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The evolving role of PARP inhibitors in advanced ovarian cancer Cover

The evolving role of PARP inhibitors in advanced ovarian cancer

Forum of Clinical Oncology
Volume 12 (2021): Issue 1 (May 2021)
By: Sofia Levva,  Aglaia Skolariki,  Eleni Sogka,  Alexandros Bokas,  Avraam Assi,  Marianna K. Pispirigou and  Panagiotis Koliou  
Open Access
|Aug 2021

Figures & Tables

Clinical trials of niraparib combinations with other agents in ovarian cancer_

StudyCombinationYearPhaseCancer typeNiraparib dosageStatuts / Outcome
NCT04217798Etoposide2020IIResistant/Refractory Ovarian cancer200mg dailyTo be initiated
NCT04149145M4344 – ATR inhibitor2020I/IIResistant/Recurrent Ovarian cancerStarting with 100mg, escalating to 200mgTo be initiated
NCT03895788Brivanib2019IRecurrent Ovarian cancer100mg or 200 mg, dailyRecruiting
NCT03602859-ENGOT-OV44 /FIRST studyDostarlimab – anti-PD-12018III1st line non-mucinous Ovarian cancer300mg dailyRecruiting
NCT03695380Cobimetinib +/Atezolizumab2018IbPlatinum sensitive ovarian cancer200mg dailyRecruiting
NCT03955471 – MOONSTONE trialTSR-042 anti-PD-12019IIRecurrent platinum-resistant Ovarian cancerN/ARecruiting
ENGOT-OV24-NSGO/AVANOVA trialBevacizumab2019I/IIOvarian cancer, Platinum-sensitive300mg D1-21PFS benefit with the combination [11,9 months (95% CI 8,5–16,7) vs 5,5 months (3,8 – 6,3)], HR 0,35 (95% CI 0·21–0·57), p<000,1Ⴕ
NCT04267939BAY1895344 ATR inhibitor2020IbPARPi naïve and with a platinum-resistant/refractory disease or PD after PARPi maintenanceN/ARecruiting
NCT03574779 OPAL trialDostarlimab and bevacizumab2018IIRecurrent Ovarian cancer200mg or 300mg dailyActive – not recruiting- no results yet
NCT03326193 OVARIO trialbevacizumab2018IIPlatinum sensitive Ovarian cancer300mg dailyActive – not recruiting- no results yet
NCT03598270 ANITA trialAtezolizumab2018IIIPlatinum sensitive relapse200mg or 300mg dailyRecruiting
NCT02657889 - TOPACIO/KEYNOTE-162 trialPebrolizumab I/IITriple negative Breast cancer or recurrent ovarian cancer200mgORR of 25% in all PROC and ORR of 45% in tBRCAmut patients, well toleratedᶧ
NCT03154281Everolimus2017IRecurrent ovarian or breast cancer100mg or200mg or 300mg dailyRecruiting
NCT03586661Copanlisib2018IEndometrial and Ovarian cancerEscalating doseRecruiting

Clinical trials of rucaparib combinations with other agents in ovarian cancer_

StudyCombinationYearPhaseCancer typeRucaparib dosageStatuts / Outcome
NCT03462212 (MITO25)Carboplatin/Paclitaxel +/− Bevacizumab2018IIResistant/Refractory Ovarian cancer400mg or 500mg 0r 600mg BIDᵒRecruiting
ATHENA trialNivolumab2018I/IIPlatinum Sensitive Ovarian cancer600mg BIDRecruiting
NCT03840200Ipatasertib (Akt inhibitor)2019IbBreast, Prostate and Ovarian cancer600mg BIDRecruiting
NCT02873962Nivolumab and bevacizumab2016II2nd line Ovarian cancer600mg BIDRecruiting
NCT03992131 (SEASTAR trial)Lucitanib (VEGF 1–3 inhibitor) or Sacituzumab (anti-Trop-2 monoclonal antibody linked with SN-38)2019I/IISolid tumors600mg BIDRecruiting
NCT03824704 – ARIES trialNivolumab2019IIPlatinum sensitive recurrent Ovarian cancerN/AActive/not Recruiting
NCT03552471Mirvetuximab Soravtansine (olate receptor alpha targeting antibody-drug conjugate)2018IRecurrent Ovarian cancer600mg BIDRecruiting
NCT04267939BAY1895344 ATR inhibitor2020IbPARPi naïve and with a platinum-resistant/refractory disease or PD after PARPi maintenanceN/ARecruiting
NCT03574779 OPAL trialDostarlimab and bevacizumab2018IIRecurrent Ovarian cancer200mg or 300mg dailyActive – not recruiting- no results yet
NCT03326193 OVARIO trialbevacizumab2018IIPlatinum sensitive Ovarian cancer300mg dailyActive – not recruiting- no results yet

Recruiting clinical trials of olaparib combinations with other agents in ovarian cancer_

StudyCombinationYearPhaseCancer type
NCT03772561Durvalumab2018ISolid tumors
NCT03682289ATR kinase inhibitor AZD67382019IISolid tumors
NCT02485990Tremelimumab2020IRecurrent or persistent ovarian cancer
NCT02953457Durvalumab and tremelimumab2016IIRecurrent or resistant Mbrca Ovarian cancer
NCT04123366Pebrolizummab2020IISolid tumors, mHRD, dHRD
NCT03162627Selumetinib2017I/IIEndometrial, Ovarian cancer and other solid tumors
NCT03462342 (CAPRI Trial)Ceralasertib (AZD6738)2018IIRecurrent Ovarian cancer
NCT03579316Adavosertib2018IIOvarian cancer

