A Phase 3 interventional study of Olaparib in Non-Germline BRCA Mutated Ovarian Cancer, sponsored by AstraZeneca. Completed at 91 sites in 19 countries. Open to female participants aged 18 Years to 95 Years. Per ClinicalTrials.gov, last updated 2024-08-21.
Sponsored by AstraZeneca · Phase 3, Interventional, and Treatment
The purpose of the study is to assess the efficacy and safety of single-agent olaparib as a maintenance treatment in patients with relapsed High Grade Serous Ovarian Cancer (including patients with primary peritoneal and/or fallopian tube cancer) or high grade endometrioid cancer who do not have known deleterious or suspected deleterious germline BRCA mutations (non-gBRCAm) and who had responded following platinum based chemotherapy
Maintenance monotherapy with the potent polyadenosine 5'diphosphoribose [Poly (ADP-ribose)] polymerisation (PARP) inhibitor (PARPi) olaparib will significantly prolong progression-free survival (PFS) in platinum sensitive relapsed non-germline breast cancer susceptibility gene (BRCA) mutated ovarian cancer patients who are in complete or partial response following platinum based chemotherapy.
Olaparib is a potent PARPi (PARP-1, -2 and -3) that is being developed as an oral therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy and other anticancer agents. PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). Inhibiting PARP enzymes leads to the persistence of SSBs, which are then converted to the more serious DNA double strand breaks (DSBs) during the process of DNA replication. During the process of cell division, DSBs can be efficiently repaired in normal cells by homologous recombination (HR) repair. Tumours with HR deficiencies (HRDs), such as ovarian cancers in patients with BRCA1/2 mutations, cannot accurately repair the DNA damage, which may become lethal to cells as it accumulates. In such tumour types, olaparib may offer a potentially efficacious and less toxic cancer treatment compared with currently available chemotherapy regimens.
While multiple randomized controlled trials (RCTs) have demonstrated that platinum sensitive BRCAm patients have profound response to maintenance treatment with PARP inhibitors, PARP inhibitors target cells with homologous recombination deficiency (HRD), of which BRCA mutation is only one type. Consistent with the mechanism of action of PARP inhibition, response has also been seen in multiple RCTs in patients who are platinum sensitive but whose tumours do not harbor BRCA mutations. Presumably these responders have defects in other components of HRR pathways, though currently available diagnostic technology is not adequate to reliably identify the full spectrum of HRR deficiencies. Instead, these data support the hypothesis that platinum sensitivity itself is a clinical selection factor for HRD.
Key Inclusion Criteria:
Exclusion Criteria:
Olaparib will be supplied as film-coated tablets containing 150 mg or 100 mg of olaparib. Patients will be administered olaparib orally twice daily (bid) at 300 mg.
Drug: Olaparib
300 mg twice daily - oral
Also known as: Lynparza
Progression Free Survival (PFS)
PFS is defined as the time from date of first dose until the date of objective radiological disease progression. Assessed according to modified Response Evaluation Criteria In Solid Tumours Version 1.1 (RECIST 1.1) or death (by any cause in the absence of progression). Progression was determined by investigator assessment, RECIST 1.1. Calculated using the Kaplan-Meier technique. Confidence intervals (CI) for median PFS was derived based on Brookmeyer-Crowley method.
Time frame: Up to maximum of 32 months
Time to First Subsequent Therapy or Death (TFST)
TFST is defined as the time from date of first dose to date of first subsequent treatment commencement or death due to any cause if this occurs before commencement of first subsequent treatment. Calculated using the Kaplan-Meier technique. CI for median TFST was derived based on Brookmeyer-Crowley method.
Time frame: Up to a maximum of 43 months
Time to Treatment Discontinuation or Death (TDT)
TDT is defined as the time from date of first dose to date of study drug discontinuation or death due to any cause if this occurs before study drug discontinuation. Calculated using the Kaplan-Meier technique. CI for median TDT was derived based on Brookmeyer-Crowley method.
Time frame: Up to a maximum of 43 months
PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status
HRD/BRCAm status was based on the central blood and tumour assessments. Assessed according to modified RECIST 1.1 or death (by any cause in the absence of progression). Progression was determined by investigator assessment, RECIST 1.1. Calculated using the Kaplan-Meier technique. CI for median PFS was derived based on Brookmeyer-Crowley method.
