NCT02476968: ORZORA

To Assess the Efficacy and Safety of Olaparib Maintenance Monotherapy in the Treatment of Ovarian Cancer

Completed Phase 4 Results posted Last updated 10 September 2022

What this trial tests

Phase 4 trial testing Olaparib in BRCA or HRR+ Mutated Ovarian Cancer Patients in 181 participants. Completed in 17 December 2021.

Timeline

28 September 2015

Primary endpoint
17 April 2020

17 December 2021

Quick facts

Lead sponsor	AstraZeneca
Phase	Phase 4
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	single group
Masking	none
Primary purpose	other
Enrollment	181
Start date	28 September 2015
Primary completion	17 April 2020
Estimated completion	17 December 2021
Sites	58 locations across Italy, United Kingdom, Hungary, Poland, Canada, Bulgaria, Spain, Czechia

Drugs / interventions tested

• Olaparib (olaparib) — full drug profile →

Conditions studied

• BRCA or HRR+ Mutated Ovarian Cancer Patients — all drugs for BRCA or HRR+ Mutated Ovarian Cancer Patients →

Sponsor

AstraZeneca — full company profile →

Who can join

Adults 18 to 130, female only, with BRCA or HRR+ Mutated Ovarian Cancer Patients. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Progression-Free Survival (PFS) Primary · Tumour assessments at baseline then every 12 weeks relative to date of enrolment until RECIST 1.1-defined progression. Assessed until primary analysis DCO of 17 April 2020 (up to maximum of 55 months).

To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of PFS. The PFS was defined as the time from the date of enrolment until date of objective radiological disease progression (assessed by the Investigator via Response Evaluation Criteria in Solid Tumors, version 1.1 \[RECIST 1.1\]), or death (by any cause in absence of disease progression) regardless of whether the patient withdrew from therapy or received another anti-cancer therapy prior to disease progression. Objective progression was defined as

Group	Value	95% CI
Overall BRCAm	18.0	14.3 – 22.1
sBRCAm	16.6	12.4 – 22.2

Overall Survival (OS); Assessed at Primary Analysis Secondary · From baseline until death due to any cause. Assessed until primary analysis DCO of 17 April 2020 (up to maximum of 55 months).

To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of OS. The OS was defined as the time from the date of enrolment until death due to any cause regardless of whether the patient withdrew from therapy or received another anti-cancer therapy. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Pre-specified analysis of OS was performed at the time of primary analysis of PFS; a further analysis of OS was pe

Group	Value	95% CI
Overall BRCAm	47.6	36.1 – NA
sBRCAm	NA	33.2 – NA

Time to Second Progression (PFS2) or Death; Assessed at Primary Analysis Secondary · Tumour assessments (and blood samples for CA-125, if applicable) at baseline then every 12 weeks relative to date of enrolment until second progression. Assessed until primary analysis DCO of 17 April 2020 (up to maximum of 55 months).

To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of PFS2. The PFS2 was defined as the time from the date of enrolment to the earliest progression event subsequent to that used for the primary variable PFS or death (by any cause) in the absence of progression. Patients whose progression event for PFS was death had this counted as a progression event for PFS2 also. The date of second progression was recorded by the Investigator and defined according to local standard clinical practice and could invo

Group	Value	95% CI
Overall BRCAm	30.9	24.7 – 40.0
sBRCAm	24.7	21.8 – 36.1

Time to First Subsequent Therapy (Treatment) or Death (TFST); Assessed at Primary Analysis Secondary · From enrolment to first subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation. Assessed until primary analysis DCO of 17 April 2020 (up to maximum of 55 months).

To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of TFST. The TFST was defined as the time from the date of enrolment to the earlier of first subsequent anti-cancer therapy start date (excluding radiotherapy), or death date. Pre-specified analysis of TFST was performed at the time of the primary analysis; a further analysis of TFST was performed at the final analysis (and reported as a separate outcome measure).

Group	Value	95% CI
Overall BRCAm	37.6	23.5 – 47.6
sBRCAm	31.5	19.5 – NA

Time to Second Subsequent Therapy (Treatment) or Death (TSST); Assessed at Primary Analysis Secondary · From enrolment to second subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation. Assessed until primary analysis DCO of 17 April 2020 (up to maximum of 55 months).

