Drug Class: DNA Damage Repair Pathway Inhibitors

DNA Damage Repair Pathway Inhibitors: PARP

First-line treatment with/without extended (maintenance) treatment

Progression Free Survival (months)

Median length of time before the cancer comes back or gets worse

Overall Survival (months)

The length of time where half the patients in the study are still alive

No Prior Therapies

Maintenance after first-line therapy: Treatment to prevent relapse after complete or partial response to therapy

Progression Free Survival (months)

Median length of time before the cancer comes back or gets worse

Overall Survival (months)

The length of time where half the patients in the study are still alive

1 Prior Therapy

Maintenance after therapy for recurrence: Treatment to control disease after complete or partial response to therapy

Progression Free Survival (months)

Median length of time before the cancer comes back or gets worse

Overall Survival (months)

The length of time where half the patients in the study are still alive

2 Prior Therapies 3 Prior Therapies 4 Prior Therapies Prior Therapies Not Reported

Platinum-Sensitive (Pt-S): Treatment given for recurrence occurring 6 months or more after last platinum-based treatment

Objective Response Rate (%)

Percentage of patients whose tumors shrink or go away after treatment

Progression Free Survival (months)

Median length of time before the cancer comes back or gets worse

1 Prior Therapy 2 Prior Therapies Prior Therapies Not Reported

Platinum-Resistant/Refractory (Pt-R/Rf): Treatment given for recurrence occurring less than 6 months after last platinum-based treatment or for progression during last platinum-based treatment

Objective Response Rate (%)

Percentage of patients whose tumors shrink or go away after treatment

Progression Free Survival (months)

Median length of time before the cancer comes back or gets worse

2 Prior Therapies 3 Prior Therapies Prior Therapies Not Reported

Treatment given for recurrence occurring at any time after last platinum-based treatment

Objective Response Rate (%)

Percentage of patients whose tumors shrink or go away after treatment

Progression Free Survival (months)

Median length of time before the cancer comes back or gets worse

3 Prior Therapies 3.5 Prior Therapies 4 Prior Therapies 5 Prior Therapies Prior Therapies Not Reported

DNA Damage Repair Pathway Inhibitors: ATR

Platinum-Resistant/Refractory (Pt-R/Rf): Treatment given for recurrence occurring less than 6 months after last platinum-based treatment or for progression during last platinum-based treatment

Objective Response Rate (%)

Percentage of patients whose tumors shrink or go away after treatment

Progression Free Survival (months)

Median length of time before the cancer comes back or gets worse

2 Prior Therapies

DNA Damage Repair Pathway Inhibitors: PARP

First-line treatment with/without extended (maintenance) treatment

For more detailed information, please click on the clinical trial ID number.

Trial ID # Phase Drugs Clinical Trial Title Key Conclusion and Results
Drugs in Clinical Development
NCT02470585; VELIA III Carboplatin, Paclitaxel, Veliparib A Phase 3 Placebo-Controlled Study of Carboplatin/Paclitaxel With or Without Concurrent and Continuation Maintenance Veliparib (PARP Inhibitor) in Subjects With Previously Untreated Stages III or IV High-Grade Serous Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Veliparib added to chemotherapy and continued as maintenance significantly extends PFS in all newly diagnosed patients, but shows most benefit in BRCA MUT patients

CarboPt+Pac+Vel w/Vel maint vs CarboPt+Pac+Vel vs CarboPt+Pac:

All patients:
PFS: 23.5 vs 15.2 vs 17.3 months*
BRCA MUT:
PFS: 34.7 vs 21.1 vs 22.0 months*
BRCA WT:
PFS: 18.2 vs 14.5 vs 15.1 months

pub 2019

NCT03326193; OVARIO II Bevacizumab, Carboplatin, Niraparib, Paclitaxel Phase 2, Single-arm, Open-label Study to Evaluate the Safety and Efficacy of Niraparib Combined With Bevacizumab as Maintenance Treatment in Patients With Advanced Ovarian Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer Following Front-line Platinum-based Chemotherapy With Bevacizumab

Niraparib + bevacizumab maintenance treatment does not appear to cause cumulative toxicities and shows promising PFS

