Ad hoc Analysis of the Phase III ENGOT-OV16/NOVA Study: Niraparib Efficacy in Germline BRCA Wild-type Recurrent Ovarian Cancer with Homologous Recombination Repair Defects

Mansoor Raza Mirza, Gabriel Lindahl, Sven Mahner, Andrés Redondo, Michel Fabbro, Bobbie J Rimel, Jørn Herrstedt, Amit M Oza, Ulrich Canzler, Jonathan S Berek, Antonio González-Martín, Phillipe Follana, Rosemary Lord, Masoud Azodi, Kasey Estenson, Zebin Wang, Yong Li, Divya Gupta, Ursula Matulonis, Bin Feng, Mansoor Raza Mirza, Gabriel Lindahl, Sven Mahner, Andrés Redondo, Michel Fabbro, Bobbie J Rimel, Jørn Herrstedt, Amit M Oza, Ulrich Canzler, Jonathan S Berek, Antonio González-Martín, Phillipe Follana, Rosemary Lord, Masoud Azodi, Kasey Estenson, Zebin Wang, Yong Li, Divya Gupta, Ursula Matulonis, Bin Feng

Abstract

In this analysis, we examined the relationship between progression-free survival (PFS) and mutation status of 18 homologous recombination repair (HRR) genes in patients in the non-germline BRCA-mutated (non-gBRCAm) cohort of the ENGOT-OV16/NOVA trial (NCT01847274), which evaluated niraparib maintenance therapy for patients with recurrent ovarian cancer. This post hoc exploratory biomarker analysis was performed using tumor samples collected from 331 patients enrolled in the phase III ENGOT-OV16/NOVA trial's non-gBRCAm cohort. Niraparib demonstrated PFS benefit in patients with either somatic BRCA-mutated (sBRCAm; HR, 0.27; 95% confidence interval, CI, 0.08-0.88) or BRCA wild-type (BRCAwt; HR, 0.47; 95% CI, 0.34-0.64) tumors. Patients with BRCAwt tumors with other non-BRCA HRR mutations also derived benefit from niraparib (HR, 0.31; 95% CI, 0.13-0.77), as did patients with BRCAwt/HRRwt (HRR wild-type) tumors (HR, 0.49; 95% CI, 0.35-0.70). When patients with BRCAwt/HRRwt tumors were further categorized by genomic instability score (GIS), clinical benefit was observed in patients with homologous recombination-deficient (GIS ≥ 42; HR, 0.33; 95% CI, 0.18-0.61) and in patients with homologous recombination-proficient (HRp; GIS < 42; HR, 0.60; 95% CI, 0.36-0.99) disease. Although patients with sBRCAm, other non-BRCA HRR mutations, or GIS ≥ 42 benefited the most from niraparib treatment, PFS benefit was also seen in HRp (GIS < 42) patients without HRR mutations. These results support the use of niraparib in patients with recurrent ovarian cancer regardless of BRCA/HRR mutation status or myChoice CDx GIS.

Significance: We retrospectively evaluated the mutational profile of HRR genes in tumor samples from 331 patients from the non-germline BRCA-mutated cohort of the phase III NOVA trial of patients with platinum-sensitive high-grade serous ovarian cancer. Patients with non-BRCA HRR mutations generally benefited from second-line maintenance treatment with niraparib compared with placebo.