To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of TSST. The TSST was defined as the time from the date of enrolment to the earlier of the date of second subsequent anti-cancer therapy start date, or death date. Pre-specified analysis of TSST was performed at the time of the primary analysis; a further analysis of TSST was performed at the final analysis (and reported as a separate outcome measure).

Group	Value	95% CI
Overall BRCAm	47.6	29.4 – NA
sBRCAm	NA	24.7 – NA

Time to Discontinuation of Treatment or Death (TDT) Secondary · From enrolment to study treatment discontinuation or death (up to maximum of 6 years).

To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of TDT. The TDT was defined as the time from the date of enrolment to the earlier of the date of study treatment discontinuation or death.

Group	Value	95% CI
Overall BRCAm	19.8	14.3 – 22.9
sBRCAm	19.0	13.5 – 22.8

Change From Baseline in Functional Assessment of Cancer Therapy - Ovarian (FACT-O) Trial Outcome Index (TOI) Scores Over Time Secondary · QoL questionnaires at baseline, Day 29 (Week 4), then every 12 weeks for 24 months or DCO for primary analysis, whichever came first. QoL questionnaires also collected at discontinuation of study treatment visit and 30 days post last dose.

To assess the Quality of Life (QoL) of patients with BRCAm and sBRCAm ovarian cancer by evaluation of FACT-O TOI. The TOI score was derived from the sum of the scores of the 25 items included in the physical well-being (7 items), functional well-being (7 items), and additional concerns ovarian cancer subscale (11 items) of the FACT-O questionnaire version 4. The FACT-O TOI score ranges from 0-100, with a higher score indicating better QoL. A change (increase or decrease) in score of at least 10 points from baseline was defined as clinically meaningful. A positive change in score from baseline

Week 4

Group	Value	95% CI
Overall BRCAm	-2.2	± 9.82
sBRCAm	-1.9	± 9.59

Week 16

Group	Value	95% CI
Overall BRCAm	-1.3	± 10.04
sBRCAm	-0.3	± 10.85

Week 28

Group	Value	95% CI
Overall BRCAm	1.2	± 9.44
sBRCAm	3.2	± 10.25

Week 40

Group	Value	95% CI
Overall BRCAm	1.6	± 10.72
sBRCAm	4.1	± 10.48

Week 52

Group	Value	95% CI
Overall BRCAm	3.2	± 9.03
sBRCAm	4.9	± 7.84

Week 64

Group	Value	95% CI
Overall BRCAm	1.8	± 9.88
sBRCAm	0.8	± 9.72

Week 76

Group	Value	95% CI
Overall BRCAm	1.4	± 9.27
sBRCAm	0.3	± 9.83

Week 88

Group	Value	95% CI
Overall BRCAm	2.0	± 9.97
sBRCAm	1.5	± 10.86

Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Total Scores Over Time Secondary · QoL questionnaires at baseline, Day 29 (Week 4), then every 12 weeks for 24 months or DCO for primary analysis, whichever came first. QoL questionnaires also collected at discontinuation of study treatment visit and 30 days post last dose.

To assess the QoL of patients with BRCAm and sBRCAm ovarian cancer by evaluation of FACIT-F. The FACIT-F is a 13-item questionnaire to assess patients' fatigue experience and its impact on their daily lives over the past 7 days. The FACIT-F total score ranges from 0-52, with a higher score indicating a lower level of fatigue (and better QoL). Changes in scores of ≥3 points were defined to be clinically meaningful. A positive change in score from baseline indicates an improvement.

