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The evolving role of PARP inhibitors in advanced ovarian cancer

Sofia Levva
Sofia Levva
, 
Aglaia Skolariki
Aglaia Skolariki
, 
Eleni Sogka
Eleni Sogka
, 
Alexandros Bokas
Alexandros Bokas
, 
Avraam Assi
Avraam Assi
, 
Marianna K. Pispirigou
Marianna K. Pispirigou
 e 
Panagiotis Koliou
Panagiotis Koliou
   | 09 ago 2021
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INFORMAZIONI SU QUESTO ARTICOLO
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Article Category: Research Article
Pubblicato online: 09 ago 2021
Pagine: 82 - 104
Ricevuto: 02 gen 2021
Accettato: 18 feb 2021
DOI: https://doi.org/10.2478/fco-2021-0002
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© 2021 Sofia Levva et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Clinical trials of niraparib combinations with other agents in ovarian cancer.

Study Combination Year Phase Cancer type Niraparib dosage Statuts / Outcome
NCT04217798 Etoposide 2020 II Resistant/Refractory Ovarian cancer 200mg daily To be initiated
NCT04149145 M4344 – ATR inhibitor 2020 I/II Resistant/Recurrent Ovarian cancer Starting with 100mg, escalating to 200mg To be initiated
NCT03895788 Brivanib 2019 I Recurrent Ovarian cancer 100mg or 200 mg, daily Recruiting
NCT03602859-ENGOT-OV44 /FIRST study Dostarlimab – anti-PD-1 2018 III 1st line non-mucinous Ovarian cancer 300mg daily Recruiting
NCT03695380 Cobimetinib +/Atezolizumab 2018 Ib Platinum sensitive ovarian cancer 200mg daily Recruiting
NCT03955471 – MOONSTONE trial TSR-042 anti-PD-1 2019 II Recurrent platinum-resistant Ovarian cancer N/A Recruiting
ENGOT-OV24-NSGO/AVANOVA trial Bevacizumab 2019 I/II Ovarian cancer, Platinum-sensitive 300mg D1-21 PFS 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
NCT04267939 BAY1895344 ATR inhibitor 2020 Ib PARPi naïve and with a platinum-resistant/refractory disease or PD after PARPi maintenance N/A Recruiting
NCT03574779 OPAL trial Dostarlimab and bevacizumab 2018 II Recurrent Ovarian cancer 200mg or 300mg daily Active – not recruiting- no results yet
NCT03326193 OVARIO trial bevacizumab 2018 II Platinum sensitive Ovarian cancer 300mg daily Active – not recruiting- no results yet
NCT03598270 ANITA trial Atezolizumab 2018 III Platinum sensitive relapse 200mg or 300mg daily Recruiting
NCT02657889 - TOPACIO/KEYNOTE-162 trial Pebrolizumab I/II Triple negative Breast cancer or recurrent ovarian cancer 200mg ORR of 25% in all PROC and ORR of 45% in tBRCAmut patients, well toleratedᶧ
NCT03154281 Everolimus 2017 I Recurrent ovarian or breast cancer 100mg or200mg or 300mg daily Recruiting
NCT03586661 Copanlisib 2018 I Endometrial and Ovarian cancer Escalating dose Recruiting

Clinical trials of rucaparib combinations with other agents in ovarian cancer.

Study Combination Year Phase Cancer type Rucaparib dosage Statuts / Outcome
NCT03462212 (MITO25) Carboplatin/Paclitaxel +/− Bevacizumab 2018 II Resistant/Refractory Ovarian cancer 400mg or 500mg 0r 600mg BIDᵒ Recruiting
ATHENA trial Nivolumab 2018 I/II Platinum Sensitive Ovarian cancer 600mg BID Recruiting
NCT03840200 Ipatasertib (Akt inhibitor) 2019 Ib Breast, Prostate and Ovarian cancer 600mg BID Recruiting
NCT02873962 Nivolumab and bevacizumab 2016 II 2nd line Ovarian cancer 600mg BID Recruiting
NCT03992131 (SEASTAR trial) Lucitanib (VEGF 1–3 inhibitor) or Sacituzumab (anti-Trop-2 monoclonal antibody linked with SN-38) 2019 I/II Solid tumors 600mg BID Recruiting
NCT03824704 – ARIES trial Nivolumab 2019 II Platinum sensitive recurrent Ovarian cancer N/A Active/not Recruiting
NCT03552471 Mirvetuximab Soravtansine (olate receptor alpha targeting antibody-drug conjugate) 2018 I Recurrent Ovarian cancer 600mg BID Recruiting
NCT04267939 BAY1895344 ATR inhibitor 2020 Ib PARPi naïve and with a platinum-resistant/refractory disease or PD after PARPi maintenance N/A Recruiting
NCT03574779 OPAL trial Dostarlimab and bevacizumab 2018 II Recurrent Ovarian cancer 200mg or 300mg daily Active – not recruiting- no results yet
NCT03326193 OVARIO trial bevacizumab 2018 II Platinum sensitive Ovarian cancer 300mg daily Active – not recruiting- no results yet

Recruiting clinical trials of olaparib combinations with other agents in ovarian cancer.

