Crabb, S. J. et al. (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. (doi: 10.1200/JCO.22.00405) (PMID:35960902) (PMCID:PMC9788980)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Trevethan, Miss Avril and Dempsey, Miss Laura and Soulis, Mrs Eileen and Hinsley, Miss Samantha and Jones, Professor Robert |
| Authors: | Crabb, S. J., Hussain, S., Soulis, E., Hinsley, S., Dempsey, L., Trevethan, A., Song, Y., 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., and Jones, R. J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Journal of Clinical Oncology |
| Publisher: | American Society of Clinical Oncology |
| ISSN: | 0732-183X |
| ISSN (Online): | 1527-7755 |
| Published Online: | 12 August 2022 |
| Copyright Holders: | Copyright © 2022 American Society of Clinical Oncology |
| First Published: | First published in Journal of Clinical Oncology 41(1):54-64 |
| Publisher Policy: | Reproduced under a Creative Commons license |
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