Advancements in bladder cancer care: A closer look at the latest innovations

The management of bladder cancer is evolving rapidly, with a new regimen recently approved for patients with advanced disease

Bladder cancer is the commonest malignancy involving the urinary system. It accounts for 3 per cent of cancer cases worldwide annually, with incidence rates increasing year-on-year. Bladder cancer affects about 490 people in Ireland each year.

Despite chemotherapy and immunotherapy, long-term survival remains poor for patients with advanced bladder cancer and there is an urgent need for innovative treatment combinations to improve survival. 

There was much excitement at last year’s annual European Society for Medical Oncology (ESMO) Congress (Madrid, 20–24 October), when during a dedicated Presidential Symposium, practice-changing results were presented from two phase 3 trials in patients with previously untreated, locally advanced, or unresectable metastatic urothelial carcinoma.

For the first time in decades, people with advanced bladder cancer now have more effective treatment options, supported by large clinical trial data, which have led to recent changes to clinical guidelines.

Disease overview

Bladder cancers are divided into:

1. Urothelial carcinomas (also known as transitional cell carcinomas) (90 per cent) arising from urothelial cells.

2. Squamous cell carcinomas (SCC) (2-to-5 per cent) arising from the squamous cells lining the bladder.

3. Adenocarcinoma, either primary (arising from the urothelium), or secondary (more common).

4. Others: Small cell carcinoma and sarcoma of the bladder .

Risk factors

• Cigarette smoking;

• Obesity;

• Use of opium;

• Occupational carcinogens in metal workers, painters, rubber industry workers, leather workers, textile and electrical workers, miners, cement workers;

• Hair dyes;

• Arsenic;

• Aristolochic acid: Present in Chinese herbs;

• Chronic inflammation of the bladder from prolonged indwelling catheters, bladder calculi, recurrent or chronic bladder infections; 

• Schistosomiasis for SCC.

Clinical features

• Painless haematuria: Most common presenting symptom (85 per cent of cases).

• Pain: Usually due to locally advanced or metastatic tumours.

1. Flank pain: When tumour obstructs the ureter.

2. Suprapubic pain: Due to invasion of perivesical soft tissues and nerves.

3. Bone pain: Due to bone metastases. 

4. Persistent headache: Due to intracranial metastases.

• Voiding symptoms: Due to decrease in bladder capacity, detrusor overactivity, obstruction of bladder neck or urethra.

• Constitutional symptoms: Fatigue, weight loss, and anorexia in advanced/metastatic disease.

Tests

• Urinalysis.

• Cystoscopy: The gold standard for the initial diagnosis and staging of bladder cancer.

• Urine cytology: Used as an adjunct to cystoscopy.

• CT: The preferred imaging modality for all patients with bladder cancer.

• Other imaging modalities: MRI, ultrasound, intravenous pyelogram.

• Imaging studies for metastatic disease: PET, CT of the thorax for evidence of lung lesions, radionuclide bone scans for bone metastases.

Staging is by the TNM classification system.

Treatment

Based on classification of bladder carcinoma:

1. Non-muscle invasive bladder cancer (NMIBC): Confined to the mucosa and submucosa and does not penetrate through the lamina propria into the underlying muscle layer. About 75 per cent of patients have NMIBC at diagnosis.

2. Muscle invasive bladder cancer (MIBC): Penetrates the lamina propria and into the muscle layers of the bladder.

3. Metastatic disease.

For the first time in decades people with advanced bladder cancer now have more effective treatment options, supported by large clinical trial data

NMIBC

A transurethral resection of bladder tumour (TURBT) is initially performed and findings will enable risk stratification, which in turn will determine appropriate management. This risk stratification is based on guidelines from the European Association of Urology (EAU). These guidelines are regularly updated, including this year, to take account of the latest knowledge, clinical trial data, and other relevant information.

A low-risk NMIBC is classified as:

1. No carcinoma in situ (CIS): High-grade intraepithelial neoplasm without invasion into subepithelial connective tissue.

2. Solitary low-grade Ta: Ta tumours are papillary lesions that tend to recur.

3. <3cm.

Intermediate risk: Not meeting criteria for low or high grade.