Conflict of interest statement

G. Lindahl reports personal fees from Honoraria for lectures outside the submitted work. S. Mahner reports grants, personal fees, and other from AbbVie, AstraZeneca, Clovis, Eisai, GSK, Hubro, Medac, MSD, Novartis, Nykode, Olympus, PharmaMar, Pfizer, Roche, Sensor Kinesis, Teva, and Tesaro outside the submitted work. A. Redondo reports personal fees from GSK, MSD; personal fees and other from AstraZeneca; other from Clovis; grants and personal fees from Pharmamar; and grants from Eisai outside the submitted work. M. Fabbro reports personal fees from GSK and AstraZeneca outside the submitted work. B.J. Rimel reports other from GSK, Merck, Immunogen, and personal fees from Deep6AI outside the submitted work. A.M. Oza reports PI and Steering Committees with AstraZeneca, GSK, and Clovis; advisory Board member with AstraZeneca and Morphosys. U. Canzler reports personal fees from AstraZeneca, Lilly, and Roche outside the submitted work. J.S. Berek reports grants from Tesaro during the conduct of the study. A. González-Martín reports personal fees from Alkermes, Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, ImmunoGen, Merck Sharp & Dohme, MacroGenics, Novartis, Oncoinvent, Pfizer/Merck, PharmaMar, Roche, Sotio, Sutro and grants from GSK and Roche outside the submitted work. P. Follana reports personal fees from GSK, AstraZeneca, and Clovis outside the submitted work. R. Lord reports personal fees from GSK outside the submitted work. Z. Wang reports other from GSK during the conduct of the study; other from GSK outside the submitted work. D. Gupta reports other from GSK during the conduct of the study; other from GSK outside the submitted work; and D. Gupta is an employee of GSK which sponsored the NOVA trial. U. Matulonis reports personal fees from GSK, AstraZeneca, Merck, Novartis, Next Cure, Agenus, 2X oncology, Symphogen, Alkermes, and Morphosys during the conduct of the study; personal fees from Clearity Foundation and Ovarian Cancer Research Alliance outside the submitted work. B. Feng is an employee of GSK. No disclosures were reported by the other authors.

© 2022 The Authors; Published by the American Association for Cancer Research.

Figures

FIGURE 1
FIGURE 1
HRR status in the non-gBRCAm cohort of NOVA. A, GIS distribution by biomarker. B, GIS by biomarker. Of the 331 patients with HRR results, 41 did not have a GIS available for analysis; 2 patients had both BRCA mutation and non-BRCA HRRm and were classified as sBRCAm. BRCAwt, BRCA wild type; gBRCAm, germline BRCA mutated; GIS, genomic instability score; HRR, homologous recombination repair; HRRm, homologous recombination repair mutated; HRRwt, homologous recombination repair wild type; sBRCAm, somatic BRCA mutated.
FIGURE 2
FIGURE 2
Efficacy by biomarker subgroup in the non-gBRCAm cohort presented by biomarker allocation flowchart (A) and forest plot (B). BRCAwt, BRCA wild type; DDR, DNA damage repair; gBRCAm, germline BRCA mutated; GIS, genomic instability score; HR, hazard ratio; HRRm, homologous recombination repair mutated; HRRwt, homologous recombination repair wild type; sBRCAm, somatic BRCA mutated.
FIGURE 3
FIGURE 3
Clinical benefit of niraparib in patients with sBRCAm versus patients with BRCAwt tumors in the NOVA non-gBRCAm cohort. Kaplan--Meier estimates of progression-free survival in the niraparib group and in the placebo group among patients with biallelic sBRCAm (A), sBRCAm (B), and BRCAwt tumors (C). BRCAwt, BRCA wild type; gBRCAm, germline BRCA mutated; mPFS, median progression-free survival; sBRCAm, somatic BRCA mutated.
FIGURE 4
FIGURE 4
Clinical benefit of niraparib in patients with non-BRCA HRRm versus patients with BRCAwt/HRRwt tumors in the NOVA non-gBRCAm cohort. Kaplan--Meier estimates of PFS in the niraparib group and in the placebo group among patients with non-BRCA HRRm (A), BRCAwt/HRRm (B), non-BRCA biallelic HRRm (C), and non-BRCA monoallelic or unknown allelic status HRRm tumors (D). BRCAwt, BRCA wild type; gBRCAm, germline BRCA mutated; HRRm, homologous recombination repair mutated; HRRwt, homologous recombination repair wild type; mPFS, median progression-free survival.
FIGURE 5
FIGURE 5
Clinical benefit of niraparib in patients with BRCAwt/HRRwt tumors with GIS ≥ 42 versus <42 in NOVA non-gBRCAm cohort. Kaplan--Meier estimates of PFS in the niraparib group and in the placebo group among patients with BRCAwt/HRRwt GIS ≥ 42 (A) and BRCAwt/HRRwt GIS < 42 (B) tumors. BRCAwt, BRCA wild type; gBRCAm, germline BRCA mutated; GIS, genomic instability score; HRRwt, homologous recombination repair wild type; mPFS, median progression-free survival.

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