Table 1

Classes of therapy targeting replication stress in gynecological cancers

Drug	Phase	Population and treatment	Activity	Toxicity	Reference
ATR inhibitors
Berzosertib (M6620; VX-970)	I/II	Platinum-sensitive ovarian cancer Gemcitabine (480–800 mg/m² D1 and D8) + carboplatin (AUC 4, D1) + berzosertib (90–120 mg/m² D2 and D9), every 21 days	Recruitment ongoing	N/A	NCT02627443
	II	Platinum-resistant ovarian cancer Gemcitabine (1000 mg/m² D1 and D8) ± berzosertib (210 mg/m² D2 and D9), every 21 days	PFS: 22.9 weeks vs 14.7 weeks (HR 0.57; 90% CI 0.33 to 0.997; p=0.047)	No increase in toxicity reported	21
	Ib/II	Platinum-resistant ovarian cancer Carboplatin (AUC 5, D1) + avelumab (1600 mg, D1) + berzosertib (40–90 mg/m²) every 21 days	Recruitment completed	N/A	NCT03704467
Ceralasertib (AZD6738)	II	Platinum-sensitive or platinum-resistant HGSOC Ceralasertib (160 mg D1–7) + olaparib tablets (300 mg BD D1–28), every 28 days	Recruitment ongoing	N/A	CAPRI; NCT03462342
	II	Recurrent gynecological cancers, including patients with clear cell subtype and rare subtypes of ovarian/uterine cancer, with or without ARID1A loss Ceralasertib + olaparib	Recruitment ongoing	N/A	ATARI; NCT04065269
	II	Advanced solid tumors harboring damaging mutations in HR DNA repair genes or mutations in ATM, CHK2, MRN(MRE11/NBS1/RAD50), APOBEC Olaparib alone, olaparib + capivasertib, olaparib + adavosertib, olaparib + vistusertib	Recruitment ongoing	N/A	OLAPCO; NCT02576444
	I	Advanced solid tumors Durvalumab + varying schedules of ceralasertib	DCR (overall): 36%	Grade ≥3 TEAE: fatigue (15%), diarrhea (11%), nausea (9%). 13% of patients had ceralasertib-related serious AE, including two patients with drug-induced liver injury	46
M4344	I/II	PARPi-resistant recurrent ovarian cancer 4-week lead-in of niraparib monotherapy followed by combination of niraparib (fixed dose daily) + M4344 (100–200 mg daily), every 28 days	Not yet recruiting	N/A	NCT04149145
BAY1895344	I	Advanced solid tumors Escalating doses of BAY1895344 monotherapy	ORR: 30.7% in patients treated at ≥40 mg twice daily. All responders had ATM loss of expression and/or ATM mutation, and median duration of response approached 1 year. Durable response in one patient who had BRCA1-mutated and olaparib- and chemotherapy-resistant HGSOC	Grade ≥4 TEAE: neutropenia (33% in 80 mg cohort, 17% in 60 mg cohort), thrombocytopenia (17% in 80 mg cohort)	57
WEE1 inhibitors
Adavosertib (AZD1775; MK-1775)	II	Recurrent platinum-resistant HGSOC Gemcitabine (1000 mg/m² D1, D8 and D15) ± adavosertib (175 mg daily D1–2, D8–9 and D15–16), every 28 days	PFS: 4.6 months vs 3.0 months (HR 0.56, 95% CI:0.35 to 0.90, p=0.015). OS: 11.5 months vs 7.2 months (HR 0.56, 95% CI 0.34 to 0.92, p=0.022). PR rate: 21% vs 3% (p=0.02)	Grade ≥3 TEAE: anemia (31% vs 18%), thrombocytopenia (31% vs 6%), neutropenia (62% vs 30%)	28
	II	Recurrent platinum-resistant recurrent ovarian cancer Adavosertib (175–225 mg BD, various schedules) + gemcitabine (800 mg/m² D1, D8 and D15) or paclitaxel (80 mg/m² D1, D8 and D15) or carboplatin (AUC 5, D1) or pegylated liposomal doxorubicin (40 mg/m² D1)	ORR (overall): 31.9%. Highest ORR noted in cohort receiving adavosertib (225 mg BD D1–3, 8–10 and 15–17) with carboplatin (AUC 5, D1), every 21 days. ORR in this cohort was 66.7%. PFS (median, overall): 5.5 months	Grade ≥3 TEAE: anemia(33%), neutropenia (45.7%), thrombocytopenia (31.9%), diarrhea (10.6%), vomiting (10.6%)	29
