TABLE 2.
Clinical Utility
| Study and Year of Publication | Design | No. of Patients | Treatment | Included Histologic Subtypes | Genomic Alteration | Survival Results |
|---|---|---|---|---|---|---|
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| First-line therapy and ma inte nance | ||||||
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| Coleman et al,28 2019 | Phase III RCT: VELIA | 1,140 | Veliparib (150 mg twice a day) plus carboplatin/paclitaxel then veliparib (400 mg twice a day) maintenance therapy | HGSOC | All-comers population, with and without a BRCA mutation | PFS overall: HR, 0.68 (95% CI, 0.56 to 0.83) |
| PFS by subgroup: HRD BRCAm: HR, 0.44 (95% CI, 0.28 to 0.68) HRD BRCAwt: HR, 0.74 (95% CI, 0.52 to 1.06) HRP BRCAwt: HR, 0.81 (95% CI, 0.60 to 1.09) | ||||||
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| Maintenance after front-line therapy | ||||||
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| Moore et al,23 2018 | Phase III RCT: SOLO1 | 391 | Olaparib (300-mg tablet formulation) | HGSOC | Germline and somatic BRCA1 and BRCA2 | PFS overall: HR, 0.30 (95% CI, 0.23 to 0.41) |
| PFS by subgroup: Germline BRCA1m: HR, 0.4 (95% CI, 0.29 to 0.56) Germline BRCA2m: HR, 0.2 (95% CI, 0.10 to 0.38) | ||||||
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| Ray-Coquard et al,29 2019 (abstract) | Phase III RCT: PAOLA-1 | 806 | Olaparib (300 mg twice a day) plus bevacizumab | HGS/endometrioid | All-comers population, with and without a BRCA mutation | PFS overall: HR, 0.59 (95% CI, 0.49 to 0.72) |
| PFS by subgroup: Tumor BRCAm: HR, 0.31 (95% CI, 0.20 to 0.47) BRCAwt: HR, 0.71 (95% CI, 0.58 to 0.88) HRD (including tumor BRCAm): HR, 0.33 (95% CI, 0.25 to 0.45) HRD/BRCAwt: HR, 0.43 (95% CI, 0.28 to 0.66) HRP or unknown/BRCAwt: HR, 0.92 (95% CI, 0.72 to 1.17) | ||||||
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| González-Martin et al,30 2019 | Phase III RCT: PRIMA | 733 | Niraparib (300 mg) | HGS/endometrioid | All-comers population, with and without a BRCA mutation | PFS overall: HR, 0.62 (95% CI, 0.50 to 0.76) |
| PFS by subgroup: HRD/BRCAm: HR, 0.40 (95% CI, 0.27 to 0.62) HRD/BRCAwt: HR, 0.50 (95% CI, 0.31 to 0.83) HRP: HR, 0.68 (95% CI, 0.49 to 0.94) | ||||||
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| Maintenance therapy for recurrent platinum-sensitive disease | ||||||
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| Ledermann et al, 2012,18 2014,19 and 201620; Matulonis et al,21 2016, Dougherty et al,16 2017 |
Phase II RCT: Study 19 (BRCA mutation analyzed retrospectively) | 316 | Olaparib (400-mg capsule formulation) | HGSOC | Germline and somitic BRCA1 and BRCA2 | PFS overall (BRCAm subset, n = 136): HR, 0.18 (95% CI, 0.1 to 0.31) |
| PFS: gBRCAm: HR, 0.17 (95% CI, 0.09 to 0.34) sBRCAm: HR, 0.23 (95% CI, 0.04 to 1.12) OS overall (BRCAm subset, n = 136): HR, 0.62 (95% CI, 0.41 to 0.94) | ||||||
| OS by subgroupa: BRCAm: HR, 0.62 (95% CI, 0.41 to 0.94) gBRCAm: HR, 0.64 (95% CI, 0.39 to 1.04) sBRCAm: HR, 0.26 (95% CI, 0.04 to 1.21) BRCA1m: HR, 0.60 (95% CI, 0.36 to 0.99) BRCA2m: HR, 0.62 (95% CI, 0.29 to 1.37) | ||||||
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| Pujade-Lauraine et al,24 2017 | Phase III RCT: SOLO2 | 295 | Olaparib (300-mg tablet formulation) | HGSOC | Germline and somitic BRCA1 and BRCA2 | PFS overall: HR, 0.30 (95% CI, 0.22 to 0.41) |