PFS (6 months): 90%
PFS (12 months): 75%
PFS (18 months): 62%
PFS (24 months): 53%

pub 2022

NCT00989651; GOG-9923 I Carboplatin, Cisplatin, Paclitaxel, Veliparib, Bevacizumab A Phase I Study of Intravenous Carboplatin/Paclitaxel or Intravenous and Intraperitoneal Paclitaxel/Cisplatin in Combination With Continuous or Intermittent /CTEP-Supplied Agent ABT-888 (NSC #737664) and CTEP-Supplied Agent Bevacizumab (NSC #704865) in Newly Diagnosed Patients With Previously Untreated Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer

Patients receiving IP cisplatin + IV/IP paclitaxel show promising PFS and OS when compared to patients receiving IV carboplatin+paclitaxel, however differences may be reflective of selection bias toward patients enrolled on the IP chemotherapy arm

IV vs weekly IV vs IP (all w/ Vel cont):

PFS: 24.5 vs 23.5 vs 43.2 months
OS: 65.2 vs 66.5 vs NR months

pub 2020, abs Mar 2020

*Statistically significant result

Maintenance after first-line therapy: Treatment to prevent relapse after complete or partial response to therapy

For more detailed information, please click on the clinical trial ID number.

Trial ID # Phase Drugs Clinical Trial Title Key Conclusion and Results
Standard of Care Targeted Drugs
NCT01844986; SOLO-1 III Olaparib Prescribing Information A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Advanced (FIGO Stage III-IV) Ovarian Cancer Following First Line Platinum Based Chemotherapy (SOLO-1)

Considerably improved PFS and OS for BRCA MUT patients with olaparib maintenance treatment; the benefit derived from 2 years of maintenance olaparib is sustained beyond the end of treatment

Ola maint vs Placebo:

PFS: 56.0 vs 13.8 months*
PFS (5 years): 48 vs 21%
OS: NR vs 75.2 months*
OS (7 years): 67.0 vs 46.5%

pub 2018, 2021, 2022

NCT02477644; PAOLA-1 III Bevacizumab, Carboplatin, Olaparib, Paclitaxel Prescribing Information Randomized, Double-Blind, Phase III Trial Olaparib vs. Placebo Patients With Advanced FIGO Stage IIIB-IV High Grade Serious or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer Treated Standard First-Line Treatment

Dual maintenance therapy with olaparib and bevacizumab improves PFS and OS compared with bevacizumab maintenance alone for BRCA MUT and HRD+ patients

Ola vs Placebo:

All patients:
PFS: 22.1 vs 16.6 months*
OS: 56.5 vs 51.6 months

HRD+ (incl. BRCA MUT)
PFS: 46.8 vs 17.6 months*
OS: 75.2 vs 57.3 months*

BRCA MUT:
PFS: 37.2 vs 21.7 months*
OS: 75.2 vs 66.9 months*

HRD+ (excl. BRCA MUT):
PFS: 28.1 vs 16.6 months*
OS: NR vs 52.0 months

HRD-:
PFS: 16.9 vs 16.0 months
OS: 36.8 vs 40.4 months

pub 2019, pub 2022, abs Sep 2022 and presentation

NCT02655016; PRIMA III Niraparib Prescribing Information A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy

Considerably improved PFS for all patients that received niraparib maintenance treatment

Nir maint vs Placebo:

All patients:
PFS: 13.8 vs 8.2 month*
HRD+ (excl. BRCA MUT):
PFS: 19.6 vs 8.2 months*
HRD-:
PFS: 8.4 vs 5.4 months*

pub 2019, pub 2022, abs Sep 2022

NCT03709316; PRIME III Niraparib Prescribing Information A Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Phase III Clinical Trial Evaluating the Efficacy and Safety of ZL-2306 (Niraparib) for Maintenance Treatment in Patients With Advanced Ovarian Cancer, Fallopian Tube Carcinoma or Primary Peritoneal Cancer (Collectively Referred to as Ovarian Cancer) Who Have Achieved Effective Response After First-line Platinum-containing Chemotherapy

Niraparib with individually starting dose (ISD regimen) significantly improves PFS compared with placebo and is associated with a better safety profile

PFS: 24.8 vs 8.3 months*
HRD+ (excl. gBRCA MUT): 24.8 vs 11.1 months*
HRD-: 14.0 vs 5.5 months*

abs Mar 2022

Drugs in Clinical Development
NCT03522246; ATHENA-MONO/GOG-3020 III Rucaparib ATHENA (A Multicenter, Randomized, Double-Blind, Placebo- Controlled Phase 3 Study in Ovarian Cancer Patients Evaluating Rucaparib and Nivolumab as Maintenance Treatment Following Response to Front-Line Platinum-Based Chemotherapy)

Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD

Ruc maint vs Placebo:

All patients:
PFS: 20.2 vs 9.2 month*

HRD+ (incl. BRCA MUT):
PFS: 28.7 vs 11.3 months*

BRCA MUT:
NR vs 14.7 months*

BRCA WT/LOH high:
PFS: 20.3 vs 9.2 months*

BRCA WT/LOH low:
PFS: 12.1 vs 9.1 months*

pub 2022

*Statistically significant result

Maintenance after therapy for recurrence: Treatment to control disease after complete or partial response to therapy

For more detailed information, please click on the clinical trial ID number.

Trial ID # Phase Drugs Clinical Trial Title Key Conclusion and Results
Standard of Care Targeted Drugs
NCT01874353; SOLO-2 III Olaparib Prescribing Information Phase III Randomised, Double Blind, Placebo Controlled Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed BRCA Mutated Ovarian Cancer Patients With a Complete or Partial Response Following Platinum Based Chemotherapy (SOLO-2)

Improved PFS and OS with olaparib maintenance treatment in gBRCA MUT patients

Ola vs Placebo:

PFS: 19.1 vs 5.5 months*
OS: 51.7 vs 38.8 months
TFST: 27.4 vs 7.2 months*

pub 2017, pub 2021

NCT01847274; NOVA III Niraparib Prescribing Information A Phase 3 Randomized Double-blind Trial of Maintenance With Niraparib Versus Placebo in Patients With Platinum Sensitive Ovarian Cancer (NOVA)

Improved PFS for gBRCA MUT patients with niraparib maintenance; the benefit of niraparib maintenance therapy extends beyond first progression

Nir vs Placebo:

gBRCA MUT:
PFS: 21.0 vs 5.5 months*

pub 2016, pub 2019, abs Mar 2021

NCT01968213; ARIEL3 III Rucaparib Prescribing Information Phase 3 Study of Rucaparib as Switch Maintenance After Platinum in Relapsed High Grade Serous and Endometrioid Ovarian Cancer (ARIEL3)

Improved PFS and PFS2 in BRCA MUT patients, but no OS benefit with rucaparib maintenance

Ruc vs Placebo:

BRCA MUT:
PFS: 16.6 vs 5.4 months*
OS: 45.9 vs 47.8 months

pub 2017, pub 2020, abs Jun 2021 and poster, pub 2021, abs Oct 2022

NCT00753545; Study 19 II Olaparib Prescribing Information Phase II Randomised, Double Blind, Multicentre Study to Assess the Efficacy of AZD2281 in the Treatment of Patients With Platinum Sensitive Relapsed Serous Ovarian Cancer Following Treatment With Two or More Platinum Containing Regimens (Study 19)

Improved PFS and OS with olaparib maintenance

Ola vs Placebo:

All:
PFS: 8.4 vs 4.8 months*
OS: 29.8 vs 27.8 months*
BRCA WT:
PFS: 7.4 vs 5.5 months*
OS: 24.5 vs 26.6 months
BRCA MUT:
PFS: 11.2 vs 4.3 months*
OS: 34.9 vs 30.2 months*

pub 2012; 2014; 2016

NCT03402841; OPINION IIIb Olaparib Prescribing Information A Phase IIIb, Single-arm, Open-label Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed Non-Germline BRCA Mutated Ovarian Cancer Patients Who Are in Complete or Partial Response Following Platinum Based Chemotherapy

Maintenance olaparib demonstrates activity in non-gBRCA MUT ovarian cancer patients with no new safety signals

non-gBRCA MUT: PFS: 9.2 months
HRD-: PFS: 7.3 months
HRD+ (excl. sBRCA MUT): PFS: 9.7 months
sBRCA MUT: PFS: 16.4 months

pub 2022

NCT02476968; ORZORA IV Olaparib An Open Label, Single Arm, Multicentre Study to Assess the Clinical Effectiveness and Safety of Lynparza (Olaparib) Capsules Maintenance Monotherapy in Platinum Sensitive Relapsed Somatic or Germline BRCA Mutated Ovarian Cancer Patients Who Are in Complete or Partial Response Following Platinum Based Chemotherapy (ORZORA).

