Highlights
- •Patients with recurrent ovarian cancer (OC) who responded to rucaparib treatment in Study 10 and ARIEL2 were characterized.
- •Duration of response (DOR) was used to group long- (≥1 y), intermediate- (6 mo to <1 y), and short-term responders (<6 mo).
- •The majority of long- and intermediate-term responders with BRCA wild-type OC had high genome-wide loss of heterozygosity.
- •BRCA structural variants were common in long-term responders and associated with longer DOR than other alteration types.
- •Our analyses show that reversion-resistant BRCA structural variants contribute to extended DOR to PARP inhibitor therapy.
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.
Keywords
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Article info
Publication history
Published online: September 30, 2021
Accepted:
August 30,
2021
Received in revised form:
August 26,
2021
Received:
May 20,
2021
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
