A New Era in Bladder Cancer Research: Breakthroughs and Insights From 2023

Bladder cancer management is a landscape that continues to see significant changes, and those changes will hopefully be associated with better patient survival and the prevention of bladder cancer-associated morbidities. Approximately 40 clinical trials related to bladder cancer were published at the end of 2022 and throughout 2023, a number that highlights the progress being made in the field.

Immunotherapeutic Agents

To kick things off, 5-year results on the efficacy and safety of pembrolizumab for metastatic urothelial carcinoma (UC) in patients initially enrolled in the KEYNOTE-045 and KEYNOTE-052 trials were released in December 2022.¹ Immune checkpoint inhibitors are a first-line option for patients who are ineligible for or failed platinum-containing chemotherapy. KEYNOTE-045 demonstrated longer-term responses and the favorable overall survival (OS) of pembrolizumab compared with docetaxel, paclitaxel, or vinflunine chemotherapy.² OS was longer for the pembrolizumab cohort compared with the chemotherapy cohort (10.1 months vs 7.2 months, respectively), with better OS at 36 and 48 months. This trend was also seen for progression-free survival (PFS; 9.5% vs 2.7%, respectively, at 48 months). KEYNOTE-052 demonstrated a confirmed objective response rate (ORR) of 28.6% and a median duration of response of 30.1 months for patients with metastatic UC who were cisplatin ineligible.³ Participants also demonstrated durable responses and tolerability, with no new safety signals.

BAYOU

The BAYOU randomized trial investigated the use of durvalumab, an anti-PD-L1 agent, plus olaparib, a PARP inhibitor, compared with durvalumab and placebo for patients with metastatic UC.⁴ The basis for this study, which included 154 patients, was that homologous recombination repair gene mutations are common in UC and may respond to a PARP inhibitor. The study authors did not find a benefit to PFS with the addition of olaparib over placebo.

JAVELIN Bladder 100

Published in 2020, the phase 3 JAVELIN Bladder 100 trial investigated avelumab as first-line maintenance with best supportive care in patients with advanced UC and found that it improved OS compared with best supportive care alone.⁵ These patients had received first-line gemcitabine plus cisplatin or carboplatin and had not progressed prior to starting avelumab, an anti-PD-L1 immune checkpoint inhibitor. A study published in the Journal of Clinical Oncology analyzed the clinical trial updates after 2 or more years of follow-up data.⁶ Median follow-up was 38.0 and 39.6 months, respectively, for the avelumab and control arms. OS was 23.8 months compared with 15.0 months and favored avelumab across all subgroups. Median PFS was 5.5 months in the avelumab cohort compared with 2.1 months in the control group, and the 2-year PFS rate was 23.4% and 7.1%, respectively. A total of 98.3% of patients in the avelumab cohort developed an adverse event (AE), and 53.8% of AEs were grade 3 or higher. The authors concluded that these results “further support the recommendation of avelumab [first-line] maintenance as standard of care for patients with advanced urothelial carcinoma that has not progressed with [first-line] platinum-containing chemotherapy, with level 1 evidence.”

Several papers investigating the subgroup analyses of the JAVELIN Bladder 100 cohort were published in 2023 and found that the results were consistent across subgroups,⁷ including in the Asian population that was included in the study.⁸ In another JAVELIN Bladder 100-related paper, researchers analyzed the patient-reported outcomes of trial participants and found improved survival was not compromised by diminishing quality of life.⁹

TITAN-TCC

TITAN-TCC, a multicenter, single-arm, phase 2 trial conducted in Europe, investigated the use of nivolumab with or without ipilimumab in patients with advanced UC with evidence of progression despite having received platinum-based chemotherapy.¹⁰ Nivolumab is a PD-1 inhibitor that has been approved as a second-line treatment for metastatic UC based on results of the CheckMate-275 trial.¹¹

Dual checkpoint inhibitor-containing therapy has been studied in several malignancies, including UC. Nivolumab plus ipilimumab was investigated in CheckMate-032, which found that the combination therapy led to longer median OS, though it also had a higher rate of serious AEs.¹² While previous investigations of the TITAN-TCC trial population found a 45% ORR, the authors of CheckMate-032 aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost. The treatment regimen involved a complex administration, including maintenance and boost regimens. The study initially enrolled 83 patients, and 44 received the combination immunotherapeutic regimen. The ORR was 33%, and 7% of patients had a complete response. The most common serious AEs were enterocolitis and diarrhea, and investigators reported 2 treatment-related deaths secondary to enterocolitis. The authors concluded that their regimen of nivolumab and nivolumab plus ipilimumab “significantly improved the objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial.” They noted the regimen can be considered a potential “rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma.”