PFS in patients with Pt-S OC who received maintenance olaparib is similar irrespective of somatic or germline BRCA status and activity of maintenance olaparib is also seen in patients with a non-BRCA HRR gene mutations

gBRCA MUT vs sBRCA MUT vs HRRm:
PFS: 18.0 vs 16.6 vs 16.4 months

abs Mar 2021

Drugs in Clinical Development
NCT01847274; NOVA III Niraparib A Phase 3 Randomized Double-blind Trial of Maintenance With Niraparib Versus Placebo in Patients With Platinum Sensitive Ovarian Cancer (NOVA)

Improved PFS for all patients with niraparib maintenance with greatest activity in BRCA MUT patients; the benefit of niraparib maintenance therapy extends beyond first progression

Nir vs Placebo:

non-gBRCA MUT:
PFS: 9.3 vs 3.9 months*
gBRCA MUT:
PFS: 21.0 vs 5.5 months*
HRD-:
PFS: 6.9 vs 3.8 months*
HRD+ (excl. BRCA MUT):
PFS: 9.3 vs 3.7 months*

pub 2016, pub 2019, abs Mar 2021

NCT01968213; ARIEL3 III Rucaparib Phase 3 Study of Rucaparib as Switch Maintenance After Platinum in Relapsed High Grade Serous and Endometrioid Ovarian Cancer (ARIEL3)

Improved PFS and PFS2, but no OS benefit for all patients with rucaparib maintenance

Ruc vs Placebo:

All:
PFS: 10.8 vs 5.4 months*
OS: 36.0 vs 43.2 months
BRCA MUT/BRCA WT LOH High:
PFS: 13.6 vs 5.4 months*
OS: 40.5 vs 47.8 months
BRCA MUT:
PFS: 16.6 vs 5.4 months*
OS: 45.9 vs 47.8 months

pub 2017, pub 2020, abs Jun 2021 and poster, pub 2021, abs Oct 2022

NCT03106987; OReO/ENGOT Ov-38 III Olaparib A Phase IIIb, Randomised, Double-blind, Placebo-controlled, Multicentre Study of Olaparib Maintenance Retreatment in Patients With Epithelial Ovarian Cancer Previously Treated With a PARPi and Responding to Repeat Platinum Chemotherapy

Rechallenge with maintenance olaparib following response to Pt-based therapy provides a significant improvement in PFS vs placebo, irrespective of BRCA status

Ola vs Placebo:

BRCA MUT:
PFS: 4.3 vs 2.8 months*
PFS at 12 months: 19 vs 0%

non-BRCA MUT:
PFS: 5.3 vs 2.8 months*
PFS at 12 months: 12 vs 0%

abs Sept 2021

*Statistically significant result

Platinum-Sensitive (Pt-S): Treatment given for recurrence occurring 6 months or more after last platinum-based treatment

For more detailed information, please click on the clinical trial ID number.

Trial ID # Phase Drugs Clinical Trial Title Key Conclusion and Results
Drugs in NCCN Guidelines
NCT02354131; AVANOVA II Niraparib, Bevacizumab Part 1: AVANOVA1 - A Phase I Study to Evaluate the Safety and Tolerability of Bevacizumab-niraparib Combination Therapy and Determine the Recommended Phase 2 Dose (RP2D) in Women With Platinum-sensitive Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer Part 2: AVANOVA2 - A Two-arm, Open-label, Phase II Randomized Study to Evaluate the Efficacy of Niraparib Versus Niraparib-bevacizumab Combination in Women With Platinum-sensitive Epithelial Ovarian, Fallopian Tube, or Peritoneal Cancer.

Promising improvement of activity with niraparib+bevacizumab compared to niraparib alone

Nir+Bev vs Nir:

ORR: 62 vs 30%*
PFS: 12.5 vs 5.5 months*

pub 2019, abs May 2020 and poster

Drugs in Clinical Development
NCT02446600; NRG-GY004 III Carboplatin, Cediranib, Gemcitabine, Liposomal doxorubicin, Paclitaxel, Olaparib A Phase III Study Comparing Single-Agent Olaparib or the Combination of Cediranib and Olaparib to Standard Platinum-Based Chemotherapy in Women With Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Cediranib+olaparib has similar activity to standard of care in relapsed platinum sensitive ovarian cancer but does not improve PFS; in gBRCA MUT patients cediranib+olaparib and olaparib alone shows substantial activity