Week 4

Group	Value	95% CI
Overall BRCAm	-2.9	± 8.21
sBRCAm	-2.9	± 7.58

Week 16

Group	Value	95% CI
Overall BRCAm	-2.5	± 7.54
sBRCAm	-2.7	± 9.26

Week 28

Group	Value	95% CI
Overall BRCAm	-1.2	± 7.95
sBRCAm	-0.6	± 7.25

Week 40

Group	Value	95% CI
Overall BRCAm	-0.3	± 7.91
sBRCAm	0.9	± 7.02

Week 52

Group	Value	95% CI
Overall BRCAm	0.6	± 7.43
sBRCAm	1.3	± 7.25

Week 64

Group	Value	95% CI
Overall BRCAm	0.8	± 7.26
sBRCAm	0.5	± 8.47

Week 76

Group	Value	95% CI
Overall BRCAm	-0.3	± 8.57
sBRCAm	-1.1	± 8.74

Week 88

Group	Value	95% CI
Overall BRCAm	0.3	± 8.45
sBRCAm	-0.9	± 5.81

Change From Baseline in Functional Living Index-Emesis (FLIE) Questionnaire Total Scores Over Time Secondary · FLIE questionnaires at baseline, weekly until Day 29 (Week 4), then every 12 weeks for 24 months or DCO for primary analysis, whichever came first. FLIE questionnaires also collected at discontinuation of study treatment visit and 30 days post last dose.

The FLIE captures the impact of nausea and vomiting on patient's QoL. The FLIE consists of 18 items (9 nausea-specific and 9 vomiting-specific items), rated from 1 to 7. Two domain scores and a total score are derived; the total score ranges 18-126 and a higher score indicates a lower impact (and better QoL). A positive change in score from baseline indicates an improvement.

Week 1

Group	Value	95% CI
Overall BRCAm	-6.1	± 18.62
sBRCAm	-1.6	± 18.28

Week 2

Group	Value	95% CI
Overall BRCAm	-4.5	± 18.40
sBRCAm	-2.6	± 15.97

Week 3

Group	Value	95% CI
Overall BRCAm	-4.1	± 14.57
sBRCAm	-3.9	± 13.23

Week 4

Group	Value	95% CI
Overall BRCAm	-4.8	± 18.48
sBRCAm	-5.4	± 19.92

Week 16

Group	Value	95% CI
Overall BRCAm	-2.3	± 11.50
sBRCAm	-6.3	± 11.00

Week 28

Group	Value	95% CI
Overall BRCAm	-1.6	± 13.87
sBRCAm	-3.0	± 7.94

Week 40

Group	Value	95% CI
Overall BRCAm	-0.1	± 14.07
sBRCAm	-3.2	± 14.56

Week 52

Group	Value	95% CI
Overall BRCAm	0.9	± 14.41
sBRCAm	-1.9	± 11.64

OS; Assessed at Final Analysis Secondary · From baseline until death due to any cause (up to maximum of 6 years).

To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of OS. The OS was defined as the time from the date of enrolment until death due to any cause regardless of whether the patient withdrew from therapy or received another anti-cancer therapy. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive.

Group	Value	95% CI
Overall BRCAm	46.8	37.9 – 54.4
sBRCAm	43.2	31.7 – NA

PFS2 or Death; Assessed at Final Analysis Secondary · Tumour assessments (and blood samples for CA-125, if applicable) at baseline then every 12 weeks relative to date of enrolment until second progression (up to maximum of 6 years).

To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of PFS2. The PFS2 was defined as the time from the date of enrolment to the earliest progression event subsequent to that used for the primary variable PFS or death (by any cause) in the absence of progression. Patients whose progression event for PFS was death had this counted as a progression event for PFS2 also. The date of second progression was recorded by the Investigator and defined according to local standard clinical practice and could invo

Group	Value	95% CI
Overall BRCAm	34.0	29.3 – 44.2
sBRCAm	29.3	23.7 – 44.2

TFST; Assessed at Final Analysis Secondary · From enrolment to first subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation (up to maximum of 6 years).

To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of TFST. The TFST was defined as the time from the date of enrolment to the earlier of first subsequent anti-cancer therapy start date (excluding radiotherapy), or death date.

Group	Value	95% CI
Overall BRCAm	32.1	25.8 – 40.0
sBRCAm	31.7	18.0 – NA

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of olaparib up to and including 30 days following the date of discontinuation of olaparib. Maximum timeframe of approximately 6 years.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

gBRCAm

Serious: 27/87 (31%)

Deaths: 40/87

sBRCAm

Serious: 13/55 (24%)

Deaths: 28/55

Overall BRCAm

Serious: 40/143 (28%)

Deaths: 68/145

HRRm

Serious: 7/32 (22%)

Deaths: 14/33

Unassigned (Not BRCAm, Not HRRm^)

Serious: 1/2 (50%)

Deaths: 2/3

Serious adverse events (38 terms)

