Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS).

ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC).

Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID.

The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks.

Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration.

Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer.

This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017-004166-10).

BMC cancer. 2021 May 24*** epublish ***

P Grivas, Y Loriot, R Morales-Barrera, M Y Teo, Y Zakharia, S Feyerabend, N J Vogelzang, E Grande, N Adra, A Alva, A Necchi, A Rodriguez-Vida, S Gupta, D H Josephs, S Srinivas, K Wride, D Thomas, A Simmons, A Loehr, R L Dusek, D Nepert, S Chowdhury

Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, 98109, USA. ., Department of Medicine, Gustave Roussy Cancer Campus, INSERM U981, Université Paris-Saclay, 39 Rue Camille Desmoulins, 94800, Villejuif, France., Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain., Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA., Division of Hematology, Oncology, and Blood and Marrow Transplant, University of Iowa and Holden Comprehensive Cancer Center, 200 Hawkins Drive, Iowa City, IA, 52242, USA., Studienpraxis Urologie, Steinengrabenstraße 17, 72622, Nürtingen, Germany., Division of Hematology/Oncology, Comprehensive Cancer Centers of Nevada, 3730 S Eastern Avenue, Las Vegas, NV, 89169, USA., Department of Medical Oncology, MD Anderson Cancer Center, Calle de Arturo Soria, 270 28033, Madrid, Spain., Department of Medicine, Indiana University Simon Cancer Center, 535 Barnhill Drive, Indianapolis, IN, 46202, USA., Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 1500 E Medical Center Drive, Ann Arbor, MI, 48109, USA., Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133, Milan, Italy., Medical Oncology Department, Hospital del Mar, Passeig Maritim 25-29, 08003, Barcelona, Spain., Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, 1950 Circle of Hope, Salt Lake City, UT, 84112, USA., Department of Medical Oncology, Guy's and St. Thomas' NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, UK., Division of Medical Oncology, Stanford University School of Medicine, 875 Blake Wilbur Drive, Stanford, CA, 94305, USA., Clovis Oncology, Inc., 5500 Flatiron Parkway, Boulder, CO, 80301, USA., Department of Medical Oncology, Guy's and St. Thomas' NHS Foundation Trust & Sarah Cannon Research Institute, Great Maze Pond, London, SE1 9RT, UK.

Read an Expert Commentary by Bishoy Faltas, MD