Ola+Ced vs Ola vs Treatment of Physician's Choice (TPC):

ORR: 69.4 vs 52.4 vs 71.3%
PFS: 10.4 vs 8.2 vs 10.3 months
OS: 30.5 vs 29.2 vs 31.3 months

pub 2022

NCT01116648 II Cediranib, Olaparib Phase I/II Study of Cediranib and Olaparib in Combination for Treatment of Recurrent Papillary-Serous Ovarian, Fallopian Tube, or Peritoneal Cancer or for Treatment of Recurrent Triple-Negative Breast Cancer

Improved ORR, PFS and OS for olaparib+cediranib combination in patients with gBRCA WT or unknown BRCA status

Ola+Ced vs Ola:

gBRCA WT or UNK:
ORR: 76 vs 32%*
PFS: 23.7 vs 5.7 months*
OS: 37.8 vs 23.0 months*

gBRCA MUT:
ORR: 83 vs 63%
PFS: 16.4 vs 16.5 months
OS: 44.2 vs 40.1 months

pub 2014; 2019

NCT01540565 II Veliparib A Phase II Evaluation of the Poly (ADP-Ribose) Polymerase (PARP)-1 and -2 Inhibitor Veliparib (ABT-888) (NSC#737664) in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients Who Carry a Germline BRCA1 or BRCA2 Mutation

Veliparib shows encouraging activity in gBRCA MUT OC

ORR: 35%
PFS: 11.0 months

Pt-S: ORR: 35%; PFS: 11.0 months
Pt-R: ORR: 20%; PFS: 5.8 months

pub 2015

NCT01891344; ARIEL2 II Rucaparib A Phase 2, Open-Label Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (ARIEL2)

Improved ORR and PFS with rucaparib treatment in BRCA MUT patients

BRCA MUT vs BRCA WT LOH high vs BRCA WT LOH low:

ORR: 80 vs 29 vs 10%*
PFS: 12.8 vs 5.7 vs 5.2 months*

pub 2017, abs May 2020 and poster

NCT02345265 II Cediranib, Olaparib A Phase 2 Study of Olaparib and Cediranib for the Treatment of Recurrent Ovarian Cancer

Olaparib+cediranib is effective independent of gBRCA status

ORR: 74.3%

abs Jun 2018

NCT02983799; LIGHT II Olaparib Non-Randomized, Open-Label Phase II Study to Assess Olaparib Tablets as a Treatment for Subjects With Different HRD Tumor Status and With Platinum-Sensitive, Relapsed, High-Grade Serous or High-Grade Endometrioid Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer That Have Received at Least 1 Prior Line of Chemotherapy

Olaparib treatment has activity across all cohorts with similar efficacy in the gBRCA MUT and sBRCA MUT cohorts. For non-BRCA MUT patients, longer median PFS and higher ORR are observed in the HRD+ cohort

gBRCA MUT:
ORR: 69%; PFS: 11.0 months
sBRCA MUT:
ORR: 64%; PFS: 10.8 months
HRD+ (excl. BRCA MUT):
ORR: 29%; PFS: 7.2 months
HRD-:
ORR: 10%; PFS: 5.4 months

pub 2022

NCT02734004; MEDIOLA I/II Bevacizumab, Durvalumab, Olaparib A Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination With Olaparib (PARP Inhibitor) in Patients With Advanced Solid Tumors

Promising activity of olaparib+durvalumab in gBRCA MUT OC patients; olaparib+durvalumab+bevacizumab shows promising activity in non-gBRCA MUT patients regardless of LOH score and mutation status of common DDR genes

Ola+Dur, gBRCA MUT:
ORR: 71.9%
DCR (7 months): 65.6%
PFS: 11.1 months

Ola+Dur, non-gBRCA MUT:
ORR: 34%
CBR: 28%
PFS: 5.5 months

Ola+Dur+Bev, non-gBRCA MUT:
ORR: 87%
CBR: 77%
PFS: 14.7 months
DoR: 11 months

abs Oct 2019, abs Sep 2020, pub 2020

NCT03333915 I/II Pamiparib An Open Label, Multi-Center Phase I/II Study to Evaluate Efficacy and Safety of BGB-290 in Chinese Subjects With Advanced Ovarian Cancer, Fallopian Cancer, and Primary Peritoneal Cancer or Advanced Triple Negative Breast Cancer