MORPHEUS-UC

The MORPHEUS-UC trial results were published in 2023 and found that for patients with locally advanced or metastatic UC who progressed after platinum-based chemotherapy, there was little difference between immunotherapy protocols.¹³ A total of 76 patients were randomized to atezolizumab plus magrolimab (n=16), atezolizumab plus niraparib (n=15), atezolizumab plus tocilizumab (n=15), or atezolizumab monotherapy (n=30), which was the control.

CHECKMATE 901

One of the 2 trials on bladder cancer published in the New England Journal of Medicine in 2023 analyzed results of the CheckMate 901 study on the addition of the anti-PD-1 agent nivolumab to gemcitabine-cisplatin for patients with advanced UC.¹⁴ Before CheckMate 901, nivolumab was approved for use in patients who had received prior platinum-based chemotherapy. In the first part of the 2-part, phase 3, multinational, randomized trial, patients were assigned to either intravenous nivolumab plus gemcitabine-cisplatin every 3 weeks for up to 6 cycles, followed by nivolumab every 4 weeks for a maximum of 2 years, or gemcitabine-cisplatin alone every 3 weeks for up to 6 cycles. The second part of the trial assigned patients to either nivolumab plus ipilimumab or platinum-based chemotherapy.

A total of 608 patients were randomized, 304 to receive nivolumab plus gemcitabine-cisplatin and 304 to receive gemcitabine-cisplatin alone. In the combination cohort, 74.0% of patients received complete treatment compared with 54.5% of those in the gemcitabine-cisplatin cohort. Approximately 15% of patients in both cohorts received carboplatin instead of cisplatin. Median follow-up was 33.6 months, and median OS was 21.7 months in the combination cohort compared with 18.9 months in the gemcitabine-cisplatin cohort (hazard ratio [HR], 0.78; 95% CI, 0.63-0.96; P=.02). OS was 70.2% at 12 months and 47.0% at 24 months in the combination cohort compared with 62.7% at 12 months and 40.7% at 24 months in the gemcitabine-cisplatin cohort. PFS was also improved in the combination cohort (HR, 0.72; 95% CI, 0.59-0.88; P=.001). Median PFS was 7.9 months and 7.6 months in the combination and gemcitabine-cisplatin cohorts, respectively. In the combination cohort, PFS was 34.2% at 12 months and 23.5% at 24 months compared with 21.8% at 12 months and 9.6% at 24 months in the gemcitabine-cisplatin cohort. These results were confirmed across subgroup analyses and when patients were stratified based on PD-L1 expression of 1% or more. A similar overall rate of treatment-related AEs (trAEs) was appreciated in both cohorts, although the rate was higher for the combination cohort when AEs were deemed to be related to trial treatment.

Chemotherapeutic Agents

A phase 3 trial investigated the use of soluble EphB4-human serum album (sEphB4-HAS) in combination with pembrolizumab for patients with metastatic UC who had been previously treated with platinum-based chemotherapy and had evidence of disease recurrence or progression.¹⁵ The study included 70 patients divided into 2 cohorts based on whether they had received just 1 prior platinum-based chemotherapy or an additional systemic chemotherapy. After a median follow-up period of approximately 23.0 months, the regimen had acceptable toxicity and a median OS of 14.6 months, leading the investigators to conclude that “the combination of sEphB4-HAS and pembrolizumab appeared synergistic, with improved overall survival and objective response rate compared with historical data for PD-1/PD-L1 monotherapy.”

A study published in the Journal of Clinical Oncology investigated the use of rucaparib compared with placebo in patients with metastatic UC who were DNA repair deficiency biomarker positive.¹⁶ This small randomized, controlled trial included 40 patients who were randomized to either rucaparib or placebo after being treated with 10 weeks of chemotherapy with no evidence of progression. The authors reported a PFS of 60% and 100% in patients managed with rucaparib and placebo, respectively, during the follow-up period. Median PFS was 35.3 weeks in the rucaparib arm and 15.1 weeks in the placebo arm. trAEs included fatigue (63.2%), nausea (36.8%), rash (21.1%), and elevated alanine aminotransferase (57.9%).

Studies targeting HER2 for metastatic UC have been limited, but HER2 has been targeted in other solid tumors, including breast cancer. Authors of a phase 2 study aimed to investigate the use of a trastuzumab biosimilar in combination with paclitaxel for patients with recurrent or metastatic UC who were HER2 positive.¹⁷ They evaluated its efficacy in a cohort of 27 patients, and 26 were evaluated for treatment response. The ORR was 48.1%. Only 1 patient had a complete response, 44.4% had a partial response, 37.0% had stable disease, and 11.1% had disease progression. Response duration was approximately 7 months. At a median of 10.5 months, PFS and OS were 8.4% and 13.5%, respectively. The most common trAE was peripheral neuropathy (approximately 90.0%), and the most common grade 3 or 4 AEs were neutropenia (approximately 6.0%), thrombocytopenia (7.4%), and anemia (7.4%). This important study highlights the need for precision medicine in the management of UC.

