PARP inhibitors for metastatic urothelial carcinoma: a systematic review of efficacy and safety
PARP inhibitors for metastatic urothelial carcinoma: a systematic review of efficacy and safety
Background: poly (ADP-ribose) polymerase (PARP) inhibitors have activity in various cancers. Metastatic urothelial carcinoma (MUC) is platinum sensitive and a subset harbour DNA repair gene alterations.
Objective: to assess evidence for efficacy and safety of PARP inhibition for MUC.
Methods: This systematic review included randomised clinical trials (RCTs) evaluating PARP inhibitors as monotherapy, or in therapeutic combinations, compared to relevant comparators or best supportive care. The primary endpoint was progression free survival (PFS). We searched MEDLINE (Ovid), EMBASE, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials from March 2013 to March 2023. Each study was appraised using the Cochrane Risk of Bias 2 Tool. Study results were synthesised descriptively. Registration: PROSPERO CRD42023403145.
Results: from 247 identified reports, we included three phase 2 RCTs including 252 patients. Two RCTs assessed PARP inhibition in unselected patient groups (one first line platinum ineligible, one post chemotherapy maintenance) and found no evidence of efficacy. All three RCTs assessed subgroups defined by biomarker selection for somatic DNA repair defects. Two of these identified PFS benefit with PARP inhibition compared to a relevant comparator (one first line in combination with immunotherapy, one maintenance monotherapy). Safety outcomes were consistent with prior experience of PARP inhibitors. The risk of bias across the outcomes was generally low.
Conclusions: PARP inhibitors lack efficacy for unselected MUC patients. Phase 2 RCTs support further investigation of PARP inhibition within biomarker-selected patient subsets. The optimal biomarker is not yet determined. Limitations in the current evidence relate to small sample sizes and low statistical power.
Bladder cancer, PARP inhibitor, biomarker, homologous recombination deficiency, immunotherapy, maintenance therapy, systematic review, urothelial carcinoma
365-376
Crabb, Simon J.
bcd1b566-7677-4f81-8429-3ab0e85f8373
Khalid, Taha
a89abb5a-05ac-4a1e-8712-e65953e1516d
Woods, Lois
8149aa11-7664-4052-a18b-98f7bde83180
Frampton, Geoff
26c6163c-3428-45b8-b8b9-92091ff6c69f
Shepherd, Jonathan
dfbca97a-9307-4eee-bdf7-e27bcb02bc67
13 December 2023
Crabb, Simon J.
bcd1b566-7677-4f81-8429-3ab0e85f8373
Khalid, Taha
a89abb5a-05ac-4a1e-8712-e65953e1516d
Woods, Lois
8149aa11-7664-4052-a18b-98f7bde83180
Frampton, Geoff
26c6163c-3428-45b8-b8b9-92091ff6c69f
Shepherd, Jonathan
dfbca97a-9307-4eee-bdf7-e27bcb02bc67
Crabb, Simon J., Khalid, Taha, Woods, Lois, Frampton, Geoff and Shepherd, Jonathan
(2023)
PARP inhibitors for metastatic urothelial carcinoma: a systematic review of efficacy and safety.
Bladder Cancer, 9 (4), .
(doi:10.3233/BLC-230071).
Abstract
Background: poly (ADP-ribose) polymerase (PARP) inhibitors have activity in various cancers. Metastatic urothelial carcinoma (MUC) is platinum sensitive and a subset harbour DNA repair gene alterations.
Objective: to assess evidence for efficacy and safety of PARP inhibition for MUC.
Methods: This systematic review included randomised clinical trials (RCTs) evaluating PARP inhibitors as monotherapy, or in therapeutic combinations, compared to relevant comparators or best supportive care. The primary endpoint was progression free survival (PFS). We searched MEDLINE (Ovid), EMBASE, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials from March 2013 to March 2023. Each study was appraised using the Cochrane Risk of Bias 2 Tool. Study results were synthesised descriptively. Registration: PROSPERO CRD42023403145.
Results: from 247 identified reports, we included three phase 2 RCTs including 252 patients. Two RCTs assessed PARP inhibition in unselected patient groups (one first line platinum ineligible, one post chemotherapy maintenance) and found no evidence of efficacy. All three RCTs assessed subgroups defined by biomarker selection for somatic DNA repair defects. Two of these identified PFS benefit with PARP inhibition compared to a relevant comparator (one first line in combination with immunotherapy, one maintenance monotherapy). Safety outcomes were consistent with prior experience of PARP inhibitors. The risk of bias across the outcomes was generally low.
Conclusions: PARP inhibitors lack efficacy for unselected MUC patients. Phase 2 RCTs support further investigation of PARP inhibition within biomarker-selected patient subsets. The optimal biomarker is not yet determined. Limitations in the current evidence relate to small sample sizes and low statistical power.
Text
blc_2023_9-4_blc-9-4-blc230071_blc-9-blc230071
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More information
Accepted/In Press date: 22 November 2023
e-pub ahead of print date: 13 December 2023
Published date: 13 December 2023
Additional Information:
Funding Information:
SJC was the lead investigator for the rucaparib randomisation within the ATLANTIS clinical trial which was funded by Cancer Research UK (A18386). The rucaparib randomised comparison received funding, and provision of rucaparib and placebo, from Clovis Oncology. Clovis Oncology also provided advice in defining the components of the DRD biomarker and funding to Foundation Medicine to undertake biomarker analysis.
Publisher Copyright:
© 2023 – The authors.
Keywords:
Bladder cancer, PARP inhibitor, biomarker, homologous recombination deficiency, immunotherapy, maintenance therapy, systematic review, urothelial carcinoma
Identifiers
Local EPrints ID: 485785
URI: http://eprints.soton.ac.uk/id/eprint/485785
ISSN: 2352-3735
PURE UUID: 3eb26884-900b-4816-9d67-5092d5356217
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Date deposited: 19 Dec 2023 17:35
Last modified: 18 Mar 2024 03:54
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Author:
Taha Khalid
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