	II	Recurrent platinum-sensitive TP53-mutant recurrent ovarian cancer Paclitaxel (175 mg/m² D1) + carboplatin (AUC 5, D1) + adavosertib (225 mg BD for 2.5 days)/matched placebo, every 21 days	PFS: 42.9 weeks vs 34.9 weeks (HR 0.55, 95% CI 0.32 to 0.95, p=0.030)	Grade ≥3 TEAE: 78% vs 65%	27
	II	Advanced refractory solid tumors with tumor CCNE1 amplification, defined by CCNE1 amplification >7, or found on approved next-generation tumor sequencing panels Adavosertib monotherapy (D1–5 and 8–12), every 21 days	Recruitment ongoing	N/A	NCT03253679
	II	Recurrent ovarian, primary peritoneal, or fallopian tube cancer, who have progressed during PARP inhibition Randomized, non-comparative study Adavosertib (daily D1–5 and 8–12) every 21 days (Arm A) or adavosertib (daily D1–3 and 8–10) + olaparib (twice daily D1–21) every 21 days (Arm B)	Recruitment ongoing	N/A	NCT03579316
	II	Advanced refractory solid tumors harboring mutations in TP53, KRAS or both Olaparib + adavosertib	Active, not recruiting	N/A	OLAPCO; NCT02576444
	I	Advanced refractory solid tumors harboring mutations including BRCA1/2, BRIP, FANCA, PALB2, ATM or CCNE1 amplification Olaparib (BD on D1–5 and 15–19) + adavosertib (daily on D8–12 and 22–26), every 28 days	Not yet recruiting	N/A	STAR; NCT04197713
	II	Recurrent or persistent serous uterine cancer Adavosertib monotherapy (daily D1–5 and 8–12), every 21 days	Not yet recruiting	N/A	NCT03668340
	I	Locally advanced uterine, cervical or vaginal cancer Adavosertib in combination with cisplatin and external beam radiotherapy	Recruitment ongoing	N/A	NCT03345784
CHK1/2 inhibitors
Prexasertib	II	Recurrent HGSOC or endometrioid ovarian cancer, regardless of platinum sensitivity All patients were either BRCA1/2-wildtype or had negative family history of hereditary breast and ovarian cancer Prexasertib monotherapy (105 mg/m² D1 and 15), every 28 days	PR rate (assessable per protocol): 33% (8/24)	Grade ≥3 TEAE: neutropenia (93%), leukopenia (82%), thrombocytopenia (25%), anemia (11%). 7% of patients had a treatment-related serious AE	30
	II	Advanced ovarian, breast or castrate-resistant prostate cancers with BRCA1/2 mutation Prexasertib monotherapy (105 mg/m² D1 and 15), every 28 days	Recruitment ongoing	N/A	NCT02203513
	II	Advanced solid tumors with either MYC amplification, Rb loss or FBXW7 mutation; homologous recombination repair deficiency or CCNE1 amplification Prexasertib monotherapy (105 mg/m² D1 and 15), every 28 days. Prexasertib monotherapy (105 mg/m² D1 and 15), every 28 days	Active, not recruiting	N/A	NCT02873975
	I	Advanced solid tumors, including patients who have previously been treated with a PARPi Prexasertib + olaparib	Recruitment ongoing	N/A	NCT03057145
	I	Advanced solid tumors Prexasertib + LY3300054 (novel PD-L1 inhibitor)	Recruitment ongoing	N/A	NCT03495323