Reaction	System	gBRCAm	sBRCAm	Overall BRCAm	HRRm	Unassigned (Not BRCAm, Not…
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Acute myeloid leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—
Angina unstable	Cardiac disorders	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—
Cardiac failure	Cardiac disorders	—	—	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—	—	—
Glaucoma	Eye disorders	—	—	—	—	—
Mesenteric vein thrombosis	Gastrointestinal disorders	—	—	—	—	—
Sudden death	General disorders	—	—	—	—	—
Colonic abscess	Infections and infestations	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—
Biliary colic	Hepatobiliary disorders	—	—	—	—	—
Lower respiratory tract infection	Infections and infestations	—	—	—	—	—
Procedural pain	Injury, poisoning and procedural complications	—	—	—	—	—
Femoral neck fracture	Injury, poisoning and procedural complications	—	—	—	—	—
Burkitt's lymphoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Papillary thyroid cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Dysarthria	Nervous system disorders	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Pleural effusion	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Transient ischaemic attack	Nervous system disorders	—	—	—	—	—
Deep vein thrombosis	Vascular disorders	—	—	—	—	—

Other adverse events (62 terms — click to expand)

Reaction	System	gBRCAm	sBRCAm	Overall BRCAm	HRRm	Unassigned (Not BRCAm, Not…
Nausea	Gastrointestinal disorders	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Dysgeusia	Nervous system disorders	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—	—	—
Influenza like illness	General disorders	—	—	—	—	—
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—	—	—
Abdominal distension	Gastrointestinal disorders	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—	—
White blood cell count decreased	Investigations	—	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—	—
Depression	Psychiatric disorders	—	—	—	—	—
Peripheral swelling	General disorders	—	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—	—

Most-reported serious reactions: Anaemia, Urinary tract infection, Pulmonary embolism, Acute myeloid leukaemia, Thrombocytopenia, Angina unstable, Atrial fibrillation, Cardiac failure.

Data from ClinicalTrials.gov NCT02476968 adverse events section.

Sponsor's own description

This is a prospective, open-label, single arm, multi-center study to assess the real world clinical effectiveness and safety of olaparib maintenance monotherapy as the capsule formulation (in line with the EU approved prescribing information) and will be conducted in platinum-sensitive relapsed high grade epithelial ovarian cancer patients (including patients with primary peritoneal and / or fallopian tube cancer) who carry germline or somatic BRCA mutations (documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious \[known or predicted to be detrimental/lead to loss of function\]).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. DNA Repair Pathways in Cancer Therapy and Resistance.
   Li LY, Guan YD, Chen XS, Yang JM, et al · · 2020 · cited 254× · PMID 33628188 · DOI 10.3389/fphar.2020.629266
2. PARP Inhibitors in Ovarian Cancer: A Review.
   O'Malley DM, Krivak TC, Kabil N, Munley J, et al · · 2023 · cited 128× · PMID 37268756 · DOI 10.1007/s11523-023-00970-w
3. PARP1 in Carcinomas and PARP1 Inhibitors as Antineoplastic Drugs.
   Wang L, Liang C, Li F, Guan D, et al · · 2017 · cited 67× · PMID 28991194 · DOI 10.3390/ijms18102111
4. PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers.
   Luo L, Keyomarsi K. · · 2022 · cited 56× · PMID 35435784 · DOI 10.1080/13543784.2022.2067527
5. BRCA mutations in the manifestation and treatment of ovarian cancer.
   Pan Z, Xie X. · · 2017 · cited 28× · PMID 29228641 · DOI 10.18632/oncotarget.18280
6. Maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer: Outcomes by somatic and germline BRCA and other homologous recombination repair gene mutation status in the ORZORA trial.
   Pignata S, Oza A, Hall G, Pardo B, et al · · 2023 · cited 18× · PMID 37030280 · DOI 10.1016/j.ygyno.2023.03.019
7. The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy.
   Matias-Barrios VM, Dong X. · · 2023 · cited 18× · PMID 36678591 · DOI 10.3390/ph16010094
8. Emerging treatment options for ovarian cancer: focus on rucaparib.
   Mariappan L, Jiang XY, Jackson J, Drew Y. · · 2017 · cited 17× · PMID 29290694 · DOI 10.2147/ijwh.s151194