New Therapies Set Stage for Dramatic Changes in Bladder Cancer

Matthew Galsky, MD

The vast majority of patients with urothelial cancer of the bladder present with non—muscleinvasive disease, and a large proportion can be effectively managed with transurethral resections with or without intravesical medication. However, once the disease invades the bladder’s muscle layer, the risk of metastatic dissemination increases, prompting a need for more intensive treatment.

Surgery or radiation can be curative for localized muscle-invasive disease. However, approximately 50% of patients will develop metastatic recurrence and approximately 5% of patients present de novo with metastatic disease. Therefore, the field’s major efforts over the past decade have focused on improving systemic treatment either as a primary treatment for patients with evidence of metastatic disease or as a combination therapy, integrated with surgery or radiation for localized disease.

In the early 2000s, practice-changing approaches in localized disease were realized, building on decades of past investigation. Importantly, 2 large randomized clinical trials demonstrated that neoadjuvant cisplatin-based chemotherapy improved survival in patients, solidifying this approach as a standard of care. Another study showed a significant improvement in locoregional disease-free survival with the use of concurrent chemotherapy and definitive radiation in muscle-invasive disease. Results from this study reinforced the applicability of “trimodality” therapy as a bladder-sparing approach with curative intent.

Like most malignancies, urothelial cancer is characterized by substantial heterogeneity both in treatment methodology and patient outcomes. Major advances over the past 20 years have defined the molecular landscape of urothelial cancer. Several groups have identified subtypes of muscle-invasive urothelial cancer that correlate with different prognoses and potentially even different benefit from neoadjuvant chemotherapy. This work recently culminated in a consensus classification of 6 molecular subtypes of muscle-invasive bladder cancer. These subtypes are poised to become the focus of prospective trials seeking to establish the clinical utility of this information.

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Mutations in FGFR3, present in 10% to 15% of muscle-invasive urothelial cancers, were recently shown to confer sensitivity to treatment with small molecule FGFR3 inhibitors in patients with platinumresistant metastatic disease. The FDA approved the first targeted systemic therapy for the treatment of urothelial cancer, erdafitinib (Balversa), in April 2019.

Immune checkpoint blockade has dramatically changed the treatment landscape for urothelial cancer. Some of the first presurgical trials tested ipilimumab (Yervoy) in patients with urothelial cancer and demonstrated proof-of-concept pharmacodynamic effects, including infiltration of T cells in posttreatment cystectomy specimens. After demonstrating activity in advanced solid tumors not typically thought to be sensitive to immunotherapy such as lung cancer, PD-1/ PD-L1 inhibitors became the focus of clinical investigation. This work led to the approval of 5 agents for the treatment of platinum-resistant metastatic disease between 2016 and 2017: atezolizumab (Tecentriq), nivolumab (Opdivo), durvalumab (Imfinzi), avelumab (Bavencio), and pembrolizumab (Keytruda).

For decades, standard frontline treatment for metastatic disease has been cisplatin-based chemotherapy. However, renal impairment and other comorbidities cause a large subset of patients to be considered cisplatin ineligible. PD-1/PD-L1 inhibitors filled a void for these patients, offering them a safe and tolerable treatment alternative.

Although frontline treatment for cisplatin-eligible patients with metastatic disease has remained unchanged for 20 years, an unprecedented number of frontline randomized phase III trials are enrolling both cisplatin-eligible and cisplatin- ineligible patients. The first of these trials to report results, IMvigor130 (NCT02807636), randomized patients to platinum-based chemotherapy with atezolizumab versus single-agent atezolizumab versus platinum-based chemotherapy. Findings demonstrated a significant improvement in progression-free survival with the addition of atezolizumab to chemotherapy versus chemotherapy alone. There was also an improvement in overall survival at interim analysis.

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The number of new therapies that have shown singleagent activity in metastatic disease, the earlier use of immune checkpoint blockade, and our continued attempts to refine our knowledge of the pathogenesis of urothelial carcinoma are expected to dramatically change treatment algorithms and outcomes over the next 5 to 10 years.

Key recurrent somatic alterations that are suspected or confirmed to have therapeutic implications have also been identified in urothelial cancer. For example, mutations in the nucleotide excision repair gene ERCC2 and other genes involved in DNA damage response and repair have been associated with high rates of pathological complete response with neoadjuvant cisplatin-based chemotherapy. These alterations are being tested as predictors of response to systemic chemotherapy in patients with muscle-invasive disease. The goal is to discover whether systemic treatment might be curative in this group and dispel the need for cystectomy.