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Emerging Frontiers in Advanced Bladder Cancer: Paradigm Shifts in Diagnosis and Treatment

Thank you for visiting UroToday’s Center of Excellence for Advanced Bladder Cancer (aUC). I am delighted to serve as its new editor. This Center of Excellence curates evergreen content on emerging diagnostic and treatment information in a rapidly changing field. Locally advanced and metastatic urothelial cancer (aUC) is an aggressive disease, with estimated 5-year survival being only around 8%.1 We have seen tremendous advances in recent years, including the approval of immunotherapies, targeted therapies, and antibody-drug conjugates which can significantly extend survival and improve quality of life for patients with aUC. While platinum-based chemotherapy was the standard of care for over four decades, we have now seen a paradigm shift with novel therapies for the first-line treatment of patients with aUC. In this editorial, I discuss some of the most noteworthy updates on aUC presented at ASCO 2024 (held May 31—June 4 in Chicago) and ASCO GU (held January 25—27 in San Francisco).

Updates from EV 302: EV 302 is a global, open-label, randomized phase 3 trial in which 1L dual therapy with enfortumab vedotin (EV) plus the PD-1 inhibitor pembrolizumab (P) significantly improved progression-free survival (PFS) and OS compared with standard platinum-based chemotherapy in patients with aUC. Topline results, which were published in March 2024 in the New England Journal of Medicine, included a more than 50% reduction in risk of disease progression or death in the EV-P arm compared with platinum-based chemotherapy.2 EV-P was associated with a near-doubling of median OS (31.5 months vs 16.1 months with platinum-based chemotherapy). The OS benefit extended to all subgroups of patients, including patients who were cisplatin-ineligible and those with clinical characteristics historically associated with poor treatment response, including visceral metastases and compromised renal function.3

Patient-reported outcomes (PROs) provide a key window into the patient journey, showing us the impact of treatment on patients’ physical, cognitive, and social functioning, pain, and quality of life. At ASCO 2024, we reported on PROs from EV 302, which were assessed with the EORTC Quality of Life Questionnaire and the Brief Pain Inventory (BPI) Short Form completed at baseline, weekly for 12 weeks, and every 3 weeks thereafter, including after disease progression.4 Compared with platinum-based chemotherapy, EV-P was associated with greater improvements in pain and preserved quality of life through 26 weeks of follow-up in the EV 302 trial. Of note, EV-P recipients who had moderate to severe pain at baseline reported a more than two-point improvement in BPI between weeks 3 and 26. Furthermore, while quality of life deteriorated in the chemotherapy arm, it worsened only transiently in the EV-P arm before returning to baseline. Taken together, these data suggest that 1L EV-P not only extends OS but also helps preserve quality of life in patients with aUC, and that it significantly outperforms platinum-based chemotherapy on relevant PRO measures.

At ASCO 2024, researchers also reported the results of a subgroup analysis of 478 patients from EV 302 who were classified as platinum-eligible at randomization. Dual-therapy EV-P reduced estimated risk of death by 47% compared with platinum-based chemotherapy, consistent with findings for the overall study population. Safety findings also were consistent, and no new safety signals were identified.

These data provide robust support for 1L EV-P for treating aUC, including in cisplatin-eligible patients. Based on these data, the National Comprehensive Cancer Network (NCCN) now recommends EV-P as the preferred (category 1) 1L treatment for patients with aUC, regardless of cisplatin eligibility.5 Likewise, the European Society for Medical Oncology (ESMO) regards EV-P as the new standard of care in 1L aUC, and recommends that other regimens, including nivolumab-cisplatin-gemcitabine and platinum-based chemotherapy plus maintenance avelumab, be used only if EV-P is not an option.6

Updates from JAVELIN Bladder 100: Professional societies recommend 1L maintenance therapy with the PD-L1 inhibitor avelumab as an option for patients whose aUC has not progressed after receiving 1L platinum-based chemotherapy.5-7 This recommendation is based on the results of the global phase 3 JAVELIN Bladder 100 trial, in which the addition of 1L avelumab maintenance therapy to best supportive care until disease progression or toxicity significantly improved OS and PFS compared with best supportive care only.8 During a poster session at ASCO 2024, we learned that avelumab’s survival benefits extended to patients with low tumor burden (i.e., nonvisceral metastases or lymph-node only disease prior to 1L treatment).9 Median OS was prolonged by nearly 14 months in patients with visceral metastases, and by more than 9 months in patients with node-only disease. No new safety signals were detected, although grade >3 adverse events were reported in 19% of avelumab recipients compared with no patients in the BSC-only arm. Note that avelumab and all other immune checkpoint inhibitors can cause immune-related adverse events (irAEs), and thus their use requires careful patient education, monitoring, and treatment adjustment/cessation/referral if irAE severity exceeds grade 1-2.