Pamiparib showes antitumor activity with durable responses in patients with gBRCA MUT platinum sensitive or platinum resistant ovarian cancer and has a manageable safety profile

Pt-S:
ORR: 64.6%
PFS: 15.2 months

pub 2021

NCT02660034 I/Ib Pamiparib, Tislelizumab A Phase 1/1b, Open Label, Multiple Dose, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Antitumor Activity of the Anti-PD-1 Monoclonal Antibody BGB-A317 in Combination With the PARP Inhibitor BGB-290 in Subjects With Advanced Solid Tumors

Pamiparib+tislelizumab is well tolerated and associated with antitumor responses in both BRCA WT and BRCA MUT ovarian cancer

16 evaluable Pt-S:
ORR: 44%
DCR: 63%

pub 2019

*Statistically significant result

Platinum-Resistant/Refractory (Pt-R/Rf): Treatment given for recurrence occurring less than 6 months after last platinum-based treatment or for progression during last platinum-based treatment

For more detailed information, please click on the clinical trial ID number.

Trial ID # Phase Drugs Clinical Trial Title Key Conclusion and Results
Drugs in Clinical Development
NCT01891344; ARIEL2 II Rucaparib A Phase 2, Open-Label Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (ARIEL2)

In platinum resistant patients rucaparib is most effective in patients that have BRCA1/2 mutations

BRCA MUT vs BRCA WT LOH high vs BRCA WT LOH low:

ORR: 23.4 vs 4.1 vs 5.4%
PFS: 7.2 vs 1.9 vs 1.8 months

pub 2021

NCT03699449 II Cediranib, Olaparib An uMbrella Study of BIomarker-driven Targeted Therapy In Patients With Platinum-resistant Recurrent OvariaN Cancer(AMBITION)

Olaparib+cediranib shows promising activity in BRCA MUT patients

ORR: 50%

abs Jun 2021 and poster, pub 2022

NCT03699449 II Durvalumab, Olaparib An uMbrella Study of BIomarker-driven Targeted Therapy In Patients With Platinum-resistant Recurrent OvariaN Cancer(AMBITION)

Olaparib+durvalumab shows promising activity in BRCA MUT patients

ORR: 35.7%

abs Jun 2021 and poster, pub 2022

NCT01540565 II Veliparib A Phase II Evaluation of the Poly (ADP-Ribose) Polymerase (PARP)-1 and -2 Inhibitor Veliparib (ABT-888) (NSC#737664) in the Treatment of Persistent or Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer Patients Who Carry a Germline BRCA1 or BRCA2 Mutation

Veliparib shows encouraging activity in gBRCA MUT OC

ORR: 20%
PFS: 5.8 months

Pt-S: ORR: 35%; PFS: 11.0 months
Pt-R: ORR: 20%; PFS: 5.8 months

pub 2015

NCT02345265 II Cediranib, Olaparib A Phase 2 Study of Olaparib and Cediranib for the Treatment of Recurrent Ovarian Cancer

Olaparib+cediranib combination shows activity in Pt-R patients

ORR: 20%

gBRCA WT:
ORR: 18%

gBRCA MUT:
ORR: 60% (n=5)

abs Jun 2018

NCT02889900; CONCERTO II Cediranib, Olaparib A Single Arm, Open-label, Phase IIb Study to Assess the Efficacy and Safety of the Combination of Cediranib and Olaparib Tablets in Women With Recurrent Platinum Resistant Epithelial Ovarian Cancer, Including Fallopian Tube and/or Primary Peritoneal Cancer Who do Not Carry a Deleterious or Suspected Deleterious Germline BRCA Mutation

Olaparib+cediranib has manageable toxicity and shows evidence of anti-tumor activity in heavily pretreated platinum resistant non-gBRCA MUT patients

ORR: 15.6%
PFS: 5.1 months

pub 2022

NCT03314740; BAROCCO II Cediranib, Olaparib The BAROCCO Study (Best Approach in Recurrent-Ovarian-Cancer-with Cediranib-Olaparib): an Italian Multicenter Randomized Phase II Study of Weekly Paclitaxel vs. Cediranib-Olaparib With Continuous Schedule vs. Cediranib-Olaparib With Intermittent Schedule in Patients With Platinum Resistant High Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer.

