Table 1

Classes of therapy targeting replication stress in gynecological cancers

DrugPhasePopulation and treatmentActivityToxicityReference
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 ongoingN/ANCT02627443
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 reported21
Ib/II
  • Platinum-resistant ovarian cancer

  • Carboplatin (AUC 5, D1) + avelumab (1600 mg, D1) + berzosertib (40–90 mg/m2) every 21 days

Recruitment completedN/ANCT03704467
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 ongoingN/ACAPRI; 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 ongoingN/AATARI;
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 ongoingN/AOLAPCO;
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
M4344I/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 recruitingN/ANCT04149145
BAY1895344I
  • 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 ongoingN/ANCT03253679
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 ongoingN/ANCT03579316
II
  • Advanced refractory solid tumors harboring mutations in TP53, KRAS or both

  • Olaparib + adavosertib

Active, not recruitingN/AOLAPCO;
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 recruitingN/ASTAR;
NCT04197713
II
  • Recurrent or persistent serous uterine cancer

  • Adavosertib monotherapy (daily D1–5 and 8–12), every 21 days

Not yet recruitingN/ANCT03668340
I
  • Locally advanced uterine, cervical or vaginal cancer

  • Adavosertib in combination with cisplatin and external beam radiotherapy

Recruitment ongoingN/ANCT03345784
CHK1/2 inhibitors
PrexasertibII
  • 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 ongoingN/ANCT02203513
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 recruitingN/ANCT02873975
I
  • Advanced solid tumors, including patients who have previously been treated with a PARPi

  • Prexasertib + olaparib

Recruitment ongoingN/ANCT03057145
I
  • Advanced solid tumors

  • Prexasertib + LY3300054 (novel PD-L1 inhibitor)

Recruitment ongoingN/ANCT03495323
SRA737I/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
PalbociclibII
  • 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
RibociclibII
  • Recurrent low grade serous ovarian cancer

  • Letrozole (2.5 mg daily) + ribociclib (600 mg daily D1–21), every 28 days

Recruitment ongoingN/ANCT03673124
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 ongoingN/ANCT03294694
AbemaciclibII
  • 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 ongoingN/ANCT03531645
DinaciclibI
  • Advanced solid tumors with or without BRCA1/2 mutations

  • Dinaciclib + veliparib in varying schedules

Recruitment ongoingN/ANCT01434316
SY-1365I
  • Relapsed ovarian cancer with previous platinum therapy

  • SY-1365 (D1, D15) + carboplatin (D1), every 21 days

Active, not recruitingN/ANCT03134638
DNA-PKcs inhibitors
AZD7648I/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 ongoingN/ANCT03907969
Nedisertib;
M3814
I/Ib
  • Recurrent ovarian cancer with expansion cohort in recurrent HGSOC

  • Nedisertib daily + pegylated liposomal doxorubicin

Recruitment ongoingN/ANCT04092270
RNR inhibitors
TriapineI
  • 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 ongoingN/ANCT02466971
  • 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.