In more than 20% of UCs, some aspect of tumor morphology is non-urothelial.10 Variant-histology UCs are diverse, underdiagnosed, tend to be aggressive, and show variable responses to systemic chemotherapy. There are no specific treatment guidelines for these tumors, making them an important area of unmet need. At ASCO 2024, we learned that in a post hoc analysis of long-term outcomes from JAVELIN Bladder 100 (median follow-up >38 months), patients with predominant UC mixed with a <50% histological subtype component experienced similar efficacy and safety outcomes to 1L post-platinum maintenance avelumab as the overall study population.11 These findings are consistent with a subgroup analysis of data from AVENANCE, a real-world study of 1L maintenance avelumab in patients with aUC in France.12

More research on variant histology UC is needed, including studies where outcomes in these patients are predefined. Prior translational work has shown that variant histology aUC commonly expresses Nectin 4. Based on this premise, researchers are currently enrolling a phase 2 study of doublet therapy with the Nectin 4-targeting antibody drug conjugate EV plus P for the 1L treatment of variant histology aUC (NCT05756569).13

At ASCO GU 2024, JAVELIN Bladder 100 researchers reported that in exploratory analyses, patients who received >12 months 1L maintenance avelumab had stable PROs indicative of preserved health-related quality of life.14 Treatment-emergent side effects, physical and emotional symptoms related to disease, overall functioning/well-being, the EQ-5D-5L index (a commonly used measure of health status), and the NCCN Functional Assessment of Cancer Therapy Bladder Cancer Symptom Index-18 (FBISI-18) all were assessed. Patients who received >12 months nivolumab were actually followed for a median of 38 months; not surprisingly, they tended to have a better baseline ECOG status and lower baseline prevalence of visceral metastases. However, they otherwise resembled the overall avelumab arm of the trial.

Although PROs were secondary endpoints in JAVELIN Bladder 100, improvements in multiple PROs measures and across multiple time points are promising. Previously, JAVELIN Bladder 100 investigators reported favorable short-term PROs, positive ad hoc safety data, and prolonged quality-adjusted time without symptoms of disease or toxicity (Q-TWiST)a with post-platinum avelumab plus best supportive care compared with best supportive care alone.15 Note that the Q-TWIST measure integrates safety, efficacy, and PROs into a single variable, reflecting the high priority that most patients place on quality of life as well as efficacy of cancer treatment.

Updates from CheckMate 901: In the global, open-label, randomized phase 3 CheckMate 901 trial, fixed-duration (up to 6 cycles) 1L gemcitabine-cisplatin plus up to two years maintenance therapy with the PD-1 inhibitor nivolumab significantly improved the co-primary endpoints of OS and PFS as well as the objective response rate (ORR) and duration of complete response (CR) to treatment when compared with gemcitabine-cisplatin alone. These findings were published in 2023 in the New England Journal of Medicine.16 Perhaps not surprisingly, CRs in both arms were most frequent among patients with node-only disease. At ASCO 2024, researchers reported results from a post hoc analysis of 110 patients from CheckMate 901 whose aUC had not spread beyond the pelvic, retroperitoneal, or distant lymph nodes.17 This subgroup experienced deep responses to up to two years of maintenance nivolumab, including an ORR and a CR of approximately 81% and 63%, respectively, compared with approximately 64% and 34%, respectively, among patients who received gemcitabine-cisplatin alone. Gemcitabine-cisplatin plus nivolumab was associated with an estimated 42% reduction in risk of death compared with gemcitabine-cisplatin alone, and while absolute numbers were small, quite a few nivolumab recipients were able to remain off all oncolytic therapies for reasonable periods of time. These data suggest that even though patients with node-only aUC tend to respond better to treatment in general, maintenance nivolumab can meaningfully improve depth of response and duration of survival compared with cisplatin-based chemotherapy alone. As expected, immunotherapy did not worsen chemotherapy side effects, although irAEs were seen in the nivolumab arm. Based on the data reported, the benefits of maintenance nivolumab in patients with node-only aUC appear to outweigh its risks when used in appropriately chosen individuals.

