Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS)
| Autor: | Enrique Grande, A. Loehr, Petros Grivas, Dale L. Nepert, Yohann Loriot, Sumati Gupta, Daleen Thomas, Nicholas J. Vogelzang, Min Yuen Teo, Nabil Adra, Alejo Rodriguez-Vida, Rachel L. Dusek, Simon Chowdhury, S. Srinivas, Yousef Zakharia, Andrew Simmons, Andrea Necchi, Ajjai Alva, Susan Feyerabend, Kenton Wride, Rafael Morales-Barrera, Debra H. Josephs |
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| Přispěvatelé: | University of Washington [Seattle], Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Passeig Vall d'Hebron [Barcelona, Spain], Memorial Sloane Kettering Cancer Center [New York], University of Iowa [Iowa City], Studienpraxis Urologie [Nürtingen, Germany], Comprehensive Cancer Centers [Las Vegas, NV, USA], MD Anderson Cancer Center [Madrid, Spain], Indiana State University, Department of Internal Medicine and Computational Medicine and Bioinformatics [Ann Arbor, MI, USA], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Human Tumor Immunobiology Unit [Fondazione IRCCS Istituto Nazionale dei Tumori, Milan], Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], IMIM-Hospital del Mar, Generalitat de Catalunya, Huntsman Cancer Institute [Salt Lake City], University of Utah, Guy's and St Thomas NHS Foundation Trust [London], Stanford University School of Medicine [CA, USA], Clovis Oncology, Inc. [Boulder, CO, USA], Malbec, Odile, Institut Català de la Salut, [Grivas P] Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA 98109, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Seattle Cancer Care Alliance, Seattle, WA 98109, USA. [Loriot Y] Department of Medicine, Gustave Roussy Cancer Campus, INSERM U981, Université Paris-Saclay, 94800 Villejuif, France. [Morales-Barrera R] Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Teo MY] Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. [Zakharia Y] Division of Hematology, Oncology, and Blood and Marrow Transplant, University of Iowa and Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA. [Feyerabend S] Studienpraxis Urologie, 72622 Nürtingen, Germany, Vall d'Hebron Barcelona Hospital Campus, Grivas, P., Loriot, Y., Morales-Barrera, R., Teo, M. Y., Zakharia, Y., Feyerabend, S., Vogelzang, N. J., Grande, E., Adra, N., Alva, A., Necchi, A., Rodriguez-Vida, A., Gupta, S., Josephs, D. H., Srinivas, S., Wride, K., Thomas, D., Simmons, A., Loehr, A., Dusek, R. L., Nepert, D., Chowdhury, S. |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Oncology Cancer Research Indoles DNA Repair [SDV]Life Sciences [q-bio] Administration Oral Loss of Heterozygosity Other subheadings::Other subheadings::/drug therapy [Other subheadings] Prostate cancer chemistry.chemical_compound 0302 clinical medicine Clinical endpoint Inhibidors enzimàtics - Ús terapèutic - Eficàcia RC254-282 BRCA1 Protein Bladder cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens Middle Aged Progression-Free Survival 3. Good health [SDV] Life Sciences [q-bio] 030220 oncology & carcinogenesis Bufeta - Càncer - Tractament Other subheadings::Other subheadings::/administration & dosage [Other subheadings] Female Urothelial carcinoma medicine.symptom Research Article medicine.medical_specialty Metastatic Urothelial Carcinoma Anemia Nausea Urinary Bladder Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] Poly(ADP-ribose) Polymerase Inhibitors 03 medical and health sciences Internal medicine Genetics medicine Humans Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Poly(ADP-ribose) Polymerase Inhibitors [CHEMICALS AND DRUGS] Adverse effect Rucaparib Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Urologic Neoplasms::Urinary Bladder Neoplasms [DISEASES] Response Evaluation Criteria in Solid Tumors Aged BRCA2 Protein Genomic biomarkers Carcinoma Transitional Cell Otros calificadores::Otros calificadores::/administración & dosificación [Otros calificadores] neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias urológicas::neoplasias de la vejiga [ENFERMEDADES] business.industry acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de poli(ADP-ribosa) polimerasas [COMPUESTOS QUÍMICOS Y DROGAS] medicine.disease PARP inhibitor 030104 developmental biology Urinary Bladder Neoplasms chemistry business Follow-Up Studies |
| Zdroj: | BMC Cancer BMC Cancer, BioMed Central, 2021, 21 (1), pp.593. ⟨10.1186/s12885-021-08085-z⟩ BMC Cancer, 2021, 21 (1), pp.593. ⟨10.1186/s12885-021-08085-z⟩ BMC Cancer, Vol 21, Iss 1, Pp 1-13 (2021) Scientia |
| ISSN: | 1471-2407 0339-7394 |
| DOI: | 10.1186/s12885-021-08085-z |
| Popis: | BackgroundATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC).MethodsPatients 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.ResultsOf 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 deleteriousBRCA1orBRCA2alteration.ConclusionsRucaparib 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.Trial registrationThis trial was registered inClinicalTrials.gov(NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017–004166-10). |
| Databáze: | OpenAIRE |
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