A high-risk NMIBC is classified as:

1. T1 tumours: Invade the submucosa or lamina propria and are usually high grade.

2. Presence of CIS.

3. Presence of high-grade disease.

4. Other tumours meeting the following criteria: Multiple, recurrent, >3cm, and Ta low grade.

Treatment for low risk: TURBT + single dose of perioperative intravesical chemotherapy (aims to deliver high concentration of a therapeutic agent within the bladder).

Treatment for intermediate risk: Single instillation of intravesical chemotherapy, followed by induction (weekly for six weeks) and then one year of maintenance therapy followed by surveillance.

Treatment for high risk: Such patients need restaging via TURBT in four-to-six weeks. Should there be extensive bladder involvement despite multiple TURBTs, or the presence of squamous cell/adenocarcinoma histology or men with CIS involving prostatic ducts, then radical cystectomy needs to be done. If this is not the case, then intravesical Bacillus Calmette-Guerin therapy, with induction and maintenance for three years, may be required.

All three types of risk disease need appropriate follow-up.

MIBC

Radical cystectomy is the gold standard for localised MIBC (ie T2-4a, N0, M0 disease). Other indications for radical cystectomy include BCG-refractory, BCG-relapsing, and BCG-recurrent NMIBC.

For Stage 2/3 disease, therapeutic options include:

1. Neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy. To be eligible for cisplatin-based chemotherapy, the patient must have Eastern Cooperative Oncology Group (ECOG) performance status <2, creatinine clearance >60ml/min, no significant hearing loss, no New York Heart Association (NYHA) class III or worse heart failure, and Grade <2 neuropathy (referred to as Galsky criteria).

2. Patients not fit enough or not willing to undergo radical cystectomy will receive the trimodality therapy for bladder preservation including TURBT, radiation therapy, and concurrent chemotherapy.

3. Patients who are fit enough for radical cystectomy, but fail eligibility criteria for cisplatin-based chemotherapy undergo radical cystectomy followed by bladder-preserving trimodality therapy.

High-risk disease at cystectomy includes patients with:

1. No prior neoadjuvant chemotherapy and pT3-T4a and/or node positive disease. This group can receive cisplatin-based chemotherapy if eligible including gemcitabine-cisplatin or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin.

2. Prior neoadjuvant cisplatin-based chemotherapy with pathologic yp T2-T4a and/or node-positive disease. This group along with cisplatin-ineligible patients are treated with adjuvant immunotherapy including nivolumab or pembrolizumab.

Metastatic disease

For decades, first-line treatment for locally advanced or metastatic urothelial carcinoma (la/mUC) has been platinum-based chemotherapy, with very low five-year survival rates. Recently, maintenance therapy with avelumab has resulted in longer overall survival (OS) compared to the best supportive care. However, a significant number of patients do not receive it in view of disease progression/death.

In recent studies, two new therapies have shown a significant survival benefit in patients with previously treated la/mUC. These include:

1. Enfortumab vedotin (EV), an antibody-drug conjugate directed against nectin-4.

2. Pembrolizumab, a programmed death 1 (PD-1)
inhibitor.

Moreover, a combination of these two drugs has demonstrated improved anti-tumour activity with lasting anti-tumour immunity, suggesting complementary mechanisms of action. In the US, these two drugs have been approved for patients who have la/mUC where a high response rate was noticed.

As recognised in the latest ESMO Clinical Practice Guidelines, two recent clinical trials assessing first-line treatment for advanced urothelial carcinoma of the bladder (UCB) with these agents/approaches have shown very promising results.

EV-302/KEYNOTE-A39 trial

In this trial (Powles et al, 2024), the safety and efficacy of EV and pembrolizumab (EV-P) were compared to that of platinum-based chemotherapy for patients with previously untreated la/mUC.

This trial involved 886 patients who were randomly distributed into two groups. 1:1 to receive three-week cycles of EV (1.25mg/kg; IV) on days one and eight and P (200mg; IV) on day one, or gemcitabine with cisplatin or carboplatin (EV+P: 442; chemo: 444).

Dual primary endpoints were progression free survival (PFS) and OS. Select secondary endpoints included overall response rate (ORR) and safety.

It is important to note that, where and when available, maintenance therapy was allowed in the chemotherapy group.

