First Precision Medicine Study in Advanced Urothelial Cancer Now Underway

The phase II ATLANTIS clinical trial is open for enrollment to evaluate maintenance therapy in biomarker-defined subgroups of patients with advanced urothelial cancer. This is the first study to employ a precision medicine-based approach in the United Kingdom for this patient population that has an urgent unmet need for novel therapies that can improve outcomes.

“The ATLANTIS trial reflects an exciting innovation in front-line precision cancer medicine for patients with advanced [urothelial cancer],” the study authors wrote. “The engrained translational research components have the potential to resolve some of the unanswered questions and push new frontiers in the management of this challenging disease.”

The purpose of the study is to determine if molecularly targeted maintenance therapy could delay time to progression in selected subgroups of patients with advanced urothelial cancer. The study will establish initial evidence of activity for the novel drug and biomarker combinations to justify further validation in a potential phase III clinical trial.

Several drugs are compared with placebo in the ATLANTIS study, and treatment is based on the molecularly defined subgroups or in a manner that explores predictive biomarkers. The primary end point of the study is progression-free survival (PFS). Secondary end points include overall survival (OS), response rate, maximum percentage decrease in measurable disease, safety, and tolerability.

An exploratory end point will evaluate the PFS in biomarker-defined subgroups. All patients will provide adequate tissue for biomarker analysis prior to their participation in the ATLANTIS trial. Tissue collection will provide support as a bio-resource for future research.

The adaptive study design of ATLANTIS allows for the utmost opportunity to detect signals of efficacy, and it also allows for all patients with urothelial cancer who undergo the pre-screening requirements to potentially be able to take part in the study.

Cabozantinib (Cabometyx) will be explored upon initiation of the trial, but other comparisons will include the PARP inhibitor rucaparib (Rubraca) and the potent androgen receptor antagonist enzalutamide (Xtandi).

Patients enrolled to the cabozantinib subgroup are randomized 1:1 to either receive cabozantinib or placebo. Recruitment of 140 patients is planned; the median PFS is expected to be 9 months in the experimental arm versus 6 months with placebo, which is appropriate for a new target within an untargeted patient group with a required 114 PFS events.

In the rucaparib subgroup, patients are randomized 1:1 to either the PARP inhibitor or placebo, and the hazard ratio is targeted to be 0.5. Thirty-nine PFS events are needed, so 48 patients will be recruited to this subgroup.

The enzalutamide subgroup randomizes patients 1:1 to either the experimental agent or placebo. Median PFS is expected to be 6.7 months with enzalutamide versus 4 months with placebo, and a total of 72 PFS events are required, so 80 patients are planned for enrollment to this subgroup.

The multi-arm, biomarker-directed ATLANTIS study utilizes an umbrella-design to evaluate treatment in patients with locally advanced or metastatic urothelial cancer who are unable to receive radical therapy. The umbrella design of the study will allow for new drugs to be introduced in the future.

Patients must be able to start maintenance therapy within at least 3 months and no more than 10 weeks after completion of their first-line chemotherapy.

The trial opened recruitment in November 2016 for enrollment across 32 cancer centers in the United Kingdom. Recruitment for the first subgroup is expected to complete in December 2020.

Clinical benefit has been observed in patients with urothelial cancer who have been treated with second-line therapy, particularly immune checkpoint inhibitors. Despite recent incorporation of these therapies into the frontline setting in clinical trials, there is still room for improvement in terms of outcomes for this patient population. There are currently no targeted therapies with proven activity available for the treatment of patients with urothelial cancer. The number of clinical trials testing potential eligible targets remains small.

Metastatic urothelial cancer is the eighth most common cause of cancer deaths in the United Kingdom, and the standard frontline treatment for these patients is cytotoxic chemotherapy. Relapse is almost inevitable in this patient population as most patients are initially sensitive to chemotherapy. The prognosis is poor, with a median OS of 8 months.

Should a cohort of the ATLANTIS trial be found positive, it would represent a significant breakthrough in this setting and could lead to randomized phase III studies in both the metastatic and neoadjuvant setting, according to the study authors.

_Reference

_{Fulton B, Jones R, Powles T, et al. ATLANTIS: a randomized multi-arm phase II biomarker-directed umbrella screening trial of maintenance targeted therapy after chemotherapy in patients with advanced or metastatic urothelial cancer [Published Online April 19, 2020]. Trials. DOI: 10.1186/s13063-020-04283-5.}