Treatment decisions and “fitness” for platinum-based chemotherapy: At ASCO 2024, we reported results from an online survey of 503 physicians who treat aUC in five European countries.18 In all, 69% of respondents were oncologists and 31% were urologists. Respondents reported not prescribing 1L therapy for 25% of their patients. The most commonly reported reasons were advanced patient age (62% of respondents) and poor performance status (54.7%), followed by patient refusal (45.9%) and poor kidney function (43.1%). These data help contextualize other real-world studies documenting widespread undertreatment of aUC despite guideline recommendations. Not offering treatment solely because age exceeds a predefined threshold can lead to inappropriate exclusion of patients from life-extending treatment. In reality, older adults with aUC are a heterogenous group, and overall health and performance status are better predicators of treatment tolerance than chronologic age. Whenever possible, a comprehensive geriatric assessment (GA) should be performed to guide and individualize cancer treatment decisions in older adults.19 This assessment should include physical and cognitive function, emotional health, comorbid conditions, polypharmacy, nutrition, and social support, all of which can predict cancer treatment outcomes. Adjusting treatment based on the results of a comprehensive geriatric assessment has been shown to improve survival, reduce grade >3 toxicities and falls, improve health-related quality of life, reduce unplanned hospitalizations, and help prevent early treatment discontinuation in patients with cancer.20-22 For adults aged >65 years, a GA prior to cancer treatment is recommended by ASCO, NCCN, and the International Society of Geriatric Oncology.5,23-25 ASCO’s Practical Geriatric Assessment is one GA tool, available here.26

It is relevant to note here that cisplatin ineligibility in patients with aUC has been objectively defined by Galsky and colleagues as ECOG performance status ≥2, creatinine clearance <60 mL/min, ≥grade 2 hearing loss, ≥grade 2 neuropathy, and/or NYHA Class III heart failure;27 Recently, we provided a consensus definition for platinum ineligibility by surveying 60 physicians who treat aUC. Based on the responses, we defined platinum-ineligibility as one of the following: ECOG performance status ≥3, creatinine clearance <30 ml/min, ≥grade 2 peripheral neuropathy, and/or NYHA Class III heart failure.28

Conclusions and future directions

The aUC treatment landscape continues to expand at a rapid pace, and there are many novel agents on the horizon. Ongoing trials are exploring strategies such as combining a PD-1 pathway inhibitor with another therapy, such as a tyrosine kinase inhibitor (TKI), MET inhibitor, or another immunotherapy. For example, the phase 2 JAVELIN Bladder Medley trial is evaluating avelumab plus either sacituzumab govitecan (an anti-Trop-2/topoisomerase inhibitor conjugate), M6223 (which inhibits TIGIT, an inhibitory receptor expressed on regulatory T cells and natural killer cells), or NKTR-255 (a recombinant human IL-15).29 Also, the phase 3 MAIN-CAV trial compares maintenance therapy with avelumab plus the TKI cabozantinib with maintenance avelumab alone after first-line platinum-based chemotherapy.30 Currently, EV-P should be regarded as the new 1L standard of care for treating aUC based on the results of EV 302. Studies of biomarkers to identify suitability for EV-P and optimal treatment duration will be important, particularly given the costs of these therapies. It is imperative to provide access to this regimen globally and make it affordable. Furthermore, clinical trials must continue to integrate comprehensive, predefined PRO assessments to ensure that the survival benefits of new aUC therapies are accompanied by meaningful improvements in quality of life.

Written by: Shilpa Gupta, MD, 

References

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  28. Gupta S, Bellmunt J, Plimack ER, et al.Defining “platinum-ineligible” patients with metastatic urothelial cancer (mUC). J Clin Oncol. 2022;2432-2438. doi: 10.1200/JCO.2011.34.8433
  29. Hoffman-Censits J, Grivas P, Powles T, et al. The JAVELIN Bladder Medley trial: avelumab-based combinations as first-line maintenance in advanced urothelial carcinoma. Future Oncol. 2024;20(4):179-190. doi: 10.2217/fon-2023-0492
  30. Gupta S, Ballman KV, Apolo AB, et al. MAIN-CAV: Phase III randomized trial of maintenance cabozantinib (CABO) and avelumab (Av) vs Av after first-line platinum-based chemotherapy in patients (pts) with metastatic urothelial cancer (mUC; Alliance A032001). J Clin Oncol. 2022;42(4_suppl): TPS714- TPS714. doi: 0.1200/JCO.2024.42.4_suppl.TPS714