Abstract 4488
Background
There are currently no standard treatment options for pts with metastatic urothelial carcinoma (mUC) who have progressed on or after platinum (cisplatin/carboplatin)–based chemotherapy (PBC) and/or immune checkpoint inhibitors (ICIs). Analysis of The Cancer Genome Atlas bladder cancer dataset suggests that approximately 60% of bladder tumours have homologous recombination deficiency (HRD), as identified by a deleterious mutation in a homologous recombination pathway gene or high genomic loss of heterozygosity (LOH). Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated clinical activity and are approved in other indications for tumours with HRD. We hypothesise that PARP inhibition has antitumour activity in mUC. The ATLAS (NCT03397394) trial is evaluating the efficacy and safety of the PARP inhibitor rucaparib as monotherapy treatment for pts with locally advanced (unresectable) or metastatic UC previously treated with PBC and/or ICI.
Trial design
Eligible pts must have received 1–2 prior standard-of-care treatments (eg, PBC and/or ICI) and have radiographic progression, measurable disease (RECIST v1.1) and adequate organ function. Confirmation of HRD status before enrolment is not required; however, fresh tumour or recently obtained archival tissue is mandatory for central HRD profiling. Prior PARP inhibitor treatment is exclusionary. All pts will receive rucaparib monotherapy (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 HRD-positive (signature based on tumour genomic LOH) 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 tumour samples. Pts are being enrolled in 6 countries (target, N = 200). 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%.
Clinical trial identification
NCT03397394.
Legal entity responsible for the study
Clovis Oncology, Inc.
Funding
Clovis Oncology, Inc.
Editorial Acknowledgement
Writing and editorial support, funded by Clovis Oncology, Inc. (Boulder, CO, USA) was provided by Ritu Pathak, PhD, and Shannon Davis of Ashfield Healthcare Communications (Middletown, CT, USA).
Disclosure
S. Chowdhury: Consulting or advisory role and/or on speakers bureaus: Clovis Oncology, Sanofi, Pfizer, Astellas Pharma, Janssen; Honoraria: GlaxoSmithKline, Novartis; Research funding: Sanofi, Johnson & Johnson. S. Feyerabend: Advisory boards: Janssen, Boehringer Ingelheim Pharma, Aventis; Honorarium: Janssen; Travel and accommodation expenses: Aventis. Y. Loriot: Consulting or advisory role: Janssen, Astellas, Roche, MSD, Seattle Genetics, Pfizer, Bristol-Myers Squibb, AstraZeneca; Research funding: Sanofi, Johnson & Johnson, Merck Sharp & Dohme. S. Gupta: Research support for clinical trials: Pfizer, Five Prime Therapeutics, Hoosier Oncology Group, Rexahn Pharmaceuticals, Incyte, Bristol-Myers Squibb, Novartis, LSK BioPharma, Mirati, Merck; Spouse holds stock/equity in Salarius Pharmaceuticals. D.H. Josephs: Unbranded educational speaker program with Pfizer; Travel and accommodation expenses: EUSA Pharma, Ipsen. A. Rodríguez-Vida: Consulting or advisory role and/or on Speakers bureaus: Clovis Oncology, Merck Sharp & Dohme, Pfizer, BMS, Astellas, Janssen, Bayer, Roche; Honoraria: AstraZeneca, Sanofi Aventis; Research funding from Takeda, Pfizer, Merck Sharp & Dohme. Y. Zakharia: Advisory boards: Novartis, Amgen, Roche Diagnostics, Eisai, Exelixis, Castle Bioscience. D. Nepert, K. Wride, D. Thomas, A. Loehr, A.D. Simmons: Employee of Clovis Oncology and may own stock or have stock options in that company. P. Grivas: Consulting or advisory role with Clovis Oncology, Genentech, Bristol-Myers Squibb, Merck & Co, AstraZeneca, EMD Serono, Exelixis, Dendreon, Biocept, Seattle Genetics, Foundation Medicine, Driver Inc.; Unbranded educational speaker program (with direct input in slide content): Genentech, Bristol-Myers Squibb within the previous 2 years. All other authors have declared no conflicts of interest.