| OS overall: HR, 0.80 (95% CI, 0.50 to 1.31) | ||||||
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| Coleman 201714 | Phase III RCT: ARIEL3 | 564 | Rucaparib (600-mg capsule formulation) | HGSOC or endometrioid | Germline BRCA1 and BRCA2 Somatic BRCA1 and BRCA2 Homologous recomblnation genes (BRCA1, BRCA2, ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RPA1) | PFS overall: HR, 0.37 (95% CI, 0.30 to 0.45) |
| PFS by subgroup: BRCA1: HR, 0.32 (95% CI, 0.19 to 0.53) BRCA2: HR, 0.12 (95% CI, 0.06 to 0.26) Germline: HR, 0.25 (95% CI, 0.16 to 0.39) Somitic: HR, 0.23 (95% CI, 0.10 to 0.54) BRCAm according to blood or tissue test: HR, 0.23 (95% CI, 0.16 to 0.33) BRCAwt: LOH high: HR, 0.44 (95% CI, 0.29 to 0.66) LOH low: HR, 0.58 (95% CI, 0.40 to 0.85) LOH indeterminate: HR, 0.25 (95% CI, 0.11 to 0.56) | ||||||
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| Mirza et al,22 2016 | Phase III RCT: NOVA | 553 (203 with gBRCAm) | Niraparib (300-mg capsule formulation) | Predominantly HGS histologic features | Germline and somitic BRCA1 and BRCA2 HRD (as determined by myChoice HRD test) | PFS by subgroup: gBRCAm: HR, 0.27 (95% CI, 0.17 to 0.41) No gBRCAm with HRD positlvity: HR, 0.38 (95% CI, 0.24 to 0.59) No gBRCAm: HR, 0.45 (95% CI, 0.34 to 0.61) |
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| Later-line treatment | ||||||
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| Domcheck et al,15 2016 | Phase II single arm: Study 42 | 193 ovarian subset (154 with germline BRCA 1/2 mutation) | Olaparib (400-mg capsules formulation) | HGSOC | Germline BRCA1 and BRCA2 | PFS rate: 54.6% Median PFS by subgroup: 7 months |
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| Kristeleit et al,17 2017 | Phase II single arm: Study 10 | 42 | Rucaparib (600 mg twice a day, capsule) | HGSOC or endometrioid | Germline BRCA1 and BRCA2 | PFS rate: 59.5% Median PFS by subgroup: 7.8 months |
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| Swisher et al,25 2017 | Phase II single arm: ARIEL2 | 40 | Rucaparib (600 mg twice a day, capsule) | HGSOC or endometrioid | Germline and somitic BRCA1 and BRCA2 |
BRCAm: 50% LOH low: 10% PFS HR, 0.27 (95% CI, 0.16 to 0.44) P < .0001 LOH high: 28% LOH low: 10% PFS HR, 0.62 (95% CI, 0.42 to 0.90) P = .011 |
NOTE. Clinical utility not established. Demonstrated utility is prognostic for all studies.
Abbreviations: BRCAm, BRCA mutation; BRCA1m, mutation in BRCA1 only; BRCA2m, mutation in BRCA2 only; BRCAwt, BRCA wild-type; gBRCAm, germline BRCA mutation; HGS, high-grade serous; HGSOC, high-grade serous ovarian cancer; HR, hazard ratio; HRD, homologous recombination deficient; HRP, homologous recombination proficient; LOH, loss of heterozygosity; PFS, progression-free survival; RCT, randomized controlled trial; sBRCAm, somatic BRCA mutation.
a
Homologous recombination gene mutations have been preclinically linked to poly (ADP-ribose) polymerase inhibitor sensitivity. They are mechanistically analogous to BRCAm and linked to prolonged survival and platinum sensitivity in ovarian cancer. However, it is difficult to gauge the impact of individual genes due to low prevalence and some evidence of nonmutual exclusivity.114