Characterization of patients with long-term responses to rucaparib treatment in recurrent ovarian cancer
File(s)
Author(s)
McNeish, Iain
Type
Journal Article
Abstract
Objective. To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib.
Methods. This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors.
Results. Overall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10–0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C, RAD51D, or CDK12 mutations.
Conclusion. Among patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants.
Methods. This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors.
Results. Overall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10–0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C, RAD51D, or CDK12 mutations.
Conclusion. Among patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants.
Date Issued
2021-12
Date Acceptance
2021-08-30
Citation
Gynecologic Oncology, 2021, 163, pp.490-497
ISSN
0090-8258
Publisher
Elsevier
Start Page
490
End Page
497
Journal / Book Title
Gynecologic Oncology
Volume
163
Copyright Statement
© 2021 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Cancer Research UK
Ovarian Cancer Action
National Institute for Health Research
Identifier
https://www.sciencedirect.com/science/article/pii/S0090825821013299
Grant Number
RG71079
n/a
NIHR202372
Subjects
Science & Technology
Life Sciences & Biomedicine
Oncology
Obstetrics & Gynecology
Duration of response
Ovarian carcinoma
Genomics
Rucaparib
Safety
PARP INHIBITOR RUCAPARIB
ANTITUMOR-ACTIVITY
DOUBLE-BLIND
CARCINOMA
GERMLINE
BRCA1
MONOTHERAPY
MUTATIONS
SURVIVAL
OLAPARIB
Science & Technology
Life Sciences & Biomedicine
Oncology
Duration of response
Genomics
Ovarian carcinoma
Rucaparib
Safety
Adult
Aged
Aged, 80 and over
BRCA1 Protein
BRCA2 Protein
Clinical Trials, Phase I as Topic
Clinical Trials, Phase II as Topic
Female
Follow-Up Studies
Humans
Indoles
Loss of Heterozygosity
Middle Aged
Neoplasm Recurrence, Local
Ovarian Neoplasms
Poly(ADP-ribose) Polymerase Inhibitors
Humans
Ovarian Neoplasms
Neoplasm Recurrence, Local
Indoles
BRCA1 Protein
BRCA2 Protein
Follow-Up Studies
Loss of Heterozygosity
Adult
Aged
Aged, 80 and over
Middle Aged
Female
Clinical Trials, Phase I as Topic
Clinical Trials, Phase II as Topic
Poly(ADP-ribose) Polymerase Inhibitors
Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
1114 Paediatrics and Reproductive Medicine
Publication Status
Published
Date Publish Online
2021-09-30