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    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

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    Authors
    Crabb, S. J.
    Hussain, S.
    Soulis, E.
    Hinsley, S.
    Dempsey, L.
    Trevethan, A.
    Song, Yeepei
    Barber, J.
    Frew, J.
    Gale, J.
    Faust, G.
    Brock, S.
    McGovern, U.
    Parikh, O.
    Enting, D.
    Sundar, S.
    Ratnayake, G.
    Lees, K.
    Birtle, A. J.
    Powles, T.
    Jones, R. J.
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    Affiliation
    Southampton Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom
    Issue Date
    2022
    
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    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.
    Citation
    Crabb SJ, Hussain S, Soulis E, Hinsley S, Dempsey L, Trevethan A, et al. 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 : official journal of the American Society of Clinical Oncology. 2022 Aug 12:JCO2200405. PubMed PMID: 35960902. Epub 2022/08/13. eng.
    Journal
    Journal of Clinical Oncology
    URI
    http://hdl.handle.net/10541/625565
    DOI
    10.1200/jco.22.00405
    PubMed ID
    35960902
    Additional Links
    https://dx.doi.org/10.1200/jco.22.00405
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1200/jco.22.00405
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