Clinical trials of veliparib combinations with other agents in ovarian cancer_

StudyCombinationYearPhaseCancer typeRucaparib dosageStatuts / Outcome
NCT02470585Topototecan2017I/IIResistant/Partially Sensitive Ovarian cancer30 mg BIDᵒ, on D1-3 and 8–10, q28Well tolerated, Best response – SD in 37%
NCT01113957Temozolamide2018IIRecurrent Ovarian cancerNACompleted No Results yet
NCT02470585 - VELIA trialCarboplatin and Paclitaxel2019IIINewly diagnosed Ovarian cancerInduction: 150 mg BID q21Maintenance: 300 BID for 2 weeks, escalating to 400 mg BIDPFS 23.5 vs 17.3 months (HR = 0.68; P < .001)
Japanese trialPaclitaxel-carboplatin2016INewly diagnosed Ovarian cancer100mg – 150mg BID q21Well tolerated/potential clinical benefit
NCT01459380Pegylated Liposomal Doxorubicin and carboplatin +/− bevacizumab2015IRecurrent, platinum-sensitive ovarian cancer50mg or 80mg 0r 120mgWell tolerated in low doses of veliparib
NCT01233505Capecitabine and oxaliplatin2014ISolid tumors40mg BID days 1–7, 15–21, q28Well tolerated
NCT01306032Cyclophosphamide2016IIRefractory BRCA-Positive Ovarian Cancer and Breast cancer60mg dailyWell tolerated/no PFS benefit
NCT00989651Bevacizumab and Paclitaxel plus either carboplatin or IP cisplatin2009IOvarian cancerN/AActive-not recruiting

Completed clinical trials of olaparib combinations with other agents in ovarian cancer_

StudyCombinationYearPhaseCancer typeOlaparib dosageOutcome
NCT00516438Topotecan2009ISolid tumorsStarting with cap 50mg BIDᵒ continuously, escalatingUnacceptable toxicity
NCT00572364Dacarbazine2009ISolid tumorsCap 10mg BID continuouslyTolerated, no clinical benefit
NCT00710268Bevacizumab2015ISolid tumorsCap 400mg BIDWell tolerated
NCT00819221Lip-doxorubicin2017IOvarian cancerCap 150mg BID, continuouslyTolerated and clinical benefit
NCT02430311, Chinese populationPaclitaxel2019ISolid tumorsTb 100mb BIDReduce of olaparib bioavailability
NCT01650376Carboplatin and weekly paclitaxel2019IbOvarian cancerTb 150mg BID continuouslyTolerated-clinical benefit in BRCAm
GEICO1601-ROLANDO trialLip-doxorubicin2019IIOvarian cancer, Platinum-resistantTb 300mg BID continuouslyNot recruiting, waiting for results
NCT01081951Carboplatin and paclitaxel2020IIOvarian cancer-relapsed, platinum-sensitiveCap 200mg BID continuouslyPFS: 12.2 months (combo) vs 9.6 months (carboplatin/paclitaxel), HR : 0.51 (p=0.0012) OS: data not yet available

Biochemical Characteristics of PARP inhibitors_

Molecular formulaMolecular weight (g/mol)RoutePeak plasma concentrationPotencyIC50* Nmol PARP1/2Max tolerated doseHalf-life
OlaparibC24H23FN43434.5oral1–3hrPARP1>PARP2 >>PARP35/1Tb 300mg BIDᵒ Cap 400mg BID5–11hr
RucaparibC19H18FN3O323.4oral1.9hrPARP1>PARP2 >>PARP3 And tankyrase inhibitor1.4Tb 600mg BID17–19hr
NiraparibC19H20N4O320.4oral3hrPARP1=PARP23.2/4300mg once daily36hr
VeliparibC13H16N4O244.29oral0.5 – 1.5hrPARP1 PARP25.2/2.9Tb 400mg BID5.2hr
TalazoparibC19H14F2N6O380.4oral1–2hr 1.2/0.9Cap 1mg daily90hr
DOI: https://doi.org/10.2478/fco-2021-0002 | Journal eISSN: 1792-362X | Journal ISSN: 1792-345X
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Language: English
Page range: 82 - 104
Submitted on: Jan 2, 2021
Accepted on: Feb 18, 2021
Published on: Aug 9, 2021
Published by: Helenic Society of Medical Oncology
In partnership with: Paradigm Publishing Services
Publication frequency: 2 issues per year
Keywords:
ovarian cancer,
PARP inhibitors,
BRCA mutation,
maintenance treatment,
resistance mechanisms,
homologous recombination deficiency
Related subjects:
Medicine,
Clinical medicine,
Internal medicine,
Haematology, oncology

© 2021 Sofia Levva, Aglaia Skolariki, Eleni Sogka, Alexandros Bokas, Avraam Assi, Marianna K. Pispirigou, Panagiotis Koliou, published by Helenic Society of Medical Oncology
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

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