Meet-URO12

Meet-URO12, a randomized, multicenter, open-label, phase II trial, investigated the use of niraparib, a PARP inhibitor, in addition to best supportive care versus best supportive care alone for patients with metastatic UC who had been treated with platinum-based chemotherapy and showed no evidence of progression.¹⁸ A total of 58 patents were randomized to the 2 cohorts. While the study had limitations and stopped early recruitment secondary to avelumab becoming approved for maintenance therapy, the results showed no added benefit to adding niraparib to best supportive care.

FORT-1

The phase 2/3 randomized FORT-1 trial investigated the use of rogaratinib, an oral FGFR1-4 inhibitor, compared with a chemotherapy regimen containing docetaxel, paclitaxel, or vinflunine for patients who were FGFR1/3 mRNA positive with locally advanced or metastatic UC who had been on a prior platinum-containing regimen.¹⁹ Results showed relatively similar efficacy, with ORRs of 20.7% and 19.3%, respectively, and a median OS of 8.3 months and 9.8 months, respectively. The incidence of grade 3 and 4 AEs was 43.0%/4.7% for the rogaratinib cohort and 39.0%/18.3% for the chemotherapy cohort.

THOR

The New England Journal of Medicine published results of the THOR trial in 2023. In cohort 1 of the randomized, international, multicenter trial, researchers analyzed the utilization of erdafitinib for patients who had FGFR3/2 alterations that made them susceptible to UC.²⁰ Patients included in this trial had locally advanced or metastatic UC and had progressed after platinum-containing therapy and immunotherapy with an anti-PD-1 or anti-PD-L1 agent. A total of 266 patients were randomized to a 21-day cycle of oral erdafitinib (n=136) or investigator’s choice of chemotherapy (n=130). Median duration of follow-up for survival was approximately 16 months, and follow-up was a few months longer in the erdafitinib arm. Similar rates of death were found in both cohorts. However, median OS was 12.1 months in the erdafitinib cohort compared with 7.8 months in the chemotherapy cohort (HR, 0.64; 95% CI, 41-60). Significantly more patients were alive at 6 and 12 months in the erdafitinib cohort compared with the chemotherapy cohort (6 months, 85% vs 66% and 12 months, 51% vs 38%). PFS was 5.6 and 2.7 months, respectively, in the erdafitinib and chemotherapy cohorts. A total of 6.6% of patients in the erdafitinib cohort had a complete response, while only 1 patient had a complete response in the chemotherapy cohort. Rates of trAEs were similar between the 2 groups; however, death related to treatment was lower in the erdafitinib cohort (0.7% vs 5.4%).

Monoclonal Antibody Antineoplastic Agents

EV-301

Enfortumab vedotin (EV) is an antibody-drug conjugate with a human monoclonal antibody that targets Nectin-4 and monomethyl auristatin E. The EV-301 trial that was published in 2021 investigated EV for patients with previously treated locally advanced or metastatic UC and found a clinically significant OS benefit compared with standard chemotherapy (eg, docetaxel, paclitaxel, or vinflunine).²¹ This finding led to the US Food and Drug Administration approval of the drug for patients with locally advanced or metastatic UC who had previously received a PD-1/PD-L1 inhibitor and platinum-based chemotherapy.

Several studies investigating subgroup analyses showing a consistent response to EV, including in the Japanese population, were published in 2023.²² The 2-year follow-up data from EV-301 were also published in 2023.²³ Of the 608 patients who were randomized to EV (n=301) or chemotherapy (n=307), at a median follow-up period of nearly 24 months there were fewer deaths in the EV arm (68.8% vs 77.2%), meaning a 30% reduction in risk of death. An improved PFS was also appreciated. Overall, trAEs were similar between the 2 cohorts. There were higher rates of decreased neutrophil counts, anemia, maculopapular rash, and peripheral sensory neuropathy in the EV cohort, and skin reactions, peripheral neuropathy, and hyperglycemia were more common in those patients. The authors concluded that “EV maintained a clinically meaningful overall survival benefit versus chemotherapy, consistent with findings from the EV-301 primary analysis…adverse events were manageable, and no new safety signals were observed.”

A Look Back and Future Horizons

 The year 2023 was a momentous one in regard to the way we think about and treat advanced UC. Trials such as CheckMate 901 and JAVELIN Bladder 100 improved our understanding of the role of immunotherapy in this patient population. FORT-1, THOR, and other trials continue to advance the conceptualization of precision medicine, and it will be critical to identify cancer-related factors that respond to specific agents and improve outcomes while minimizing trAEs. The EV-301 trial and research published this year on the use of EV are revolutionizing the treatment armamentarium to include agents that were not previously considered for advanced UC. We must continue to invest in bladder cancer research and improve outcomes for our patients.

David Ambinder, MD is a urology resident at New York Medical College/Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

References

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