Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

SOLO-1 GOG 3004

(Moore, 2018; Friedlander 2021; Banerjee 2021; Colombo 2021; DiSilvestro 2022)

Randomised double-blind placebo-controlled RCT

Multi-country (15 countries)

Funding: AstraZeneca, Merck many conflicts of interest

Inclusion criteria:

• 18 years or older;

• newly-diagnosed advanced FIGO stage III or IV, high-grade serous or endometrioid ovarian cancer,

primary peritoneal cancer, or fallopian tube cancer or a combination thereof

• Mutation in BRCA1, BRCA2 or both with a complete or partial response after platinum-based chemotherapy

N total at baseline:

Intervention: 246

Control: 130

Important prognostic factors²:

age ± SD:

I:53.6 (SD 9.4)

C:53.4 (SD 9.8)

BRCA1:

I:191 (73%)

C: 91 (69%)

BRCA2:

I: 66 (25%)

C:40 (31%)

Oral Olaparib (300 mg twice daily)  n=246

Placebo n=130

Median follow up time:

I: 40.7 months (IQR 34.9-72.9)

C: 41.2 months (IQR 32.2-41.6)

Discontinued treatment:

I: 124/260 (48%)

C: 94/131 (72%)

Investigator assessed 5 year Progression free survival:

I: 56.0 months

C: 13.8 months

HR=0.33 ( 95% CI 0.25-0.43)

7 year Overall Survival:

I: 67.0% still alive

C: 46.5 % still alive

HR= 0.55 (95% CI 0.40-0.76)

Health related quality of life:

Safety after 7 years of follow up:

Any treatment-emergent adverse event

I: 256 (98.5)

C: 120 (92.3)

Serious treatment-emergent adverse event

I: 55 (21.2)

C: 18 (13.8)

PRIMA-ENGOT OV26, GOG 312

Gonzalez-Martin 2019;

Barretina-Ginesta 2022; Gonzalez-Martin 2023)

Randomised double-blind placebo-controlled RCT

Multi-country (20 countries)

Accrual: Jul 2016-Jun 2018

Funding: GSK

NCT02655016

Many conflicts of interest

Inclusion criteria:

• 18 years or older;

• newly-diagnosed histologically-confirmed advanced FIGO stage III or IV, high-grade serous or endometrioid ovarian cancer,

primary peritoneal cancer, or fallopian tube cancer

• Prior enrolment, all the  pts had received six to nine cycles of first-line platinum-based chemotherapy resulting in a complete or partial response.

N total at baseline:

Intervention: 484

Control: 244

Important prognostic factors²:

age ± SD:

I:62 (range 33 to 85)

C:62 (range 33 to 88)

BRCA mutation:

I:151 (31%)

C: 71 (29%)

HRD mutation:

I: 247 (51%)

C: 126 (5-1%)

Niraparib (300mg) once daily continuously during a 28-day cycle.

N=484

Placebo

N=244

Median follow up time (clinical cut off date Nov 17,2021) :

I: 41.6 months

C: 41.9 months

Discontinued treatment:

I: 405/484

C:217/244

No lost to follow up.

PFS (by blinded independent central radiology review) with clinical cut off date May, 17 2019)

Median PFS:

Overall population:

I: 13.8 months

C:  8.2 months

HR=0.66 (95% CI 0.56-0.79)

HR-d

I: 21.9 months

C: 10.4 months

HR 0.43 (95% CI 0.31-0.59)

HR-p

I: 8.1 months

C: 5.4 months

HR 0.68 (95% CI 0.49-0.94)

HR-d BRCAwt

I: 19.6 months

C: 8.2 months

HR 0.5 (95% CI 0.31-0.83)

HR-d BRCA mut

I: 22.1 months

C: 10.9 months

HR 0.4 (95% CI 0.27-0.62)

Safety with clinical cut off date Nov 17,2021:

Any treatment-emergent adverse event

I: 479(99.0)

C:229 (93.9)

Serious treatment-emergent adverse event

I: 186 (38.4)

C: 39 (16.0)

PFS( investigator assessment) with clinical cut off date Nov 17,2021

Median PFS:

Overall population:

I: 13.8 months

C:  8.2 months

HR 0.66 (95% CI 0.56-0.79) p<0.001

HR-d

Median

I: 24.5 months

C: 11.2 months

HR 0.52 (95% CI 0.40-0.68) p<0.001

HR-d BRCAm

Median

I: 31.5 months

C: 11.5 months

HR 0.45 (95% CI 0.32-0.64)

HR-d BRCAwt

Median

I: 19.4 months

C: 10.4 months

HR 0.66 (95% CI 0.44-1.00)

HR-p

Median:

I: 8.4 months

C: 5.4 months

HR 0.65 (95% CI 0.49-0.87)

PAOLA-ENGOT-OV25

Harter 2022; Ray Cochard 2023

Randomised double-blind phase 3 study.