SRA737	I/II	Advanced HGSOC, cervical/anogenital cancers, soft tissue sarcoma or small cell lung cancer with genomic alterations (TP53, RAD50, CCNE1, MYC, ATR, CHK2, BRCA1, FANCA) SRA737 (40–600 mg daily D2–3 weekly for 3 weeks) + gemcitabine (50–300 mg/m², D1 weekly for 3 weeks), every 28 days	PR rate (overall): 4% (6/141). Fanconi anemia/ BRCA network mutations were associated with the most favorable outcomes (ORR=25%, DCR=81%)	Grade ≥3 TEAE: neutropenia (63.4%), anemia (5.8%), thrombocytopenia (3.6%), ALT increase (5.8%), AST increase (5.0%)	47
	I/II	Advanced solid tumors with genomic alterations (TP53, RAD50, CCNE1, MYC, ATR, CHK2, BRCA1, FANCA) SRA737 monotherapy (160–1300 mg daily)	DCR (HGSOC): 54%	Grade ≥3 TEAE: 68.2%	31
CDK inhibitors
Palbociclib	II	Recurrent ovarian cancer Palbociclib (125 mg daily D1–21), every 28 days	PFS: 3.7 months (95% CI 1.2 to 6.2) PR rate: 4% (1/25)	Grade ≥3 TEAE: neutropenia (13.5%), thrombocytopenia (10.8%), hypokalemia (2.7%), vomiting (2.7%)	32
Ribociclib	II	Recurrent low grade serous ovarian cancer Letrozole (2.5 mg daily) + ribociclib (600 mg daily D1–21), every 28 days	Recruitment ongoing	N/A	NCT03673124
	I	Metastatic epithelial ovarian cancer Ribociclib (600 mg daily D1–21) + PDR001 (a PD-1 inhibitor) + fulvestrant (500 mg D1, D15 for cycle 1, then D1 for subsequent cycles), every 28 days	Recruitment ongoing	N/A	NCT03294694
Abemaciclib	II	Low grade serous carcinoma, first line, who are judged as unlikely to achieve optimal debulking surgery and have been recommended neoadjuvant therapy Neoadjuvant fulvestrant (500 mg D1, D15 for cycle 1, then D1 for subsequent cycles) + abemaciclib (150 mg daily), every 28 days for 4 cycles Adjuvant treatment with the same regimen	Recruitment ongoing	N/A	NCT03531645
Dinaciclib	I	Advanced solid tumors with or without BRCA1/2 mutations Dinaciclib + veliparib in varying schedules	Recruitment ongoing	N/A	NCT01434316
SY-1365	I	Relapsed ovarian cancer with previous platinum therapy SY-1365 (D1, D15) + carboplatin (D1), every 21 days	Active, not recruiting	N/A	NCT03134638
DNA-PKcs inhibitors
AZD7648	I/II	Advanced solid tumors. AZD7648 as monotherapy or in combination with olaparib (300 mg BD daily) or pegylated liposomal doxorubicin (40 mg/m², D1), every 28 days	Recruitment ongoing	N/A	NCT03907969
Nedisertib; M3814	I/Ib	Recurrent ovarian cancer with expansion cohort in recurrent HGSOC Nedisertib daily + pegylated liposomal doxorubicin	Recruitment ongoing	N/A	NCT04092270
RNR inhibitors
Triapine	I	Platinum-resistant recurrent ovarian cancer Triapine (96 mg/m² D1–4) + cisplatin (25 mg/m² D2–3), every 21 days	Trial discontinued due to significant methemoglobinemia in 2 of 6 women (33%)	Grade ≥3 TEAE: neutropenia (33%), vomiting (17%), pulmonary toxicity (33%)	48
	III	Locally advanced newly-diagnosed cervical or vaginal cancer Cisplatin weekly, concurrent with external beam radiotherapy ± triapine (triapine on days 1,3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31 and 33)	Recruitment ongoing	N/A	NCT02466971

ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related; AUC, area under the curve; CDK, cyclin-dependent kinase; CHK1,2, checkpoint kinases 1 and 2; DCR, disease control rate; DNA-PKCs, DNA-dependent protein kinases; HGSOC, high grade serious ovarian cancer; ORR, objective response rate; PARPi, poly (ADP-ribose) polymerase inhibitor; PFS, progression-free survival; PR, partial response; RNR, ribonucleotide reductase; TEAE, treatment emergent adverse event; WEE1, WEE1-like protein kinase.