Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS)
Abstract Background ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). Methods Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD)...
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BMC
2021-05-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-021-08085-z |
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| author | 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 |
| author_facet | 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 |
| author_sort | P. Grivas |
| collection | DOAJ |
| description | Abstract Background ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). Methods 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. Results 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. Conclusions 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. Trial registration This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017–004166-10). |
| first_indexed | 2024-12-17T00:33:21Z |
| format | Article |
| id | doaj.art-dbd7ef41f9444e0d96e69e4882bd9a23 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-17T00:33:21Z |
| publishDate | 2021-05-01 |
| publisher | BMC |
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| series | BMC Cancer |
| spelling | doaj.art-dbd7ef41f9444e0d96e69e4882bd9a232022-12-21T22:10:13ZengBMCBMC Cancer1471-24072021-05-0121111310.1186/s12885-021-08085-zEfficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS)P. Grivas0Y. Loriot1R. Morales-Barrera2M. Y. Teo3Y. Zakharia4S. Feyerabend5N. J. Vogelzang6E. Grande7N. Adra8A. Alva9A. Necchi10A. Rodriguez-Vida11S. Gupta12D. H. Josephs13S. Srinivas14K. Wride15D. Thomas16A. Simmons17A. Loehr18R. L. Dusek19D. Nepert20S. Chowdhury21Department of Medicine, Division of Medical Oncology, University of WashingtonDepartment of Medicine, Gustave Roussy Cancer Campus, INSERM U981, Université Paris-SaclayPasseig Vall d’Hebron 119-129, 08035Department of Medicine, Memorial Sloan Kettering Cancer CenterDivision of Hematology, Oncology, and Blood and Marrow Transplant, University of Iowa and Holden Comprehensive Cancer CenterStudienpraxis UrologieDivision of Hematology/Oncology, Comprehensive Cancer Centers of NevadaDepartment of Medical Oncology, MD Anderson Cancer CenterDepartment of Medicine, Indiana University Simon Cancer CenterDepartment of Internal Medicine, University of Michigan Comprehensive Cancer CenterDepartment of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei TumoriMedical Oncology Department, Hospital del MarDivision of Medical Oncology, Huntsman Cancer Institute, University of UtahDepartment of Medical Oncology, Guy’s and St. Thomas’ NHS Foundation TrustDivision of Medical Oncology, Stanford University School of MedicineClovis Oncology, Inc.Clovis Oncology, Inc.Clovis Oncology, Inc.Clovis Oncology, Inc.Clovis Oncology, Inc.Clovis Oncology, Inc.Department of Medical Oncology, Guy’s and St. Thomas’ NHS Foundation Trust & Sarah Cannon Research InstituteAbstract Background ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). Methods 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. Results 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. Conclusions 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. Trial registration This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017–004166-10).https://doi.org/10.1186/s12885-021-08085-zBladder cancerUrothelial carcinomaPARP inhibitorRucaparibGenomic biomarkers |
| spellingShingle | 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 Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS) BMC Cancer Bladder cancer Urothelial carcinoma PARP inhibitor Rucaparib Genomic biomarkers |
| title | Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS) |
| title_full | Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS) |
| title_fullStr | Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS) |
| title_full_unstemmed | Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS) |
| title_short | Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS) |
| title_sort | efficacy and safety of rucaparib in previously treated locally advanced or metastatic urothelial carcinoma from a phase 2 open label trial atlas |
| topic | Bladder cancer Urothelial carcinoma PARP inhibitor Rucaparib Genomic biomarkers |
| url | https://doi.org/10.1186/s12885-021-08085-z |
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