Jul 2015-Sept 2017.

11 countries.

Funding: ARcagy Research, AstraZeneca, MSD, F. Hoffmann-LaRoche.

Many conflicts of interest

Inclusion criteria:

-18 years or older

Newly diagnosed advanced FIGO stage III or IV, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer or fallopian tube cancer or other nonmucious epithleial ovarian cancers provided they had a deleterious germline BRCA1 or BRCA2 mutation.

Important prognostic factors:

Median age:

I: 61.0 years (range 32.0-87.0)

C:60.0 years (range (26.0-85.0)

Serous histotype:

I: 519 (97%)

C: 253 (94%)

BRCA positive:

I: 161 (30%)

C: 80 (30%)

BRCA1:

I: 111 (22%)

C: 49 (18%)

BRCA2:

I: 45(8%)

C: 31 (12%)

HRD mutation:

I: 255 (47%)

132 (49%)

Olaparib orally (300mg twice daily) at least 3 weeks and no more than 9 weeks.

N=537

Intravenous bevacizumab and chemotherapy were given and bevacizumab continued after randomisation as maintenance therapy for a total duration of up to 15 months.

Placebo

N=269

Median follow up time for overall survival:

I: 61.7 months [IQR: 57.5-67.0]

C: 61.9 months [IQR: 58.1-66.8]

Discontinued treatment:

I: 339/535 

C:196/267

4 patients did not receive treatment

2 patients lost to follow up.

Overall survival (OS)

Median:

I: 56.5  months

C: 51.6 months HR 0.92, (95% CI 0.76-1.12)

P=0.4118

5-year:

I: 47.3%

C: 41.5%

HRD-positive tumors:

Median:

I: 75.2 months

C: 57.3 months

HR=0.62 (95%CI 0.45-0.85)

5-year:

I: 65.5%

C: 48.4%

HRD-positive tumors + BRCAm:

Median:

I: 75.2 months (unstable)

C: 66.9 months

HR=0.60 (95%CI 0.39-0.93)

5 year:

I: 73.2%

C: 53.8%

HRD-positive tumors -BRCAm: 

Median:

I: not reached

C: 52 months

HR=0.71 (95%CI 0.45-1.13)

5 year:

I: 54.7%

C: 44.2%

HRD-negative tumors:

Median:

I: 36.8 months

C: 40.4 Months

HR=1.19 (95CI 0.88-1.63)

5 year:

I: 25.7%

C: 32.3%

Progression free survival (PFS)

Median:

I: 22.9 months

C: 16.6 months

HR=0.63 (95% CI 0.53-0.74)

5-year:

I: 29.3%

C: 15.8%

HRD-positive tumors:

Median:

I: 46.8 months

C: 17.6 months

HR=0.41 (95%CI 0.32-0.54)

5-year:

I: 46.1%

C: 19.2%

HRD-positive tumors + BRCAm:

Median:

I: 60.7 months (unstable)

C: 21.7 months

HR=0.45 (95%CI 0.32-0.64)

5 year:

I: 50.0%

C: 25.1%

HRD-positive tumors -BRCAm: 

Median:

I: 30.0 months

C: 16.6 months

HR=0.47 (95%CI 0.32-0.7)

5 year:

I: 41.1%

C: 14.6%

HRD-negative tumors:

Median:

I: 16.6 months

C: 16.2 months

HR=1.01 (95%CI 0.77-1.33)

5 year:

I: 8.0%

C: 11.7%

EORTC Quality of Life

Not described

Safety

MDS/AML/AA

I: 9 (1.7%)

C: 6 (2.2%)

New primary malignancies

I: 22 (4.1%)

C: 8 (3.0%)

Pneumonitis/ILD/bronchiolitis

I: 7 (1.3%)

C: 2 (0.7%)

PRIME-study

Li et al, 2023

Randomised double-blind placebo-controlled phase 3 study in China.

June 29,2018 Nov 11,2019. 