Study Combination Year Phase Cancer type
NCT03772561 Durvalumab 2018 I Solid tumors
NCT03682289 ATR kinase inhibitor AZD6738 2019 II Solid tumors
NCT02485990 Tremelimumab 2020 I Recurrent or persistent ovarian cancer
NCT02953457 Durvalumab and tremelimumab 2016 II Recurrent or resistant Mbrca Ovarian cancer
NCT04123366 Pebrolizummab 2020 II Solid tumors, mHRD, dHRD
NCT03162627 Selumetinib 2017 I/II Endometrial, Ovarian cancer and other solid tumors
NCT03462342 (CAPRI Trial) Ceralasertib (AZD6738) 2018 II Recurrent Ovarian cancer
NCT03579316 Adavosertib 2018 II Ovarian cancer

Clinical trials of veliparib combinations with other agents in ovarian cancer.

Study Combination Year Phase Cancer type Rucaparib dosage Statuts / Outcome
NCT02470585 Topototecan 2017 I/II Resistant/Partially Sensitive Ovarian cancer 30 mg BIDᵒ, on D1-3 and 8–10, q28 Well tolerated, Best response – SD in 37%
NCT01113957 Temozolamide 2018 II Recurrent Ovarian cancer NA Completed No Results yet
NCT02470585 - VELIA trial Carboplatin and Paclitaxel 2019 III Newly diagnosed Ovarian cancer Induction: 150 mg BID q21Maintenance: 300 BID for 2 weeks, escalating to 400 mg BID PFS 23.5 vs 17.3 months (HR = 0.68; P < .001)
Japanese trial Paclitaxel-carboplatin 2016 I Newly diagnosed Ovarian cancer 100mg – 150mg BID q21 Well tolerated/potential clinical benefit
NCT01459380 Pegylated Liposomal Doxorubicin and carboplatin +/− bevacizumab 2015 I Recurrent, platinum-sensitive ovarian cancer 50mg or 80mg 0r 120mg Well tolerated in low doses of veliparib
NCT01233505 Capecitabine and oxaliplatin 2014 I Solid tumors 40mg BID days 1–7, 15–21, q28 Well tolerated
NCT01306032 Cyclophosphamide 2016 II Refractory BRCA-Positive Ovarian Cancer and Breast cancer 60mg daily Well tolerated/no PFS benefit
NCT00989651 Bevacizumab and Paclitaxel plus either carboplatin or IP cisplatin 2009 I Ovarian cancer N/A Active-not recruiting

Completed clinical trials of olaparib combinations with other agents in ovarian cancer.

Study Combination Year Phase Cancer type Olaparib dosage Outcome
NCT00516438 Topotecan 2009 I Solid tumors Starting with cap 50mg BIDᵒ continuously, escalating Unacceptable toxicity
NCT00572364 Dacarbazine 2009 I Solid tumors Cap 10mg BID continuously Tolerated, no clinical benefit
NCT00710268 Bevacizumab 2015 I Solid tumors Cap 400mg BID Well tolerated
NCT00819221 Lip-doxorubicin 2017 I Ovarian cancer Cap 150mg BID, continuously Tolerated and clinical benefit
NCT02430311, Chinese population Paclitaxel 2019 I Solid tumors Tb 100mb BID Reduce of olaparib bioavailability
NCT01650376 Carboplatin and weekly paclitaxel 2019 Ib Ovarian cancer Tb 150mg BID continuously Tolerated-clinical benefit in BRCAm
GEICO1601-ROLANDO trial Lip-doxorubicin 2019 II Ovarian cancer, Platinum-resistant Tb 300mg BID continuously Not recruiting, waiting for results
NCT01081951 Carboplatin and paclitaxel 2020 II Ovarian cancer-relapsed, platinum-sensitive Cap 200mg BID continuously PFS: 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 formula Molecular weight (g/mol) Route Peak plasma concentration Potency IC50* Nmol PARP1/2 Max tolerated dose Half-life
Olaparib C24H23FN43 434.5 oral 1–3hr PARP1>PARP2 >>PARP3 5/1 Tb 300mg BIDᵒ Cap 400mg BID 5–11hr
Rucaparib C19H18FN3O 323.4 oral 1.9hr PARP1>PARP2 >>PARP3 And tankyrase inhibitor 1.4 Tb 600mg BID 17–19hr
Niraparib C19H20N4O 320.4 oral 3hr PARP1=PARP2 3.2/4 300mg once daily 36hr
Veliparib C13H16N4O 244.29 oral 0.5 – 1.5hr PARP1 PARP2 5.2/2.9 Tb 400mg BID 5.2hr
Talazoparib C19H14F2N6O 380.4 oral 1–2hr 1.2/0.9 Cap 1mg daily 90hr
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