The Current Status of DNA-Repair-Directed Precision Oncology Strategies in Epithelial Ovarian Cancers
Abstract
:1. Introduction
1.1. The Biology of DNA Repair Pathways
1.1.1. DNA Repair Pathways
1.1.2. Direct Reversal
1.1.3. Base Excision Repair (BER)
1.1.4. Nucleotide Excision Repair (NER)
1.1.5. Mismatch Repair (MMR)
1.1.6. Nonhomologous End Joining (NHEJ)
1.1.7. Homologous Recombination (HR)
2. DNA Repair and Cancer
3. Limitations of Conventional Chemotherapy
4. BRCA/HRD Mutations in Ovarian Cancer
5. BRCA Deficiency
6. HR Deficiency (HRD)
7. Therapeutic Manipulation of DNA Damage Pathways to Treat Ovarian Cancer (Table 1)
7.1. PARP Inhibitors as Primary Maintenance Therapy
Trial Name | Study Title | Author and Year Published | BRCA-Mutated or HRD Tumours Only | PARPi | Comparator | Sample Size | mPFS PARPi vs. Comparator (months) | HR (95% CI) | Other Relevant Results |
---|---|---|---|---|---|---|---|---|---|
PRIMARY MAINTENANCE THERAPY | |||||||||
SOLO-1 | Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer | Moore et al., 2018 [94] and Banerjee et al., 2021 [95] | Yes | Olaparib (300 mg BD) | Placebo | 391 | 56.0 vs. 13.8 | 0.33 (0.25–0.43) | Rate of freedom from disease progression: 60% olaparib and 27% placebo (p < 0.001) |
PRIMA | Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer | González-Martín et al., 2019 [96] | No | Niraparib (200 mg or 300 mg OD) | Placebo | 733 | All: 13.8 vs. 8.2 HRD: 21.9 vs. 10.4 | All: 0.62 (0.50–0.76) HRD: 0.43 (0.31–0.59) | OS: 84% in niraparib group vs. 77% in placebo group at 24 months |
PAOLA-1 | Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer | Ray-Coquard et al., 2019 [97] | No | Olaparib (300 mg BD) plus bevacizumab (15 mg/kg IV 3 weekly) | Placebo plus bevacizumab (15 mg/kg IV 3 weekly) | 806 | All: 22.1 vs. 16.6 HRD: 28.1 vs. 16.6 | All: 0.33 (0.25–0.45) HRD: 0.43 (0.28–0.66) | |
OVARIO | OVARIO phase II trial of combination niraparib plus bevacizumab maintenance therapy in advanced ovarian cancer following first-line platinum-based chemotherapy with bevacizumab | Hardesty et al., 2022 [99] | No | Niraparib (200 or 300 mg OD) plus bevacizumab (15 mg/kg IV 3 weekly) | Nil | 105 | All: 19.6 HRD: 28.2 HR-proficient: 14.2 | PFS rate at 18 months: All: 62% HRD: 76% HR-proficient: 56% | |
ATHENA-MONO | A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45) | Monk et al., 2022 [100] | No | Rucaparib (600 mg BD) | Placebo | 538 | All: 20.2 vs. 9.2 HRD: 28.7 vs. 11.3 HR-proficient: 12.1 vs. 9.1 | All: 0.52 (0.40–0.68) HRD: 0.47 (0.31–0.72) HR-proficient: 0.65 (0.45–0.95) | All ORR: 48.8% in rucaparib group vs. 9.1% in placebo group HRD ORR: 58.8% in rucaparib group vs. 20% in placebo |
VELIA | Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer | Coleman et al., 2019 [101] | No | Veliparib (150 mg OD) plus chemotherapy followed by Veliparib maintenance | Chemotherapy plus placebo, chemotherapy plus veliparib followed by placebo maintenance | 1140 | All: 23.5 vs. 17.3 gBRCA: 34.7 vs. 22.0 HRD: 31.9 vs. 20.5 | All: 0.68 (0.56–0.83) eBRCA: 0.44 (0.28–0.68) HRD: 0.57 (0.43–0.76) | ORR: 84% in veliparib-throughout group vs. 74% in the control group after six chemotherapy cycles |
RECURRENT MAINTENANCE THERAPY | |||||||||
SOLO-2 | Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial | Pujade-Lauraine et al., 2017 [102] | Yes | Olaparib (300 mg BD) | Placebo | 295 | 19.1 vs. 5.5 | 0.30 (0.22–0.41) | 24 months without disease progression rate 43.0% in olaparib group vs. 15.1% in placebo group |
