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Multiple novel treatment approaches are currently available for urothelial cancer. What's needed now are well-designed, prospective clinical trials with standardized endpoints to identify the therapies that best optimize patient outcomes.

A recent consensus statement on bladder cancer clinical trial design in the provides detailed guidance on the elements required to build rigorous, stage-specific trials. The recommendations, made by an international consensus panel of experts convened by the International Bladder Cancer Group (IBCG) and the Society for Immunotherapy of Cancer (SITC), focus on early implementation of the best therapies, in the right sequence.

"Trial design is of utmost importance," said Ashish M. Kamat, MD, of the University of Texas MD Anderson Cancer Center in Houston, and the other consensus statement authors. Standardizing trial design and endpoints "will expose patients to agents with a high likelihood of anti-tumor efficacy yielding data with more comparable and robust data sets for meta-analyses," the team explained.

A definitive study requires rational selection of elements such as eligibility criteria, sample size, pathology considerations, statistical analyses, and correlative studies, the authors said. This is essential for all studies across the entire spectrum of urothelial cancer, they added, pointing to low- and intermediate-risk non-muscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic urothelial cancer.

Notably, the recommendations follow earlier guidance on clinical trial design and patient outcomes. In 2016, the IBCG issued aimed at improving clinical trial design for NMIBC, while the SITC in 2021 released clinical practice on immunotherapy for urothelial cancer.

In the following interview, Kamat, who is also IBCG president, discussed the findings in greater detail.

What are the most significant recommendations and why are they so important at this time?

Kamat: The IBCG-SITC panel recommendations for clinical trial design detail patient inclusion criteria, appropriate endpoints, and assessment strategies to guide statistical considerations. It is our hope that these recommendations will encourage uniformity among studies, reduce redundancy, and expedite drug development.

Can you give an example of some of the clinical trial designs in various urothelial cancer settings?

Kamat: Sure. In low- and intermediate-risk NMIBC, for instance, there are two main objectives. The first is to assess antitumor activity, and the second is to determine the effectiveness of treatment to prevent disease recurrence or progression. We recommend trial designs for ablative therapy and for adjuvant therapy.

In ablative trials, the objective is to treat existing tumors by means other than surgical resection, which is the current standard of care. So the trial would be designed to provide direct evidence of the efficacy of an investigational agent, as measured by complete response [CR] rate.

Is CR rate the primary endpoint?

Kamat: Yes, it's the primary endpoint for phase II studies, and is defined as the absence of disease at the treated tumor sites at 3 months, as determined on cystoscopy and negative urine cytology. Surgical sampling of the post-treatment scar for histological evaluation would also be an option.

What endpoint do you recommend for adjuvant therapy trials in NMIBC?

Kamat: The primary endpoint in adjuvant therapy trials of drugs used after transurethral resection of bladder tumor should be time to first recurrence compared by the log-rank test. Recurrence of NMIBC or disease progression constitutes recurrence events. Secondary endpoints may include progression-free survival, disease-specific survival, overall survival, and safety.

What is your main take-home message to physicians about these recommendations?

Kamat: As we develop newer agents in bladder cancer and the competition for enrollment into clinical trials increases, we need to make sure as a community that our patients are counseled appropriately and encouraged to enroll in meaningful studies that are well designed and can generate valid, reproducible data.

It is up to us, as physicians, to not only help design appropriate clinical trials, but to help our patients navigate the many options now available so they can select the best therapy, whether it be standard of care or a clinical trial, for their specific situation.

Read the consensus recommendations here and expert commentary here.