Funding: Zai Lab (shanghai) and partially supported by the National Major Scientific and Technological Special Project for Significant New Drugs Development in 2020. (China; grant 2020ZX09101-014) 

Many conflicts of interest

Inclusion criteria:

Eligible patients were 18 years or older and had a new diagnosis of histologically confirmed, high-grade (dominantly) serous or endometrioid epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma collectively defined as ovarian cancer) that was classified as stage III or IV according to the International Federation of Gynecology and Obstetrics criteria. Patients who received primary or interval debulking surgery were eligible regardless of cytoreductive surgery outcome (optimal, residual tumor ≤1 cm; or suboptimal, residual tumor >1 cm). Patients received 6 to 9 cycles of platinum- based chemotherapy and had a complete response or partial response as assessed by investigators.

Important prognostic factors:

Age:

Median (range)

I: 53 years (32-77)

C: 54 years (33-77)

Histology serous  subtype

I: 253 (99.2%)

C: 128 (99.2%)

Germline BRCA variant:

I: 85 (33.3%)

C: 40 (31.0%)

HR-deficient

I: 170 (66.7%)

C: 87 (67.4%)

HR proficient

I: 60 (23.5%)

C: 25 (19.4%)

HR-indeterminate

I: 25 (9.8%)

C: 17 (13.2%)

Niraparib n=255

Patients with a bodyweight of fewer than 77 kg and/or a platelet count of less than 150 × 103/μL (to convert to × 109/μL, multiply by 1) at baseline received niraparib,200mg (2 100-mg capsules). Other patients received niraparib, 300 mg (3 100-mg capsules)

Placebo n=129

Median follow up time for overall survival:

I: 27.5 months

C:27.6 months

Discontinued treatment:

I: 153/255

C:100/129

Progression free survival (PFS)

Median:

I: 24.8 months (95% CI 19.2- not estimable [NE})

C: 8.3 months (95%CI 7.3-11.1)

HR= 0.45 995%CI 0.34-0.60)

HRD subgroup:

median PFS:

I: not reached (95%CI 22.3-NE)

C: 11 months (95% CI 8.3-13.8)

HR= 0.48 (95%CI 0.34-0.68)

Germline BRCA variants:

I: not reached

C: 10.8 months

HR=0.40 (95%CI 0.23-0.68)

Without BRCA variants:

I: 19.3 months

C: 8.3 months

HR=0.48 (95% CI 0.34-0.67)

HRp:

I: 16.6 months

C: 5.5 months

HR=0.36 (95%CI 0.22-0.75)

Data for Overall survival were not mature in the ITT population.

Safety

Serious treatment-emergent adverse events (TEAEs)

I: 48 (18.8%)

C: 11 (8.5%)

ATHENA-MONO/GOG-3020/ENGOT-ov45

Monk et al, 2022

Randomized double-blind phase 3 study at 200 centers in 24 countries in Asia , Australia/New Zealand, Europe and North America.

Oct1, 2018 -Sept30,2020

Funding:

Clovis Oncology INC; in part by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20,014; C.P.)

Many conflicts of interest

Inclusion criteria:

≥ 18 years and had newly diagnosed,

histologically confirmed, advanced stage III or IV, high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer.

Patients had completed cytoreductive surgery (R0/complete resection was permitted) before chemotherapy or following neoadjuvant chemotherapy; had completed four to eight cycles of first-line platinum-doublet treatment, including a minimum of four cycles of a platinum/taxane combination (bevacizumab was only allowed during the chemotherapy phase), and achieved an investigator-assessed response; had sufficient formalin-fixed paraffin-embedded tumor tissue available for planned analyses and a known BRCA mutation result (either positive or negative) via central testing; had an Eastern Cooperative Oncology Group performance status of 0-1; and had adequate organ function.

Important prognostic factors:

Age

Median (range)

I: 61.0 years (30-83)

C: 61.0 years (31-80)

Serous histology

I: 384 (89.9%)

C: 106 (95.5%)

HRD test status

BRCA mutation

I: 91 (21.3%)

C: 24 (21.6%)

BRCA wt/LOH high

I: 94 (22.0%)

C: 25 (22.5%)

BRCA wt/ LOH low

I: 189 (44.3%)

C; 49 (44.1%)

BRCA wt/LOH indeterminate

I: 53 (12.4%)

C: 13 (11.7%)

Rucaparib n=425

( treatment ongoing n=53)

Placebo n=111

(treatment ongoing n=11)

Median duration of follow up:

I: 26.1 months (95%CI 25.8-26.9)

C: 26.2 months (95CI 24.0-27.7)

Discontinuation of the treatment

I: 271/425

C:89/110

Progression free survival

Median:

HRD population

I: 28.7 months

C: 11.3 months

HR=0.47 (95%CI 0.31-0.72)

ITT population

Media PFS

I: 20.2 months

C: 9.2 months

HR=052 (95CI 8.3-12.2)

Overall survival were immature.

