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. 2024 Oct 15;30(20):4644-4653.
doi: 10.1158/1078-0432.CCR-24-1225.

Effectiveness of PARP Inhibitor Maintenance Therapy in Ovarian Cancer by BRCA1/2 and a Scar-Based HRD Signature in Real-World Practice

Debra L Richardson #  1 , Julia C F Quintanilha #  2 , Natalie Danziger  2 , Gerald Li  2 , Ethan Sokol  2 , Alexa B Schrock  2 , Ericka Ebot  2 , Neeru Bhardwaj  2 , Tanesha Norris  2 , Anosheh Afghahi  3 , Anthony Frachioni  3 , Christina Washington  1 , Lauren Dockery  1 , Julia Elvin  2 , Ryon P Graf  2 , Kathleen N Moore  1
Affiliations

Effectiveness of PARP Inhibitor Maintenance Therapy in Ovarian Cancer by BRCA1/2 and a Scar-Based HRD Signature in Real-World Practice

Debra L Richardson et al. Clin Cancer Res. .

Erratum in

Abstract

Purpose: The purpose of the study was to compare the effectiveness of PARP inhibitor maintenance therapy (mPARPi) in real-world practice by biomarker status [BRCA1/2 alterations (BRCAalt) and a homologous recombination deficiency signature (HRDsig)] in advanced ovarian cancer.

Experimental design: Patients with ovarian cancer receiving first-line platinum-based chemotherapy and either mPARPi or no maintenance were included. Patient data were obtained by a US-based de-identified ovarian cancer Clinico-Genomic Database, from ∼280 US cancer clinics (01/2015-03/2023). Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared by biomarker status using Cox models, weighted by propensity scores.

Results: Of 673 patients, 160 received mPARPi [31.2% BRCAalt and 51.9% HRDsig(+)] and 513 no maintenance [15.6% BRCAalt and 34.1% HRDsig(+)]. BRCAalt patients receiving mPARPi versus no maintenance had favorable rwPFS [HR, 0.48; 95% confidence interval (CI), 0.26-0.87; P = 0.0154], as did BRCA wild-type (WT; HR, 0.76; 95% CI, 0.57-1.01; P = 0.0595). Favorable rwOS was not observed with mPARPi for BRCAalt or BRCA-WT. HRDsig(+) patients receiving mPARPi versus no maintenance had favorable rwPFS (HR, 0.36; 95% CI, 0.24-0.55; P < 0.001) and numerically favorable rwOS (HR, 0.46; 95% CI, 0.21-1.02; P = 0.0561). No differences were observed for HRDsig(-). mPARPi treatment interaction was observed for HRDsig(+) versus HRDsig(-) (rwPFS P < 0.001/rwOS P = 0.016) but not for BRCAalt versus BRCA-WT. Patients with BRCA-WT/HRDsig(+) receiving mPARPi had favorable rwPFS (HR, 0.40; 95% CI, 0.22-0.72; P = 0.003), whereas no difference was observed for BRCA-WT/HRDsig(-).

Conclusions: HRDsig predicted benefit of mPARPi better than BRCAalt. Patients with HRDsig(+) status experienced favorable outcomes, even if they had BRCA-WT status. In contrast, patients with HRDsig(-) status did not show significant benefit from mPARPi treatment. HRDsig might predict benefit from mPARPi regardless of BRCAalt status.

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Conflict of interest statement

D.L. Richardson reports personal fees from AstraZeneca, Mersana, Daiichi Sankyo, ProfoundBio, Eisai, and ImmuoGen and grants and personal fees from GlaxoSmithKline outside the submitted work. J.C.F. Quintanilha reports other support from Foundation Medicine, Inc and Roche during the conduct of the study. N. Danziger reports other support from Foundation Medicine, Inc and Roche during the conduct of the study. G. Li reports personal fees from Foundation Medicine, Inc and other support from Roche outside the submitted work. E.S. Sokol reports other support from Foundation Medicine and other support from Roche outside the submitted work. A.B. Schrock reports personal fees from Foundation Medicine and other support from Roche during the conduct of the study. E.M. Ebot reports personal fees from Foundation Medicine outside the submitted work and is a stockholder of Roche Holdings AG. N. Bhardwaj reports other support from Foundation Medicine outside the submitted work. A. Afghani reports other support from Roche during the conduct of the study, as well as other support from Roche outside the submitted work. C. Washington reports personal fees from AstraZeneca and grants from Robert A Winn Foundation STAAR outside the submitted work. J.A. Elvin reports full-time employment with Foundation Medicine, Inc. Foundation Medicine is an independent affiliate of the Roche Group, which provides equity interests as part of its employee benefit package. R.P. Graf reports other support from Foundation Medicine, Inc during the conduct of the study, as well as other support from Roche outside the submitted work. K.N. Moore reports personal fees from AstraZeneca, Aadi, Blueprint Pharma, Caris, Duality, BioNTech, Eisai, GSK, ImmunoGen, Janssen, Eli Lilly and Company, Merck, Novartis, Regeneron, Verastem, and Zentalis outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Cohort selection and analysis overview. Cohort selection diagram (A) and temporal visualization of the analysis cohort (B) are shown. *Four out of 160 patients receiving mPARP initiated therapy after the index date of 10 months. Chemo, chemotherapy; tx, therapy.
Figure 2.
Figure 2.
Patients receiving maintenance PARPi had more favorable outcomes with BRCAalt but not BRCA-WT. rwPFS is shown by maintenance therapy received for (A) BRCAalt and (B) BRCA-WT. rwOS is shown by maintenance therapy received for (C) BRCAalt and (D) BRCA-WT. rwOS estimates are risk set adjusted to account for delayed entry to at-risk table (see “Materials and Methods”). Kaplan–Meier curves are adjusted by propensity weights (see Supplementary Fig. S1). Analyses unadjusted for propensity weights have similar results (see Supplementary Fig. S2). Interaction terms in interaction models (see “Materials and Methods”). tx, therapy.
Figure 3.
Figure 3.
Patients receiving maintenance PARPi had more favorable rwPFS and tended to have more favorable rwOS when HRDsig(+) but not HRDsig(−). rwPFS is shown by maintenance therapy received for (A) HRDsig(+) and (B) HRDsig(−). rwOS is shown by maintenance therapy received for (C) HRDsig(+) and (D) HRDsig(−). rwOS estimates are risk set adjusted to account for delayed entry to at-risk table (see “Materials and Methods”). Kaplan–Meier curves are adjusted by propensity weights (see Supplementary Fig. S1). Analyses unadjusted for propensity weights have similar results (see Supplementary Fig. S5). tx, therapy.
Figure 4.
Figure 4.
HRDsig is superior to BRCAalt alone for enrichment of favorable rwPFS and rwOS. A, rwPFS and (B) rwOS is shown by the cohort subgroup, defined by BRCAalt and/or HRDsig. Interaction P values reflect models containing the two adjacent groups. Full interaction models are available in Supplementary Fig. S8. C, HRDsig detects 21.2% patients who are BRCA-WT and might benefit from mPARPi. D, Bimodal distribution of HRDsig score and overlap with BRCAalt status. tx, therapy.
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