drugs are as outlined previously, but like any combination therapy, the toxicities can often be additive and combination therapy may come with a greater risk of side effects.  

Setting and efficacy

These regimens have been examined in the first-line setting versus the historical standard of care, platinum-based chemotherapy.

Nivolumab plus platinum based chemotherapy

Checkmate 901, a phase III RCT,⁴¹ evaluated nivolumab plus Cis-Gem as compared with Cis-Gem alone in patients with previously untreated unresectable or metastatic urothelial carcinoma. Patients were randomised to nivolumab plus Cis-Gem for up to six cycles, followed by maintenance nivolumab, or Cis-Gem alone for up to six cycles. Median OS was significantly longer for the combination treatment at 21.7 months versus 18.9 months comparatively; (HR 0.78, 95% CI 0.63 to 0.96). Nivolumab plus Cis-Gem now supersedes Cis-Gem alone in fit patients as a first-line treatment option for advanced bladder cancer. Although not reimbursed for used in Ireland, the results of Checkmate 901 have influenced treatment recommendations in the first-line setting alongside the results of EV-302 below.

Pembrolizumab and antibody drug conjugate combinations 

On the back of EV-301, EV-302⁴² served results which have also shaped the first-line treatment paradigm of advanced urothelial cancer. EV-302, a phase III RCT, compared the efficacy and safety of EV and pembrolizumab with platinum-based chemotherapy; 886 patients were randomised to either EV-pembrolizumab or platinum based chemotherapy. Median OS was significantly improved in the EV-pembrolizumab group at an impressive 31.5 months compared to 16.1 months in the chemotherapy group (HR for death, 0.47; 95% CI, 0.38 to 0.58; p < 0.001). This is a dramatic increase with a near doubling in overall survival, representing a major step forward for the treatment of metastatic bladder cancer. Given the impressive results of this trial, a new standard of care for first-line treatment of treatment-naive advanced bladder malignancy has emerged. 

Future directions 

The significant improvement in survival for patients with the two new combination strategies outlined above, particularly EV and pembrolizumab, has been much welcomed by patients and their healthcare professionals, and has also invigorated the bladder cancer research community. 

There are a number of different therapeutics, in combination or alone, which are being explored in clinical trials, many of which are ADC type drugs, including sacituzumab govitecan and distamab vedotin, both of which have different antigen targets for the antibody component. Novel technologies such as bicycle compounds, which have antibody-like action but the synthetic advantages of a small molecule, are also being tested in clinical trials in bladder cancer.⁴³ Some of these studies will open in Ireland over the coming months, giving suitable Irish patients access to the newest therapeutics for bladder cancer. 

Landscape of treatment in 2024 in Europe 

Since the publication of EV-302 and Checkmate 901, the European Society for Medical Oncology (ESMO) has now established EV-pembrolizumab as first-line treatment for advanced bladder cancer. The majority of patients presenting with advanced bladder cancer should be eligible to receive EV or IO, however for the subgroups of patients that may be ineligible, platinum-based chemotherapy with or without IO can be considered as an alternative. 

As it stands in Ireland we do not have access to EV-pembrolizumab nor nivolumab and Cis-Gem as first-line treatment for patients with advanced bladder cancer. In Ireland, as outlined below, current treatment strategies focus on chemotherapy or single-agent immunotherapy options for patents who are chemotherapy ineligible as first line. The field of advanced bladder care treatment continues to evolve and diversify with the promise of more options for these patients in the pipeline with studies ongoing.

Current treatment paradigm

Above we have summarised the data in this article in an overview of the current treatment paradigm for locally advanced or metastatic bladder cancer. It is important to note that not all of these drugs or combination of drugs are reimbursed for use in Ireland yet. We have noted this on the diagram and this reflects availability at the time of writing this article. At all stages of disease, consideration should be given to the availability of an appropriate clinical trial for patients and discussed if appropriate. 

