Crabb, S.J. orcid.org/0000-0003-3521-9064, Hussain, S. orcid.org/0000-0003-1552-511X, Soulis, E. orcid.org/0000-0001-9022-9295 et al. (18 more authors) (2023) A randomized, double-blind, biomarker-selected, phase II clinical trial of maintenance poly ADP-ribose polymerase inhibition with rucaparib following chemotherapy for metastatic urothelial carcinoma. Journal of Clinical Oncology, 41 (1). pp. 54-64. ISSN 0732-183X
Abstract
PURPOSE A DNA repair deficiency (DRD) phenotype exists within a subset of metastatic urothelial carcinomas (mUC) predicting benefit from platinum-based chemotherapy. We tested switch maintenance therapy with the poly ADP-ribose polymerase inhibitor rucaparib, following chemotherapy, for DRD biomarker–positive mUC.
METHODS DRD biomarker–positive mUC patients, within 10 weeks of chemotherapy, and without cancer progression, were randomly assigned (1:1) to maintenance rucaparib 600 mg twice a day orally, or placebo, until disease progression. The primary end point was progression-free survival (PFS). Statistical analysis targeted a hazard ratio of 0.5 with a 20% one-sided α for this signal-seeking trial. PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model.
RESULTS Out of 248 patients, 74 (29.8%) were DRD biomarker–positive and 40 were randomly assigned. A total of 12 (60%) and 20 (100%) PFS events occurred in the rucaparib and placebo arms, respectively (median follow-up was 94.6 weeks in those still alive). Median PFS was 35.3 weeks (80% CI, 11.7 to 35.6) with rucaparib and 15.1 weeks (80% CI, 11.9 to 22.6) with placebo (hazard ratio, 0.53; 80% CI, 0.30 to 0.92; one-sided P = .07). In the safety population (n = 39) treatment-related adverse events were mostly low grade. Patients received a median duration of 10 rucaparib or six placebo cycles on treatment. Treatment-related adverse events (all grades) of fatigue (63.2% v 30.0%), nausea (36.8% v 5.0%), rash (21.1% v 0%), and raised alanine aminotransferase (57.9% v 10%) were more common with rucaparib.
CONCLUSION Maintenance rucaparib, following platinum-based chemotherapy, extended PFS in DRD biomarker-selected patients with mUC and was tolerable. Further investigation of poly ADP-ribose polymerase inhibition in selected patients with mUC is warranted.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2022 by American Society of Clinical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Female; Humans; Ovarian Neoplasms; Poly(ADP-ribose) Polymerases; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Platinum; Biomarkers; Adenosine Diphosphate Ribose; Double-Blind Method; Antineoplastic Combined Chemotherapy Protocols; Maintenance Chemotherapy |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 25 May 2023 08:51 |
Last Modified: | 25 May 2023 08:51 |
Published Version: | http://dx.doi.org/10.1200/jco.22.00405 |
Status: | Published |
Publisher: | American Society of Clinical Oncology (ASCO) |
Refereed: | Yes |
Identification Number: | 10.1200/jco.22.00405 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:199539 |