Table 1. Current status (most advanced stage) of DDR inhibitors.
| Target | Drug | Current status | reference |
|---|---|---|---|
| PARP Approved and Phase III only | Olaparib/Lynparza® |
Approved (FDA) as single agent since 2014 advanced BRCA mutated ovarian cancer1, BRCA mutated breast cancer (2018) pancreatic cancer (2019), BRCA or ATM mutated mCRPC2 (2020) gBRCA mutated HER2-ve high-risk early breast cancer (2022). Approved in combination with bevacizumab in ovarian cancer (2020) Phase III as single agent in ovarian cancer (e.g.NCT03534453, NCT03402841, NCT03106987,), Her2-ve & BRCA mutated breast cancer/TNBC2 (NCT03286842, NCT02032823). In combination with abiratrone or enzalutamide in mCRPC (NCT05171816, NCT03732820,, with cediranib or alpelisib or paclitaxel or durvalumab in ovarian cancer (NCT03278717, with pembrolizumab SCLC2 and NSCLC2, with bevacizumab in CRC2, with durvalumab in endometrial cancer |
[92] [93] |
| Rucaparib/Rubraca® |
Approved (FDA) as single agent since 2016 in advanced BRCA mutated/HRD ovarian cancer BRCA mutated mCRPC (2020). Phase III as single agent in ovarian cancer, BRCA or ATM mutated mCRPC. In combination with nivolumab in ovarian cancer, with enzalutamide in mCRPC |
[94] [95] |
|
| Niraparib/Zejula® |
Approved (FDA) as single agent since 2017 in advanced platinum-sensitive ovarian cancer Phase III as single agent in BRCAmut/HER2-ve mutated TNBC, In combination with Dostarlimab or bevacizumab or atezolizumab in ovarian cancer, with pembrolizumab in NSCLC, with abriratrone and prednisone in HRR gene mutated CRPC, in combination with Dostarlimab |
[96] [97] |
|
| Talazoparib/Talzenna® |
Approved (FDA) as single agent since 2018 in BRCA mutated Her2-ve advanced breast cancer Phase III in combination with Avelumab in advanced ovarian cancer, and enzalutamide in mCRPC |
[98] [99] |
|
| Fluzoparib |
Approved (NMPA) as single agent since 2020 in advanced platinum-sensitive ovarian cancer Phase III as single agent in platinum sensitive ovarian and pancreatic cancer, In combination with Apatinib in BRCA-mutated breast cancer |
[100] [101] |
|
| Pamiparib |
Approved (NMPA) as single agent since 2021 in advanced BRCA-mutated ovarian cancer Phase III in combination with enzalutamide in mCRPC |
[102] [103] |
|
| Veliparib | Phase III in combination with carboplatin and paclitaxel in advanced ovarian cancer, and Her2-ve BRCA associated breast cancer | [104] | |
| IMP4297 | Phase III as single agent in BRCA mutated ovarian cancer | [105] | |
| DNA-PK | M3814/Peposertib/nedisertib |
Phase II in combination with capecitabine and RT2 in CRC (NCT03770689) Phase I Single agent in solid tumours and CLL (NCT02316197) in combination with RT in locally advanced tumours (NCT02516813) gliomas (NCT04555577) H&N2 (NCT04533750), pancreatic cancer (NCT04172532), in combination with doxorubicin in ovarian cancer (NCT04092270), in combination with Avelumab and RT in solid tumours (NCT03724890), hepatobiliary cancer (NCT04068194) and mCRCP (NCT04071236) with mitoxantrone, cytarabine and etoposide in AML (NCT03983824) |
[106] |
| VX-984 | Phase I alone and combination with doxorubicin (NCT02644278) | [107] | |
| ATM | AZD0156 | Phase I monotherapy or combination with olaparib, irinotecan or 5FU (NCT02588105) | [108] |
| M4076 | Phase I monotherapy (NCT04882917) in patients with solid tumours | [109] | |
| M3541 | Phase I in combination with RT in patients with solid tumours (NCT03225105) | [110] | |
| AZD1390 | Phase I monotherapy in patients with glioma (NCT05182905) in combination with radiotherapy in brain tumours (NCT03423628), lung cancer (NCT04550104) and sarcomas (NCT05116254,) | [111] | |
| ATM/DNA-PK | XRD-0394 | Phase I in combination with palliative RT in patients with locally advanced recurrent solid tumours (NCT05002140) | [112] |
| ATR | VE-822/VX-970/M6620/Bersosertib | Phase II monotherapy in Leiomyosarcoma and osteosarcoma (NCT03718091) as monotherapy or combination with gemcitabine in ovarian cancer (NCT02595892) or cisplatin and gemcitabine in urothelial cancer(NCT02567409) or NSCLC (NCT04216316) and in combination with topotecan in SCLC (NCT04768296), or with irinotecan in p53 mutated gastric cancer (NCT03641313), or sacituzumab govitecan in SCLC and PARP-resistant HRD tumours (NCT04826341) with carboplatin ± docetaxel in mCRPC (NCT03517969) and with lurbinectedin in SCLC (NCT04802174). Also in combination with Avelumab in tumours with various DDR defects (NCT04266912) | [113] |
| AZD6738/ceralasertib |