NOVA | Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer21 | Mirza et al., 2016 [103] | No | Niraparib (300 mg OD) | Placebo | 553 | gBRCA: 21.0 vs. 5.5 non-gBRCA: 9.3 vs. 3.9 HRD: 12.9 vs. 3.8 | gBRCA: 0.27 (0.17–0.41) non-gBRCA: 0.45 (0.34–0.61) HRD: 0.38 (0.24–0.59) | |
ARIEL3 | Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial | Coleman et al., 2017 [104] | No | Rucaparib (600 mg BD) | Placebo | 564 | All:10.8 vs. 5.4 BRCAm:16.6 vs. 5.4 HRD: 13.6 vs. 5.4 | 0.36 (0.30–0.45) | |
OReO | Maintenance olaparib rechallenge in patients with ovarian carcinoma previously treated with a PARP inhibitor (PARPi): Phase IIIb OReO/ENGOT Ov-38 trial | Pujade-Lauraine et al., 2021 [105] | No | Olaparib (300 mg BD) | Placebo | 220 | BRCAm: 4.3 vs. 2.8 non-BRCAm: 5.3 vs. 2.8 | BRCAm: 0.57 (0.37–0.87) non-BRCAm: 0.43 (0.26–0.71) | |
MONOTHERAPY FOR RELAPSED DISEASE | |||||||||
SOLO-3 | Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial | Penson et al., 2020 [106] | Yes | Olaparib (300 mg BD) | Physician’s choice single-agent nonplatinum chemotherapy | 266 | 13.4 vs. 9.2 | 0.62 (0.43–0.91) | ORR: 72.2% for olaparib vs. 51.4% for chemotherapy |
ARIEL4 | Overall survival results from ARIEL4: A phase III study assessing rucaparib vs. chemotherapy in patients with advanced, relapsed ovarian carcinoma and a deleterious BRCA1/2 mutation | Oza et al., 2022 [107] and Kristeleit et al., 2022 [108] | Yes | Rucaparib (600 mg BD) | Chemotherapy | 349 | 7.4 vs. 5.7 | 0.67 (0.52–0.86) | Median OS: rucaparib group 19.4 months vs. 25.4 months in chemotherapy group |
PARP-INHIBITOR-BASED COMBINATION STRATEGIES WITH CHEMOTHERAPY FOR RELAPSED DISEASE | |||||||||
N/A | Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial | Oza et al., 2015 [109] | No | Olaparib (200 mg BD) plus chemotherapy followed by Olaparib maintenance monotherapy | Chemotherapy | 162 | 12.2 vs. 9.6 | 0.51 (0.35–0.77) | Olaparib especially effective in BCRm: HR 0.21 (0.08–0.55) |
N/A | Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer | Kummar et al., 2015 [110] | No | Veliparib (60 mg OD) plus cyclophosphamide (50 mg OD) | Cyclophosphamide (50 mg OD) alone | 75 | 2.1 vs. 2.3 | NA | One complete response in each arm, three partial responses in the veliparib group, and six partial responses in the cyclophosphamide group |
ROLANDO | Olaparib in combination with pegylated liposomal doxorubicin for platinum-resistant ovarian cancer regardless of BRCA status: a GEICO phase II trial (ROLANDO study) | Perez-Fidalgo et al., 2021 [111] | No | Olaparib (300 mg BD) plus PLD chemotherapy, followed by maintenance olaparib | Nil | 31 | 5.8 | NA | Overall disease control rate 77% (29% partial response, 48% stable disease) |
PARP INHIBITOR-BASED COMBINATION STRATEGIES WITH ANTIANGIOGENIC THERAPY FOR RELAPSED DISEASE | |||||||||
N/A | Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer | Liu et al., 2019 [112] | No | Olaparib (200 mg BD) plus cediranib (30 mg OD) | Olaparib (400 mg BD) alone | 90 | All: 16.5 vs. 8.2 Non-BRCA/unknown: 23.7 vs. 5.7 | 0.50 (0.30–0.83) | Median OS: combination arm 44.2 vs. 33.3 months in monotherapy |
NSGO-AVANOVA2/ENGOT-ov24 | Niraparib plus bevacizumab versus niraparib alone for platinum-sensitive recurrent ovarian cancer (NSGO-AVANOVA2/ENGOT-ov24): a randomised, phase 2, superiority trial | Mirza et al., 2019 [113] | No | Niraparib (300 mg OD) plus bevacizumab (15 mg/kg IV 3 weekly) | Niraparib (300 mg OD) alone | 97 | 11.9 vs. 5.5 | 0.35 (0.21–0.57) | ORR: combination 60% vs. 27% niraparib alone |