The demographic and clinical features of patients in both groups at baseline were overall well balanced. The median number of cycles was 12 (range, one-to-46) in the EV-P group and six (range, one-to-six) in the chemotherapy group.

The EV-P regimen achieved a better PFS and OS in patients compared to chemotherapy, along with a lower risk of death. Moreover, the response rate was higher with the EV-P regimen compared to chemotherapy. PFS [median, 12.5 vs 6.3 months; HR for disease progression or death, 0.45; 95% CI, 0.38-0.54; P<0.001], OS [median, 31.5 vs 16.1 months; HR for death, 0.47; 95% CI, 0.38-0.58; P<0.001].

Treatment-related adverse events of grade 3 or higher occurred in 55.9 per cent of the patients in the EV-P group and in 69.5 per cent of those in the chemotherapy group.

Overall, this trial showed a significant survival benefit of EV-P compared to chemotherapy in patients with previously untreated la/mUC. Survival benefits of EV-P were superior compared to platinum-based chemotherapy in the first-line treatment of la/mUC, both among patients who received cisplatin and those who received carboplatin. Moreover, the combination of EV-P was associated with a lower incidence of radiologic progression of primary disease compared to chemotherapy. Commenting on these findings during the ESMO 2023 Congress, Dr Andrea Apolo from the National Institutes of Health, Bethesda, US, said: “The results of this study have been long awaited as for more than two decades, platinum-based chemotherapy has been the standard of care and it is very exciting that we have now identified a combination of treatments that is superior to chemotherapy in terms of OS.”

CheckMate 901 trial

The CheckMate 901 study is the first phase 3 trial showing a beneficial impact of an upfront combination of chemotherapy plus immunotherapy. Nivolumab, an antibody directed against PD-1, is approved for the management of patients with la/mUC after platinum-based chemotherapy. It is also authorised as monotherapy for the adjuvant treatment of adults with MIBC with tumour cell PD-L1 expression ≥1 per cent, who are at high risk of recurrence after undergoing radical resection of MIBC. In the CheckMate 901 trial (van der Heijden et al, 2023), the effectiveness of nivolumab plus gemcitabine-cisplatin (NGC) was compared to gemcitabine-cisplatin (GC) alone in patients with previously untreated unresectable or metastatic UCB.

Inclusion criteria included:

1. Age ≥18 years with histologically confirmed unresectable or metastatic UCB.

2. ECOG performance status score of zero or one.

3. Eligibility to receive cisplatin therapy.

4. Patients with previous neoadjuvant therapy, radiation or adjuvant platinum-based chemotherapy with recurrence 12 months or more after completion of therapy.

5. Patients who had completed intravesical therapy at least four weeks before the start of the trial treatments.

Patients who had received systemic chemotherapy for unresectable or MUC were not permitted entry into this trial.

This trial is divided into two parts. In this article, we will focus on the first part as the second part is still ongoing. In the first part of the trial, patients were divided into two groups, one group to receive NGC, and the other GC alone. The NGC group received intravenous nivolumab at a dose of 360mg in combination with GC every three weeks for up to six cycles, followed by nivolumab at a dose of 480mg every four weeks, until disease progression, severe side-effects, withdrawal of consent, or up to a maximum of two years. The second group received GC alone every three weeks for up to six cycles.

At a median follow-up of 33.6 months, OS [HR for death, 0.78; 95% CI, 0.63-0.96; P=0.02] and PFS [HR for progression or death, 0.72; 95% CI, 0.59–0.88; P=0.001] were longer and complete response was double in the NGC group compared to the GC one (21.7 vs 11.8 per cent).

The median duration of complete response was 37.1 months with NGC and 13.2 months with GC alone. Grade 3 or higher adverse events occurred in 61.8 per cent and 51.7 per cent of the patients, respectively.

Based on the CheckMate 901 trial, the combination of NGC leads to durable responses and improved survival in patients with previously untreated unresectable or MUC.