Phase II monotherapy or combination with olaparib in CCRC2, pancreatic and other cancers (NCT036822893), In combination with olaparib in ovarian cancer (CAPRI: NCT03462342, ATARI: NCT04065269), SCLC (NCT03428607, NCT04699838, NCT02937818), BRCA mutated breast cancer (NCT04090567), TNBC (NCT03330847), mCRPC (TRAP: NCT03787680), osteosarcoma (NCT04417062) IDH-mutated tumours (NCT03878095). Also in combination with durvalumab in biliary tract (NCT04298008), SCLC (NCT04361825, NCT04699838) solid tumours and melanoma (NCT03780608, NCT05061134), with durvalumab and olaparib in TNBC (NCT03740893) NSCLC (NCT03334617) and in combination with durvalumab, olaparib or carboplatin in various advanced solid tumours (NCT02264678) |
[114] | |
| BAY1895344 Elimusertib |
Phase II monotherapy in pediatric patients with relapsed/refractory solid tumours (NCT05071209) Phase I monotherapy in advanced solid tumours and lymphomas (NCT031889653). And combination with niraparib in ovarian cancer (NCT04267939), with gemcitabine in pancreatic, ovarian and other cancers (NCT04616534), with topoisomerase inhibitors (topotecan/irinotecan) in advanced solid tumours (NCT04514497) with FOLFIRI in advanced GI cancers (NCT04535401), with RT in H&N cancer (NCT04576091), with cis-or carboplatin and gemcitabine in urothelial cancer (NCT04491942) with pembrolizumab (NCT04095273) in advanced cancer |
[115] | |
| VX-803/M4344 | Phase I monotherapy (NCT02278250) or in combination with niraparib (NCT04655183- withdrawn in favour of M1774) in advanced solid tumours | [116] | |
| M1774 | Phase I in combination with niraparib (NCT041701533) and an immune checkpoint inhibitor (NCT05396833) in advanced solid tumours | [117] | |
| CHK1 | LY2606368/prexasertib | Phase II monotherapy in BRCA mutated ovarian and breast cancer and mCRPC (NCT02203513), in platinum-resistant ovarian cancer (NCT03414047) in tumours with RS or HRD (NCT02873975) in SCLC (NCT02735980) and in combination with irinotecan in DSRCT2 or RMS2 (NCT04095221) | [118] |
| PF-477736 | Phase I in combination with gemcitabine in advanced solid tumours (NCT00437203, terminated for business reasons) | [119] | |
| MK-8776/SCH900776 |
Phase II in combination with cytarabine in AML2 (NCT01870596) Phase I in combination with cytarabine in NCT00907517) or in combination with gemcitabine in leukaemia (NCT00779584) |
[72] [73] |
|
| WEE1 | AZD1775/MK-1775/Adavosertib | Phase II monotherapy in SCLC (NCT02593019, NCT02688907), BRCA mutated cancers (NCT04439227), uterine cancer (NCT04439227, NCT04590248), solid tumours with CCNE1 amplification (NCT03253679) or SETD2 mutation (NCT03284385). As monotherapy or in combination with cytarabine in AML (NCT03718143, NCT02666950), with gemcitabine in ovarian cancer (NCT02101775) and pancreatic cancer (NCT05212025), with gemcitabine and paclitaxel in pancreatic cancer (NCT02194829),and gemcitabine and RT in pancreatic cancer (NCT02037230), with carboplatin in ovarian cancer (NCT01164995) and other molecularly defined tumours (IMPACT: NCT01827384), in combination with cisplatin in TNBC (NCT03012477) and H&N cancer (NCT02087241), with carboplatin and paclitaxel in ovarian cancer ± p53 mutation (NCT01357161, NCT02272790), squamous cell lung cancer (NCT02513563) with docetaxel (NCT02087176) or pemetrexed and carboplatin (NCT02087241) in NSCLC, with paclitaxel in gastric adenocarcinoma with p53 mutation (NCT02448329), with olaparib in advanced solid tumours (NCT02576444) or ovarian cancer (NCT03579316, NCT03330847), with topotecan and cisplatin in cervical cancer (NCT01076400), with irinotecan in under 21 year olds (NCT02095132), Also with durvalumab and Tremelimumab, or carboplatin or olaparib in SCLC (NCT02937818) | [120] |
| ZN-c3 | Phase I monotherapy in advanced solid tumours including ovarian cancer (NCT05128825, NCT04158336, NCT04972422), TNBC and advanced ovarian cancer (NCT05368506), uterine serous carcinoma (NCT04814108). In combination with niraparib (NCT05198804), or carboplatin or paclitaxel or doxorubicin or gemcitabine (NCT04516447) in platinum-resistant ovarian cancer with gemcitabine in osteosarcoma (NCT04833582) and with bevacizumab ± pembrolizumab in metastatic CCNE1 amplified and TP53 mutant solid tumors (NCT05431582) | [121] | |
| IMP7068 | Phase I monotherapy in advanced solid tumours (NCT04768868) | [122] | |
| SY-4835 | Phase I monotherapy in advanced solid tumours (NCT05291182) | [123] | |
| Polθ | ART4215 | Phase I monotherapy and in combination with the PARPi, talazoparib or niraparib, in patients with advanced cancer. (NCT04991480) | [124] |
1
Ovarian cancer refers to ovarian, fallopian and primary peritoneal cancer;
2
mCRPC, metastatic castrate-resistant prostate cancer; CRC, colorectal cancer; TNBC, triple negative breast cancer; SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; CCRC, clear cell renal cell cancer; DSRCT, Desmoplastic Small Round Cell Tumour; RMS, Rhabdomyosarcoma; AML, Acute myeloid leukaemia; RT, radiotherapy;
3
Study using ATM defect/deficiency as a biomarker for patient selection.