- •Indications and toxicities of clinically applicable PARP inhibitors
- •Novel biomarkers to predict PARP inhibitor response
- •Molecular mechanisms of PARP inhibitor resistance
- •Managing PARP inhibitor resistant ovarian cancer
1.2 Ovarian cancer and homologous recombination repair
2. PARP inhibitors
- Pujade-Lauraine E.
- Ledermann J.A.
- Selle F.
- Gebski V.
- Penson R.T.
- Oza A.M.
- et al.
- Ledermann J.A.
- Harter P.
- Gourley C.
- Friedlander M.
- Vergote I.
- Rustin G.
- et al.
|Olaparib SOLO2/ENGOT-Ov21 (n = 195)||Niraparib NOVA/ENGOT-OV16 (n = 367)||Rucaparib ARIEL2 (n = 204)/ARIEL3 (n = 374)||Veliparib Coleman, RL 2015 (n = 50)||Talazoparib|
NCT01286987 (n = 71)
|Grade 3 and 4 adverse events||Anemia 38 (18%)||Thrombocytopenia 128 (33.8%)||Anemia 22 (45%)/70 (19%)||Leukopenia 1 (2%)||Anemia 16 (23%)|
|Fatigue 8 (4%)||Anemia 93 (25.3%)||Fatigue 18 (9%)/25 (7%)||Thrombocytopenia 1 (2%)||Thrombocytopenia 13 (18%)|
|Neutropenia 8 (4%)||Neutropenia 72 (19.6%)||Neutropenia 16 (7%)/25 (7%)||Neutropenia 1 (2%)||Neutropenia 7 (10%)|
|Abdominal pain 5 (3%)||Hypertension 30 (8.2%)||Nausea 9 (4%)/14 (4%)||Nausea 2 (4%)||Fatigue 2 (3%)|
|Nausea 5 (3%)||Fatigue 30 (8.2%)||Elevated AST/ALT 25 (13%)/39 (10%)||Metabolism/nutrition 1 (2%)|
|Vomiting 5 (3%)||Nausea 11 (3.0%)||Abdominal pain 5 (2%)/9 (2%)||Other investigations 6 (12%)|
|Thrombocytopenia 2 (1%)||Abdominal pain 4 (1.1%)||Thrombocytopenia 5 (2%)/19 (5%)|
|Serious adverse events||Total 35 (18%)||Total 110 (30%)||ARIEL2: total 50 (25%)||Total 12 (24%)||Not reported.|
|Anemia 7 (4%)||Intestinal obstruction 10 (5%)|
|Abdominal pain 3 (2%)||Anemia 9 (4%)|
|Intestinal obstruction 3 (2%)||ARIEL3: total 78 (21%)|
|Anemia 16 (4%)|
|Pyrexia 6 (2%)|
|Vomiting 6 (2%)|
|Intestinal obstruction 3 (1%)|
|Changes in dose due to AE||Dose reductions 49 (25%)||Dose reductions: 244 (66.5%)||ARIEL2:||Dose Reductions: 31 (62%)||Dose reductions from 1.0 mg/day dose: 26 (34%)|
|Discontinuations 21 (11%)||Discontinuations: 54 (14.7%)||Dose reductions: 80 (39%)||Discontinuations: 31 (62%)|
|Discontinuations: 19 (9%)|
|Dose reductions: 203 (55%)|
|Discontinuations: 50 (13%)|
2.2 Clinical development
- Coleman R.L.
- Sill M.W.
- Bell-McGuinn K.
- Aghajanian C.
- Gray H.J.
- Tewari K.S.
- et al.
- Reiss K.A.
- Herman J.M.
- Armstrong D.
- Zahurak M.
- Fyles A.
- Brade A.
- et al.
- Geyer C.E.
- O'Shaughnessy J.
- Untch M.
- Sikov W.
- Hope R.S.
- M M.D.
- et al.
|Niraparib/bevacizumab||Platinum-sensitive epithelial ovarian cancer||I/II||NCT02354131||VEGFR|
|Niraparib/pembrolizumab||Triple-negative breast cancer or ovarian cancer||I/II||NCT02657889||PD-1|
|Olaparib/AT13387||Metastatic solid tumors/cannot be removed by surgery/recurrent ovarian/fallopian tube/primary peritoneal/triple-negative breast cancer||I||NCT02898207||HSP90|
|Olaparib/AZD2014/AZD5363||Recurrent endometrial, triple negative breast, and ovarian, primary peritoneal, or fallopian tube cancer||I/II||NCT02208375||mTORC1/2 or AKT|
|Olaparib/AZD2281/AZD5363/AZD1775/AZD2014||Advanced solid tumors||II||NCT02576444||PI3K/AKT, WEE1, mTORC1/2|
|Olaparib/cediranib||Time ovarian cancer worsens on olaparib||II||NCT02340611||VEGFR1/2/3|
|Olaparib/cediranib||Patients with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer||III||NCT02446600||VEGFR1/2/3|
|Olaparib/cediranib/MEDI4736||Advanced solid tumors and advanced or recurrent ovarian, triple negative breast, lung, prostate and colorectal cancers||I/II||NCT02484404||VEGFR1/2/3, PD-L1|
|Olaparib/prexasertib||Advanced solid tumors||I||NCT03057145||CHK1|
|Olaparib/tremelimumab||BRCA-deficient ovarian cancer||I/II||NCT02571725||CTLA4|
|Rucaparib/atezolizumab||Solid tumors and advanced gynecologic cancers||II||NCT03101280||PD-L1|
|Veliparib/carboplatin/paclitaxel||Maintenance therapy in newly diagnosed stage III or IV high-grade serous/epithelial ovarian/fallopian tube/primary peritoneal cancer||III||NCT02470585||Standard-of-care|
|Veliparib/dinaciclib||Advanced solid tumors (BRCA1/2 mutation)||I||NCT01434316||CDK12|
|Veliparib/floxuridine||Metastatic epithelial ovarian, primary peritoneal cavity, or fallopian tube cancer||I||NCT01749397||Nucleotide analog|
|Veliparib/irinotecan||Stage III, IIIB, IIIC, IV ovarian cancer||I||NCT00576654||Topoisomerase|
|Veliparib/irinotecan||Cancer that is metastatic or cannot be removed by surgery||I||NCT02484404||Topoisomerase|
|Veliparib/liposomal irinotecan||Malignant solid neoplasm||I||NCT02631733||Topoisomerase|
|Veliparib/nivolumab||Recurrent or refractory stage IV solid tumors that cannot be removed or lymphoma with or without alterations in DNA repair genes||I||NCT03061188||PD-1|
|Veliparib/topotecan||Solid tumors, relapsed or refractory ovarian cancer, or primary peritoneal cancer||I/II||NCT01012817||Topoisomerase|
|Veliparib/VX-970/cisplatin||Refractory solid tumors||I||NCT02723864||ATR|
3.1 Panel of HR-related biomarkers
3.1.1 Functional DNA repair
3.2 PARP expression
3.3 Implications of PARPi treatment
4. PARP inhibitor resistance
4.1 Homologous recombination repair restoration
4.1.1 Secondary BRCA1/2 mutations
4.1.2 53BP1 regulation
4.1.3 Replication fork dynamics
- Samol J.
- Ranson M.
- Scott E.
- Macpherson E.
- Carmichael J.
- Thomas A.
- et al.
4.2 Exploiting altered cell cycle regulation
4.3 Drug efflux
4.4 Signal transduction
4.5 miRNA environment
4.6 PARP expression
Conflict of interest
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