The combination of olaparib and cediranib is not superior to chemotherapy in terms of PFS in heavily pretreated Pt-R OC patients. However, this oral doublet, is active and may offer a non-chemotherapy option in this difficult to treat population

Ced+Ola (continuous) vs Ced+Ola (intermittent) vs Pac:

PFS: 5.6 vs 3.8 vs 3.1 months

gBRCA WT
PFS: 5.8 vs 3.8 vs 2.1 months

pub 2022

NCT03574779 II Bevacizumab, Dostarlimab, Niraparib A Phase 1B/2 Multicohort Umbrella Study to Evaluate the Safety and Efficacy of Novel Treatments And/Or Combinations of Treatments in Participants With Ovarian Cancer (OPAL)

Triplet therapy with niraparib, dostarlimab, and bevacizumab is tolerable and demonstrates clinical activity in patients with BRCA WT Pt-R OC without HRR gene mutations

ORR: 17.9%
DCR: 76.9%
PFS: 7.6 months

w/ prior Bev: ORR: 6%
w/o prior Bev: ORR: 27%

abs Mar 2021

NCT02657889; TOPACIO I/II Pembrolizumab, Niraparib Phase 1/2 Clinical Study of Niraparib in Combination With Pembrolizumab (MK-3475) in Patients With Advanced or Metastatic Triple-Negative Breast Cancer and in Patients With Recurrent Ovarian Cancer (TOPACIO)

Promising activity of niraparib+pembrolizumab in platinum resistant patients independent of BRCA status, HRD status and PD-L1 expression

ORR: 21%

pub 2019

NCT03333915 I/II Pamiparib An Open Label, Multi-Center Phase I/II Study to Evaluate Efficacy and Safety of BGB-290 in Chinese Subjects With Advanced Ovarian Cancer, Fallopian Cancer, and Primary Peritoneal Cancer or Advanced Triple Negative Breast Cancer

Pamiparib showes antitumor activity with durable responses in patients with gBRCA MUT platinum sensitive or platinum resistant ovarian cancer and has a manageable safety profile

Pt-R:
ORR: 31.6%
PFS: 6.2 months

pub 2021

NCT02660034 I/Ib Pamiparib, Tislelizumab A Phase 1/1b, Open Label, Multiple Dose, Dose Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics and Antitumor Activity of the Anti-PD-1 Monoclonal Antibody BGB-A317 in Combination With the PARP Inhibitor BGB-290 in Subjects With Advanced Solid Tumors

Pamiparib+tislelizumab is well tolerated and associated with antitumor responses in both BRCA WT and BRCA MUT ovarian cancer

18 evaluable Pt-R:
ORR: 22%
DCR: 50%

pub 2019

NCT01623349 I Alpelisib, Olaparib Phase I Study of the Oral PI3kinase Inhibitor BKM120 or BYL719 and the Oral PARP Inhibitor Olaparib in Patients With Recurrent Triple Negative Breast Cancer or High Grade Serous Ovarian Cancer

Encouraging activity of alpelisib+olaparib combination, also in BRCA WT patients

ORR: 34.6%
PFS: 7.2 months

gBRCA WT: ORR: 31.3%
gBRCA MUT: ORR: 33.3% (n=9)
BRCA WT: ORR: 33.3% (n=12)
BRCA MUT: ORR: 30.8% (n=13)

pub 2019

Treatment given for recurrence occurring at any time after last platinum-based treatment

For more detailed information, please click on the clinical trial ID number.

Trial ID # Phase Drugs Clinical Trial Title Key Conclusion and Results
Drugs in Clinical Development
NCT01891344; ARIEL2 II Rucaparib A Phase 2, Open-Label Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (ARIEL2)

Administration of rucaparib as active treatment should be considered in earlier lines of therapy before the emergence of platinum resistance. RAD51C/D mutation and high-level BRCA1 promotor methylation predict response to rucaparib, similar to BRCA1/2 mutations, but LOH high is only predictive of response in platinum-sensitive patients

BRCA MUT vs BRCA WT LOH high vs BRCA WT LOH low:

ORR: 80 vs 29 vs 10%*
PFS: 12.8 vs 5.7 vs 5.2 months*

pub 2021

NCT03579316 II Adavosertib, Olaparib EFFORT: Efficacy of AZD1775 in Parp Resistance; A Randomized 2-Arm, Non-Comparative Phase 2 Study of AZD1775 Alone or AZD1775 and Olaparib in Women With Ovarian Cancer Who Have Progressed During PARP Inhibition

