There are limited treatment options for patients with metastatic urothelial carcinoma who have progressed following treatment with platinum (cisplatin or carboplatin)–based chemotherapy and/or immune checkpoint inhibitor therapy. Poly(ADP-ribose) polymerase (PARP) inhibitors are approved in ovarian and breast cancer; however, there are limited data on the activity of PARP inhibitors in urothelial cancer. Nonclinical studies have shown that the PARP inhibitor rucaparib has antitumor activity through a mechanism called synthetic lethality in tumors with homologous recombination (HR) deficiency (HRD). Rucaparib also decreased tumor growth in mouse xenograft models of human cancer with or without deficiencies in BRCA. Predictive biomarkers associated with HRD and sensitivity to PARP inhibitors include BRCA1/2 mutations and tumor genomic loss of heterozygosity (LOH). Genomic LOH is a specific type of DNA damage indicative of HRD and sensitivity to PARP inhibitors. To explore the potential utility of rucaparib in urothelial cancer, The Cancer Genome Atlas muscle-invasive bladder cancer dataset was investigated for genomic evidence of HRD. Results from the analysis indicated that many urothelial tumors have high genomic LOH. In the recurrent ovarian cancer setting, both LOH high and LOH low patients benefited from rucaparib treatment. These data suggest that the PARP inhibitor rucaparib may have activity in patients with locally advanced, unresectable or metastatic urothelial cancer, regardless of tumor HRD status. The ATLAS (NCT03397394) trial will evaluate the efficacy and safety of rucaparib in patients with locally advanced/unresectable UC or mUC treated with 1–2 prior anticancer treatments.
Eligible patients must have measurable disease per RECIST v1.1, adequate organ function, and radiographic progression after 1–2 prior regimens (eg, PBC and/or ICI). Confirmation of HRD status before enrollment is not required, but fresh tumor tissue or recently obtained archival tissue is mandatory for HRD profiling. Prior PARPi treatment is exclusionary. All patients will receive oral rucaparib 600 mg BID until disease progression or other reason for discontinuation. The coprimary endpoints are confirmed objective response rate (investigator-assessed per RECIST v1.1) in the intent-to-treat and HRD-positive (signature based on tumor genomic LOH) 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, and circulating tumor DNA.
Patients are being enrolled in 6 countries (France, Germany, Italy, Spain, UK, and USA), with a target enrollment of 200 patients. 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%. The results from this trial will be awaited and will offer hope to patients and their families who have very limited treatment options available to them.
Presented by: Petros Grivas, MD, PhD, Seattle Cancer Care Alliance, Director of University of Washtington's Medicine's Genitourinary Cancers Program
Written by: Abhishek Srivastava, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Fox Chase Cancer Center, Philadelphia, PA, Twitter: @shekabhishek at the at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA