ATLAS: A phase II, open-label study of rucaparib in patients (pts) with locally advanced (unresectable) or metastatic urothelial carcinoma

Abstract

Introduction: In many countries, there are no standard treatment options for patients with metastatic urothelial carcinoma (UC) who have progressed on or after platinum (cisplatin or carboplatin)-based chemotherapy and/or immune checkpoint inhibitors (ICI), emphasizing the urgent need for new therapies. Analysis of The Cancer Genome Atlas bladder cancer dataset suggests that approximately 60% of bladder tumors have homologous recombination deficiency (HRD), as identified by a deleterious mutation in a homologous recombination pathway gene or high genomic loss of heterozygosity. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated clinical activity and are approved in other indications for tumors with HRD. We hypothesize that PARP inhibition may have antitumor activity in metastatic UC. The ATLAS trial (NCT03397394) is evaluating the efficacy and safety of the PARP inhibitor rucaparib in patients with locally advanced (unresectable) or metastatic UC previously treated with platinum-based chemotherapy and/or ICI. Methods: Eligible patients must have received 1-2 prior standard-of-care treatments (platinum-based chemotherapy and/or ICI), have radiographic progression, measurable disease (per RECIST v1.1), and adequate organ function. Assessment of HRD status before enrollment is not required; however, fresh tumor or recently obtained archival tissue is required for HRD profiling. Prior PARP inhibitor treatment is exclusionary. All patients will receive rucaparib monotherapy (600 mg twice daily) until disease progression or other reason for discontinuation. Coprimary endpoints are confirmed objective response rate (investigator-assessed per RECIST v1.1) in both HRD-positive (signature based on tumor genomic loss of heterozygosity) and intent-to-treat populations. Secondary endpoints include response duration, progression-free survival, overall survival, safety, and pharmacokinetics. Exploratory endpoints include evaluation of molecular biomarkers associated with response and resistance to rucaparib, including changes in plasma and tumor samples. The study has >90% power to reject the null hypothesis (P = 0.10) at a 5% significance level if the true response rate for rucaparib is 20%. Results: ATLAS is currently enrolling up to 200 patients in 6 countries, including Germany. Conclusions: ATLAS will assess the efficacy and safety of rucaparib in patients with previously treated locally advanced or metastatic UC.