Adavosertib alone and in combination with olaparib demonstrates efficacy in patients with PARPi-resistant OC irrespective of BRCA status

Ada+Ola vs Ada: ORR: 29 vs 23%; DoR: 6.4 vs 5.5 months: DCR (4 months): 89 vs 63%; PFS: 6.8 vs 5.5 months

BRCA MUT:
Ada+Ola vs Ada (n=15): ORR: 19 vs 20%; DoR: 6.4 vs 5.6 months; DCR (4 months): 81 vs 67%; PFS: 5.6 vs 5.6 months

BRCA WT:
Ada+Ola vs Ada: ORR: 39 vs 31%; DoR: 8.7 vs 4.1 months; DCR (4 months): 94 vs 69%; PFS: 8.4 vs 4.1 months

abs Jun 2021 and presentation

NCT02511795 Ib Adavosertib, Olaparib A Phase Ib Study of AZD1775 and Olaparib in Patients With Refractory Solid Tumours

Olaparib+adavosertib shows anti-tumor activity, particularly at the twice daily (BID) schedule

ORR: 15%
DCR: 85%

abs Apr 2019 and poster

NCT02484404 I/II Cediranib, Durvalumab, Olaparib Phase I/II Study of the Anti-Programmed Death Ligand-1 Antibody Durvalumab (MEDI4736) in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Cancers

Promising response rates for olaparib, cediranib and durvalumab combinations in OC

Ola+Dur:
ORR: 15%
DCR (4 months): 53%

Ola+Ced+Dur: 7 evaluable
ORR: 42.9%
DCR: 71.4%
Most patients Pt-R, BRCA WT

pub 2017; abs Oct 2018, pub 2019

NCT01286987 I Talazoparib A Phase 1, First In Human, Single-arm, Open-label Study Of Once A Day, Orally Administered Talazoparib (Bmn 673) In Patients With Advanced Or Recurrent Solid Tumors

Talazoparib shows promising activity in gBRCA MUT OC

ORR: 41.7%
CBR: 66.7%
PFS: 9.1 months

pub 2017

NCT02338622 I Capivasertib, Olaparib A Phase I Multi-centre Trial of the Combination of Olaparib (PARP Inhibitor) and AZD5363 (AKT Inhibitor) in Patients With Advanced Solid Tumours

Capivasertib+olaparib is safe and tolerable and anti-tumor activity is observed in patients harboring tumors with BRCA MUT and BRCA WT cancers with or without somatic DDR and/or PI3K-AKT pathway alterations

ORR: 24%
DCR (4 months): 45.8%

pub 2020

NCT01650376 1b Carboplatin, Paclitaxel, Olaparib Phase Ib With Expansion of Patients at the MTD Study of Olaparib Plus Weekly (Metronomic) Carboplatin and Paclitaxel in Relapsed Ovarian Cancer Patients

Olaparib can be safely administered with metronomic carboplatin and paclitaxel in recurrent ovarian cancer, but BRCA MUT patients experience most benefit

ORR: 54%

BRCA MUT vs BRCA WT:
PFS: 12.1 vs 4.8 months*
OS: 24.1 vs 10.4 months*

pub 2019

*Statistically significant result

DNA Damage Repair Pathway Inhibitors: ATR

Platinum-Resistant/Refractory (Pt-R/Rf): Treatment given for recurrence occurring less than 6 months after last platinum-based treatment or for progression during last platinum-based treatment

For more detailed information, please click on the clinical trial ID number.

Trial ID # Phase Drugs Clinical Trial Title Key Conclusion and Results
Drugs in Clinical Development
NCT02595892 II Berzosertib, Gemcitabine Phase 2 Study of M6620 (VX-970) in Combination With Gemcitabine Versus Gemcitabine Alone in Subjects With Platinum-Resistant Recurrent Ovarian or Primary Peritoneal Fallopian Tube Cancer

Addition of berzosertib to gemcitabine increases PFS without additional toxicity, the benefit was observed mainly in patients with platinum-free interval less than 3 months

Ber+Gem vs Gem:

PFS: 5.7 vs 3.7 months*

pub 2020, pub 2021

*Statistically significant result

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