References 

1. Irish Cancer Society Bladder cancer. [Online]. Irish Cancer Society. Available at: www.cancer.ie/cancer-information-and-support/cancer-types/bladder-cancer [Accessed July 11, 2024]
2. Lin W, Pan X, Zhang C, Ye B, Song J. Impact of age at diagnosis of bladder cancer on survival: a surveillance, epidemiology, and end results-based study 2004. Cancer Control 2023. 30:1-14. doi: 10.1177/10732748231152322
3. National Cancer Registry Ireland. (2021). Incidence Statistics. NCRI. Available at: www.ncri.ie/data/incidence-statistic [Accessed 12 July 2024]
4. Chin J, Siddiqui K, Tran C. (). Metastatic Bladder Cancer. In: Ahmad A (Ed). Introduction to Cancer Metastasis. London: Academic Press 2017; 177-98
5. Park J, Citrin D, Agarwal P, Apolo A. Multimodal management of muscle-invasive bladder cancer. Curr Prob Cancer 2014; 38:80-108
6. Sternberg CN, de Mulder P, Schornagel JH et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC i. Eur J Cancer 2006; 42(1):50-4 
7. Brennan P, Bogillot O, Cordier S et al. Cigarette smoking and bladder cancer in men: a pooled analysis of 11 case-control studies. International Journal of Cancer 2000; 86(2):289-94 
8. Hird A, Saskin R, Liu Y et al. Association between chronic bladder catheterisation and bladder cancer incidence and mortality: a population-based retrospective cohort study in Ontario, Canada. BMJ 2021; 11(9):e050728
9. Gu J, Wu X. Genetic susceptibility to bladder cancer risk and outcome. Personalized Medicine 2011; 8(3):365-74
10. Chrouser K, Leibovich B, Bergstrahl E, Zincke H, Blute M. Bladder cancer risk following primary and adjuvant external beam radiation for prostate cancer. J Urol 2005; 174(1):107-11 
11. Post R, Kiemeney L, Ligtenberg M et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet 2010; 47(7):464-70
12. Rezaei F, Tabatabaee H, Rahmanian V, Mirahmadizadeh A, Hassanipour S. The correlation between bladder cancer and obesity, overweight, physical inactivity, and tobacco use: an ecological study in Asian Countries. Annal Global Health 2019; 85(1):102
13. Mostafa M, Sheweita S, O’Connor P. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev 1999; 12(1):97–111
14. Black A, Black P. Variant histology in bladder cancer: diagnostic and clinical implications. Trans Cancer Res 2020; 9(10):6565-75 
15. Schardt J, Roth B, Seiler R. Forty years of cisplatin-based chemotherapy in muscle-invasive bladder cancer: are we understanding how, who and when? World J Urol 2019; 37(1):1759-65
16. HSE. (2016). NCCP National SACT Regimen. [Online]. National Cancer Control Program. Available at: https://www.hse.ie/eng/services/list/5/cancer/profinfo/chemoprotocols/genitourinary/338-methotrexate [Accessed 15 July 2024]
17. Sternberg C, Mulder P, Schornagel J et al.  Randomized Phase III Trial of High–Dose-Intensity Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (MVAC) Chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors. J Clin Oncol 2001; 19(10):2638-46
18. Maase H, Hansen S, Roberts J et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder. J Clin Oncol 2000; 18(7):3068-77 
19. Maiorano B, Giorgi U, Ciardiello D et al. Immune-checkpoint inhibitors in advanced bladder cancer: seize the day. Biomedicines 2019; 10(2):411 
20. Petrioli R, Frediani B, Manganelli A et al. Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. A randomized phase II study. Cancer 1996; 77(2):344-51
21. Dreicer R, Manola J, Roth B et al. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer 2004; 100(8):1639-45
22. De Santis M, Bellmunt J, Mead G et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with urothelial cancer. J Clin Oncol 2012; 30(2):191-9
23. Gunlusoy B, Arslan M, Vardar E et al. The efficacy and toxicity of gemcitabine and cisplatin chemotherapy in advanced/metastatic bladder urothelial carcinoma. Actas Urológicas Españolas 2012; 36(9):515-20
24. National Cancer Control Program. (2015). NCCP National SACT Regimen. [Online]. HSE. Available at: https://www.hse.ie/eng/services/list/5/cancer/profinfo/chemoprotocols/gastrointestinal/383-gemcitabi [Accessed 15 July 2024]
25. Sideris S, Aoun F, Zanaty M et al. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in uroth. Mol Clin Oncol 2016; 4(6):1063-7
26. McCaffrey J, Hilton S, Mazumdar M et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol 1997; 15(5):1853-7
27. de Wit R, Kruit W, Stoter G et al. Docetaxel (Taxotere): an active agent in metastatic urothelial cancer; results of a phase II study in non-chemotherapy-p. Br J Cancer 1998; 78(10):1342-5
28. Naidoo J, Page D, Li B et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Annal Oncol 2015; 26(12):2375-91
29. Haanen J, Obeid M, Spain L et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annal Oncol 2022; 33(12):1217-38
30. Hoffmann-Centis J, Grivas P, Van der Heijden M et al. IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma. J Clin Oncol 2016; 34(2):1 
31. Balar A, Castellano D, O’Donnell P et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (Keynote-052): a multicentre, single arm, phase 2 study. Lancet 2017; 18(11):1483-92
32. Powles T, Park S, Voog E et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. New Engl J Med 2020; 383(13):1218-30
33. Sridhar SS, Powles T, Gupta S et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): Long-term follow-up from the JAVELIN Bladder 100 trial in subgroups defined by 1L chemotherapy regimen and analysis of overall survival (OS) from start of 1L chemotherapy. J Clin Oncol 2023; 41(6):suppl 5. doi: 10.1200/JCO.2023.41.6_suppl.5
34. Fradet Y, Bellmunt J, Vaughn D et al. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advance. Annal Oncol 2019; 30(6):970-6
35. Powles T, Durán I, van der Heijden M et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma. Lancet 2018; 24(391):748-57
36. Rodler S, Eismann L, Schlenker B et al. Expression of Nectin-4 in variant histologies of bladder cancer and its prognostic value – need for biomarker testing in high-risk patients? Cancers 2022; 14(18):4411 
37. Powles T, Rosenberg J, Sonpavde G et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 2021; 384(12):1125-35
38. Ascione C, Napolitano F, Esposito D et al. Role of FGFR3 in bladder cancer: Treatment landscape and future challenges. Cancer Treat Rev 2023; 115(1):1
39. Subbiah V, Verstovsek S. Clinical development and management of adverse events associated with FGFR inhibitors. Cell Rep Med 2023; 4(10):101204
40. Loriot Y, Matsubara N, Park S et al. Phase 3 THOR study: Results of Erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (FGFRalt). J Clin Oncol 2023; 41(17):1
41. van der Heijden M, Sonpavde G, Powles T et al. (). Nivolumab plus gemcitabine-cisplatin in advanced urothelial carcinoma. N Engl J Med 2023; 389(19):1778-89
42. Powles T, Valderrama B, Gupta S et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med 2024; 390(10):875-88 
43. Loriot Y, Petrylak D, Kalebasty A et al. TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes. Annal Oncol 2024 35(4):392-401