TEAE of any grade:

I: 411/425 (96.7%)

C: 102/110 (92.7%)

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

SOLO1 (Friedlander, 2021; Banerjee 2021; Moore 2018; Colombo 2021; DiSilvestro 2022)

Definitely yes;

Reason: Randomisation was performed centrally with a block design, with stratification according to the clinical response after platinum-based chemotherapy

Definitely yes;

Reason: Patients were assigned to a trial group through an interactive Web-based or voice-response system

Definitely yes;

Reason; Quadruple (participant, care provider, investigator, outcome assessor) source : clinnicaltria.gov

Definitely yes ;

Reason : Loss to follow-up was infrequent in intervention and control group. Reasons for discontinuation were given.

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: Industry-sponsored trial with several authors disclosing a financial conflict of interest. A cross-over between trial groups was not specified in the protocol. Change of primary outcome due to low rate of the originally planned outcome.

LOW

PRIMA

(Gonzalez-Martin, 2019; Barretina-Ginesta, 2022 Gonzalez-Martin, 2023)

Probably yes;

Reason: Randomisation was performed in a double-blind manner with the use of an interactive Webresponse system, with stratification according to clinical response after first-line platinum-based chemotherapy (complete or partial response), receipt of neoadjuvant chemotherapy (yes or no), and status regarding tumour homologous recombination (deficient vs proficient or not determined)

Definitely yes;

Reason: Randomisation was done in a double-blind manner with the use of an interactive Webresponse system.

Definitely yes;

Reason; Quadruple (participant, care provider, investigator, outcome assessor) source : clinnicaltrial.gov

The objective assessment of progressive disease was determined by central radiological and clinical review in a blinded manner, according to RECIST version 1.1.14

Definitely yes ;

Reason : Loss to follow-up was infrequent in intervention and control group. Reasons for discontinuation were given.

Probably yes;

Reason: QoL reported only on figure.

Probably yes;

Reason: Industry-sponsored trial with several authors disclosing a financial conflict of interest.

The sponsor (GSK) was responsible for overseeing the collection, analysis and interpretation of the data.

LOW

PAOLO-1

(Ray Coquard, 2019; Harter 2022; Ray Coquard, 2023)

Definitely yes;

Reason:

Randomisation was performed centrally with the use of a bock design with stratification

Definitely yes;

Reason:

Patients were assigned to trial arms (olaparib or matching placebo) with the use of an interactive Web of voice response system

Probably yes;

Triple (participant, care provided, investigator)

The objective assessment of outcomes is not described

Definitely yes ;

Reason : Loss to follow-up was infrequent in intervention and control group.

Reasons for discontinuation were given.

Probably yes;

Reason: Sponsors were not asked to approve the final content

Probably yes;

Reason: Industry-sponsored trial.

After discontinuation of the intervention, patients could receive other treatment at the investigator’s discretion. 

LOW

PRIME study

Li et al, 2023

Probably yes

Reason: Patients were centrally randomized through an interactive web-response system.

Probably yes

Reason:

Study participants , investigaotrs, central assessors, and the study sponsor were masked to the treatment assignment.

Probably yes

Reason:

The objective assessment of progressive disease was done by blinded independent central review (BICR) according to RECIST

Definitely yes ;

Reason : Loss to follow-up was infrequent in intervention and control group.

Reasons for discontinuation were given.

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: Industry-sponsored trial with several authors disclosing a financial conflict of interest.

LOW

ATHENA study

Monk et al, 2021; Monk et al, 2022

Probably yes

Reason:

Randomisation assignment was computer-generated (block size of 10).

Probably yes

Reason:

Randomisation was done in a double blinded manner.

Probably yes

Reason:

The objective assessment of progressive disease was determined by central radiological and clinical review in a blinded manner, according to RECIST

Definitely yes ;

Reason : Loss to follow-up was infrequent in intervention and control group.

Reasons for discontinuation were given.

Definitely yes

Reason: All relevant outcomes were reported;

Probably yes;

Reason: Industry-sponsored trial with several authors disclosing a financial conflict of interest.

LOW