Time frame: Up to maximum of 32 months
Chemotherapy-free Interval (CT-FI)
CT-FI is defined as the time from the date of the last dose of platinum chemotherapy prior to olaparib maintenance therapy until the date of initiation of the next anticancer therapy. Calculated using the Kaplan-Meier technique. CI for median CT-FI was derived based on Brookmeyer-Crowley method.
Time frame: Up to a maximum of 43 months
Overall Survival (OS)
OS is defined as the time from the date of first dose of olaparib to the date of death from any cause. Calculated using the Kaplan-Meier technique. CI for median OS was derived based on Brookmeyer-Crowley method.
Time frame: Up to a maximum of 43 months
Percentage of Patients With Any Improvement From Baseline in Trial Outcome Index (TOI) Score at Any Point During the Treatment Period
Improvement was defined as a functional assessment of cancer therapy - ovarian (FACT-O) TOI response of "any improvement" at any time point over the course of treatment. The TOI is an established single targeted index composed of the following scales of the FACT-O: physical and functional well-being and additional concerns. The range of possible scores for the FACT-O TOI is 0-100, with a higher score indicating better health related quality of life (HRQoL). An increase in score from baseline indicates an improvement in HRQoL.
Time frame: Baseline up to a maximum of 32 months
Percentage of Patients With a 10-Point Deterioration From Baseline in TOI Score at Any Point During the Treatment Period
10-point deterioration was defined as a FACT-O TOI response of "10-point deterioration" at any time point over the course of treatment. The TOI is an established single targeted index composed of the following scales of the FACT-O: physical and functional well-being and additional concerns. The range of possible scores for the FACT-O TOI is 0-100, with a higher score indicating better HRQoL. A decrease in score of at least 10 points from baseline was defined as a clinically meaningful deterioration.
Time frame: Baseline up to a maximum of 32 months
This was a Phase IIIb, single-arm, open-label multicentre study to assess the efficacy and safety of single-agent olaparib as a maintenance treatment in eligible patients. A total of 279 patients from 17 countries were enrolled in this study.
| Milestone | Olaparib |
|---|---|
| Started | 279 |
| Completed | 128 |
| Not completed | 151 |
| Withdrew: Withdrawal by subject | 3 |
| Withdrew: Lost to follow-up | 2 |
| Withdrew: Death | 146 |
PFS is defined as the time from date of first dose until the date of objective radiological disease progression. Assessed according to modified Response Evaluation Criteria In Solid Tumours Version 1.1 (RECIST 1.1) or death (by any cause in the absence of progression). Progression was determined by investigator assessment, RECIST 1.1. Calculated using the Kaplan-Meier technique. Confidence intervals (CI) for median PFS was derived based on Brookmeyer-Crowley method.
| months | Olaparib |
|---|---|
| Progression Free Survival (PFS) | 9.2 (7.6 to 10.9) |
TFST is defined as the time from date of first dose to date of first subsequent treatment commencement or death due to any cause if this occurs before commencement of first subsequent treatment. Calculated using the Kaplan-Meier technique. CI for median TFST was derived based on Brookmeyer-Crowley method.
| months | Olaparib |
|---|---|
| Time to First Subsequent Therapy or Death (TFST) | 13.9 (11.5 to 16.6) |
TDT is defined as the time from date of first dose to date of study drug discontinuation or death due to any cause if this occurs before study drug discontinuation. Calculated using the Kaplan-Meier technique. CI for median TDT was derived based on Brookmeyer-Crowley method.
| months | Olaparib |
|---|---|
| Time to Treatment Discontinuation or Death (TDT) | 9.6 (7.8 to 11.1) |
HRD/BRCAm status was based on the central blood and tumour assessments. Assessed according to modified RECIST 1.1 or death (by any cause in the absence of progression). Progression was determined by investigator assessment, RECIST 1.1. Calculated using the Kaplan-Meier technique. CI for median PFS was derived based on Brookmeyer-Crowley method.
| months | Olaparib |
|---|---|
| HRD status positive and/or sBRCAm subgroup | 11.1 (9.2 to 14.6) |
| HRD status positive, non-BRCAm subgroup | 9.7 (8.1 to 13.6) |
| HRD status negative subgroup | 7.3 (5.5 to 9.0) |
| sBRCAm subgroup | 16.4 (12.8 to NA) |
| gBRCAm subgroup | 12.1 (3.7 to NA) |
CT-FI is defined as the time from the date of the last dose of platinum chemotherapy prior to olaparib maintenance therapy until the date of initiation of the next anticancer therapy. Calculated using the Kaplan-Meier technique. CI for median CT-FI was derived based on Brookmeyer-Crowley method.
