The University of Southampton
University of Southampton Institutional Repository

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

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
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

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.

Concusions: 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.

1527-7755
JCO2200405
Crabb, Simon J.
bcd1b566-7677-4f81-8429-3ab0e85f8373
Hussain, Syed
2942f5a7-ac04-4309-b94e-2badb1d19852
Soulis, Eileen
111cc05c-dc15-40da-8e1b-a4859b574fb8
Hinsley, Samantha
acf114b5-f5c2-4e61-ba74-73570fe16aaa
Dempsey, Laura
995e89c5-2a9b-4d5a-b6bb-d41a9090cc00
Trevethan, Avril
ef398716-62db-4087-997a-17a10e4de57e
Song, YeePei
ca4fa47b-d3a7-463b-820f-53762332af72
Barber, Jim
53cd387a-5812-4cde-808f-7ad8a54a4231
Frew, John
53f58b0c-b0df-43a0-bc4e-d03488833525
Gale, Joanna
103ddc41-a525-4c07-b054-e518cf2a85b2
Faust, Guy
c1e8ec0f-268c-4e9a-8790-8814a3979361
Brock, Susannah
5a4351f1-52a5-465f-a420-65209be18de2
McGovern, Ursula
1b594073-cdb4-463d-af5d-2f9f0706903f
Parikh, Omi
755ebd3f-4025-4f47-888a-e7daddf5d207
Enting, Deborah
876f8e18-e6b0-4ac2-a45b-c4a8967b8c4d
Sundar, Santhanam
9debb60d-34e5-4f33-a761-867154aac479
Ratnayake, Gihan
b7f27635-aa65-4be7-8939-bd4238f01bcb
Lees, Kathryn
5ebcf983-f1c7-424a-80b5-deaebd2ea255
Birtle, Alison J
5016770c-8e37-4c38-9215-3f745f24c6fe
Powles, Thomas
55539b87-1c5e-45ae-9e07-5b2232c2236c
Jones, Robert J
ccc0201e-056c-4c4e-b4af-e35a0ee0860c
Crabb, Simon J.
bcd1b566-7677-4f81-8429-3ab0e85f8373
Hussain, Syed
2942f5a7-ac04-4309-b94e-2badb1d19852
Soulis, Eileen
111cc05c-dc15-40da-8e1b-a4859b574fb8
Hinsley, Samantha
acf114b5-f5c2-4e61-ba74-73570fe16aaa
Dempsey, Laura
995e89c5-2a9b-4d5a-b6bb-d41a9090cc00
Trevethan, Avril
ef398716-62db-4087-997a-17a10e4de57e
Song, YeePei
ca4fa47b-d3a7-463b-820f-53762332af72
Barber, Jim
53cd387a-5812-4cde-808f-7ad8a54a4231
Frew, John
53f58b0c-b0df-43a0-bc4e-d03488833525
Gale, Joanna
103ddc41-a525-4c07-b054-e518cf2a85b2
Faust, Guy
c1e8ec0f-268c-4e9a-8790-8814a3979361
Brock, Susannah
5a4351f1-52a5-465f-a420-65209be18de2
McGovern, Ursula
1b594073-cdb4-463d-af5d-2f9f0706903f
Parikh, Omi
755ebd3f-4025-4f47-888a-e7daddf5d207
Enting, Deborah
876f8e18-e6b0-4ac2-a45b-c4a8967b8c4d
Sundar, Santhanam
9debb60d-34e5-4f33-a761-867154aac479
Ratnayake, Gihan
b7f27635-aa65-4be7-8939-bd4238f01bcb
Lees, Kathryn
5ebcf983-f1c7-424a-80b5-deaebd2ea255
Birtle, Alison J
5016770c-8e37-4c38-9215-3f745f24c6fe
Powles, Thomas
55539b87-1c5e-45ae-9e07-5b2232c2236c
Jones, Robert J
ccc0201e-056c-4c4e-b4af-e35a0ee0860c

Crabb, Simon J., Hussain, Syed, Soulis, Eileen, Hinsley, Samantha, Dempsey, Laura, Trevethan, Avril, Song, YeePei, Barber, Jim, Frew, John, Gale, Joanna, Faust, Guy, Brock, Susannah, McGovern, Ursula, Parikh, Omi, Enting, Deborah, Sundar, Santhanam, Ratnayake, Gihan, Lees, Kathryn, Birtle, Alison J, Powles, Thomas and Jones, Robert J (2022) 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, JCO2200405. (doi:10.1200/JCO.22.00405).

Record type: Article

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.

Concusions: 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.

Text
jco.22.00405 - Version of Record
Available under License Creative Commons Attribution.
Download (551kB)

More information

e-pub ahead of print date: 12 August 2022

Identifiers

Local EPrints ID: 469476
URI: http://eprints.soton.ac.uk/id/eprint/469476
ISSN: 1527-7755
PURE UUID: 1c927db7-01af-40da-a2d4-4c90b9cd85c0
ORCID for Simon J. Crabb: ORCID iD orcid.org/0000-0003-3521-9064

Catalogue record

Date deposited: 15 Sep 2022 16:44
Last modified: 16 Sep 2022 01:39

Export record

Altmetrics

Contributors

Author: Simon J. Crabb ORCID iD
Author: Syed Hussain
Author: Eileen Soulis
Author: Samantha Hinsley
Author: Laura Dempsey
Author: Avril Trevethan
Author: YeePei Song
Author: Jim Barber
Author: John Frew
Author: Joanna Gale
Author: Guy Faust
Author: Susannah Brock
Author: Ursula McGovern
Author: Omi Parikh
Author: Deborah Enting
Author: Santhanam Sundar
Author: Gihan Ratnayake
Author: Kathryn Lees
Author: Alison J Birtle
Author: Thomas Powles
Author: Robert J Jones

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×