“This is the first study to show an improvement in OS using a combination of chemotherapy and immunotherapy in patients with metastatic bladder cancer,” commented Dr Apolo during the ESMO 2023 Congress. “This is highly encouraging given that previous phase 3 studies of checkpoint immunotherapy in this disease (atezolizumab in IMvigor130 and pembrolizumab in KEYNOTE-361) failed to show a statistical improvement in OS. It is interesting to note that patients in CheckMate 901 all received cisplatin whereas patients in IMvigor130 and KEYNOTE-361 received either carboplatin or cisplatin. It may therefore be that advanced bladder cancer is particularly sensitive to the specific combination of nivolumab and cisplatin.”

The two discussed studies are highly significant for patients as they are the first trials to challenge the longstanding standard of first-line platinum-based chemotherapy for patients with advanced/metastatic urothelial carcinoma. “The data for enfortumab vedotin and pembrolizumab are particularly impressive and this combination will clearly become the new standard of cancer care for this cohort of patients,” stated Dr Apolo.

“The field of urothelial carcinoma is evolving and it is fantastic news that we can now improve survival for our patients. Multiple clinical trials are ongoing, such as the phase 3 NILE study that is investigating durvalumab plus chemotherapy versus durvalumab with tremelimumab plus chemotherapy versus chemotherapy alone (NCT03682068), and we are eagerly awaiting their results.”

Treatment for metastatic disease-guideline updates

Earlier this year ESMO issued a Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma, which addresses the latest developments and includes an updated algorithm for managing treatment-naive advanced or metastatic urothelial carcinoma (UC; stage IV).

First-line therapy

1. EV-P: For patients with metastatic UCB.

2. If EV unavailable or contraindicated (patients with uncontrolled diabetes, peripheral neuropathy grade ≥2 and pre-existing significant skin disorders) and patients are eligible for both cisplatin or carboplatin, then platinum-containing chemotherapy (cisplatin or carboplatin with gemcitabine) followed by maintenance treatment with avelumab in patients with no disease progression is recommended.

3. If EV unavailable or contraindicated and patients are eligible for cisplatin only, then cisplatin/gemcitabine in combination with nivolumab is recommended as per the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP). On 25 April 2024, the CHMP adopted a positive opinion, recommending a change to the terms of the marketing authorisation for nivolumab.

Second-line therapy

If disease progression after EV-P:

1. Cisplatin or carboplatin with gemcitabine is recommended.

2. Erdafitinib is recommended in tumours with FGFR2/3 genetic alterations.

3. Sacituzumab govitecan.

If disease progression after cisplatin/carboplatin +
gemcitabine:

1. Pembrolizumab or atezolizumab.

If disease progression after NGC or cisplatin/carboplatin + gemcitabine with other agents:

1. Erdafitinib in tumours with FGFR2/3 genetic alterations.

2. EV.

3. Sacituzumab govitecan.

4. To consider single chemotherapy such as vinflunine or paclitaxel.

Finally, should the disease still progress, the patient can be offered to participate in new clinical trials. If unfit or not willing to do so, best supportive care should be offered.

The latest HSE/NCCP-approved (reimbursed) treatment regimens for bladder cancer in Ireland are available at: www.hse.ie/eng/services/list/5/cancer/profinfo/chemoprotocols/genitourinary/#Bladder%20Cancer
%20Regimens.

Future

Optimal treatment duration and managing treatment related toxicities are issues that need to be further addressed with the latest therapies.

It looks like there  will soon be more progress in other areas of bladder cancer treatment, with ongoing studies looking at biomarkers – circulating tumor DNA (ctDNA) is emerging as a promising biomarker to identify patients who need perioperative systemic therapy after radical surgery for urothelial carcinoma, and bladder-sparing treatment approaches are being evaluated to improve outcomes and quality-of-life for patients with MIBC, as discussed at this year’s American Society for Clinical Oncology (ASCO) Annual Meeting in Chicago in June.

Guidelines and trial data references

EAU Bladder Cancer Guidelines. 2024 Available at: https://uroweb.org/guidelines.

Powles T, Bellmunt J, Comperat E, et al; on behalf of the ESMO Guidelines Committee. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. Ann Oncol. 2024;35(6):485-490

van der Heijden MS, Sonpavde G, Powles T, et al; CheckMate 901 Trial Investigators. Nivolumab plus gemcitabine-cisplatin in advanced urothelial carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789 

Powles T, Valderrama BP, Gupta S, et al; EV-302 Trial Investigators. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024 Mar 7;390(10):875-888

Full references on request