| months | Olaparib |
|---|---|
| Chemotherapy-free Interval (CT-FI) | 17.9 (13.8 to 23.3) |
OS is defined as the time from the date of first dose of olaparib to the date of death from any cause. Calculated using the Kaplan-Meier technique. CI for median OS was derived based on Brookmeyer-Crowley method.
| months | Olaparib |
|---|---|
| Overall Survival (OS) | 32.7 (29.5 to 35.3) |
Improvement was defined as a functional assessment of cancer therapy - ovarian (FACT-O) TOI response of "any improvement" at any time point over the course of treatment. The TOI is an established single targeted index composed of the following scales of the FACT-O: physical and functional well-being and additional concerns. The range of possible scores for the FACT-O TOI is 0-100, with a higher score indicating better health related quality of life (HRQoL). An increase in score from baseline indicates an improvement in HRQoL.
| percentage of patients | Olaparib |
|---|---|
| Percentage of Patients With Any Improvement From Baseline in Trial Outcome Index (TOI) Score at Any Point During the Treatment Period | 64.3 (58.0 to 70.2) |
10-point deterioration was defined as a FACT-O TOI response of "10-point deterioration" at any time point over the course of treatment. The TOI is an established single targeted index composed of the following scales of the FACT-O: physical and functional well-being and additional concerns. The range of possible scores for the FACT-O TOI is 0-100, with a higher score indicating better HRQoL. A decrease in score of at least 10 points from baseline was defined as a clinically meaningful deterioration.
| percentage of patients | Olaparib |
|---|---|
| Percentage of Patients With a 10-Point Deterioration From Baseline in TOI Score at Any Point During the Treatment Period | 42.6 (36.3 to 49.0) |
Collected over Includes adverse events with an onset date on or after the date of first dose and up to and including 30 days following the date of last dose of olaparib, up to a maximum of 43 months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Olaparib 300mg BID | 146/279 (52.3%) | 58/279 (20.8%) | 268/279 (96.1%) |
| Event | Olaparib 300mg BID |
|---|---|
| AnaemiaBlood and lymphatic system disorders | 22/279 |
| PneumoniaInfections and infestations | 3/279 |
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 3/279 |
| Intestinal obstructionGastrointestinal disorders | 3/279 |
| Covid-19Infections and infestations | 2/279 |
| SepsisInfections and infestations | 2/279 |
| Breast cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 2/279 |
| Small intestinal obstructionGastrointestinal disorders | 2/279 |
| ThrombocytopeniaBlood and lymphatic system disorders | 1/279 |
| Biliary dyskinesiaHepatobiliary disorders | 1/279 |
| Event | Olaparib 300mg BID |
|---|---|
| NauseaGastrointestinal disorders | 136/279 |
| AnaemiaBlood and lymphatic system disorders | 102/279 |
| FatigueGeneral disorders | 82/279 |
| AstheniaGeneral disorders | 46/279 |
| VomitingGastrointestinal disorders | 45/279 |
| Abdominal painGastrointestinal disorders | 43/279 |
| DysgeusiaNervous system disorders | 40/279 |
| DiarrhoeaGastrointestinal disorders | 40/279 |
| Decreased appetiteMetabolism and nutrition disorders | 32/279 |
| CoughRespiratory, thoracic and mediastinal disorders | 31/279 |
The Full Analysis Set (FAS) included all enrolled patients assigned to olaparib.
| Age, Continuous(years) | Olaparib |
|---|---|
| Mean | 64.0 ± 9.19 |
| Age, Customized(Participants) | Olaparib |
|---|---|
| <50 years | 22 |
| >=50 - <65 years | 110 |
| >=65 - <75 years | 113 |
| >=75 years | 34 |
| Sex: Female, Male(Participants) | Olaparib |
|---|---|
| Female | 279 |
| Male | 0 |
| Race/Ethnicity, Customized(Participants) | Olaparib |
|---|---|
| White | 273 |
| Black or African American | 1 |
| Asian | 2 |
| Unspecified | 2 |
| Missing | 1 |
| Race/Ethnicity, Customized(Participants) | Olaparib |
|---|---|
| Hispanic or Latino | 7 |
| Not Hispanic or Latino | 271 |
| Missing | 1 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
Supporting information: Study protocol, Sap
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