7.2. PARP Inhibitors as Recurrent Maintenance Therapy
7.3. PARP Inhibitor Monotherapy for Relapsed Advanced Ovarian Cancer
7.4. PARP-Inhibitor-Based Combination Strategies for Relapsed Advanced Ovarian Cancer
7.4.1. Chemotherapy
7.4.2. Antiangiogenics
8. Interplay between DNA Damage and Antitumour Immune Responses
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
List of Abbreviations
ABH2 | Alkylated DNA repair protein alkB homolog 2 |
ABH3 | Alkylated DNA repair protein alkB homolog 3 |
AML | Acute myeloid leukaemia |
APE1 | AP-endonuclease 1 |
BER | Base excision repair |
BRCA | Breast cancer susceptibility protein |
DDB2 | DNA damage-binding protein 2 |
DDR | DNA damage response |
DNA | Deoxyribonucleic acid |
DNA-PKcs | DNA-dependent protein kinase catalytic subunit |
DSB | Double stand break |
EOC | Epithelial ovarian cancer |
FDA | Food and Drug Administration |
FEN1 | Flap-endonuclease 1 |
GG-NER | Global-genome NER |
gLOH | Genomic patterns of loss of heterozygosity |
HNPCC | Hereditary nonpolyposis colorectal cancer |
HR | Homologous recombination |
ICL | Interstrand crosslink |
IDL | Insertion/deletion loop |
IR | Ionizing radiation |
MDS | Myelodysplastic syndrome |
MGMT | Methylguanine methyltransferase |
MLH1 | MutL homolog 1 |
MMC | Mitomycin C |
MMR | Mismatch repair |
MRN | Mre11-Rad50-Nbs1 |
MSH2 | MutS homolog 2 |
MSH3 | MutS homolog 3 |
NER | Nucleotide excision repair |
NGS | Next-generation sequencing |
NHEJ | Non-homologous end joining |
OS | Overall survival |
PARP | Poly(ADP-ribose) polymerase |
PARPi | Poly(ADP-ribose) polymerase inhibitor |
PCNA | Proliferating cell nuclear antigen |
PD1 | Programmed cell death protein 1 |
PD-L1 | Programmed cell death ligand 1 |
PFS | Progression-free survival |
PLD | Pegylated liposomal doxorubicin |
PMS2 | Postmeiotic segregation increased 2 |
PNKP | Polynucleotide kinase/phosphatase |
Polβ | Polymerase beta |
ROS | Reactive oxygen species |
RPA | Replication protein A |
SDSA | Synthesis-dependent strand annealing |
SSBR | Single-strand break repair |
TC-NER | Transcription-coupled NER |
UV | Ultraviolet |
XRCC1 | X-ray cross-complementing group 1 protein |
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Tang, H.; Kulkarni, S.; Peters, C.; Eddison, J.; Al-Ani, M.; Madhusudan, S. The Current Status of DNA-Repair-Directed Precision Oncology Strategies in Epithelial Ovarian Cancers. Int. J. Mol. Sci. 2023, 24, 7293. https://doi.org/10.3390/ijms24087293
Tang H, Kulkarni S, Peters C, Eddison J, Al-Ani M, Madhusudan S. The Current Status of DNA-Repair-Directed Precision Oncology Strategies in Epithelial Ovarian Cancers. International Journal of Molecular Sciences. 2023; 24(8):7293. https://doi.org/10.3390/ijms24087293
Chicago/Turabian StyleTang, Hiu, Sanat Kulkarni, Christina Peters, Jasper Eddison, Maryam Al-Ani, and Srinivasan Madhusudan. 2023. "The Current Status of DNA-Repair-Directed Precision Oncology Strategies in Epithelial Ovarian Cancers" International Journal of Molecular Sciences 24, no. 8: 7293. https://doi.org/10.3390/ijms24087293
APA StyleTang, H., Kulkarni, S., Peters, C., Eddison, J., Al-Ani, M., & Madhusudan, S. (2023). The Current Status of DNA-Repair-Directed Precision Oncology Strategies in Epithelial Ovarian Cancers. International Journal of Molecular Sciences, 24(8), 7293. https://doi.org/10.3390/ijms24087293