Non-Germline BRCA Mutated Ovarian Cancer
Conditions
Keywords
Ovarian cancer, non-gBRCA, Platinum, Chemotherapy
Brief summary
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
Detailed description
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.
Interventions
DRUGOlaparib
300 mg twice daily - oral
Sponsors
Iqvia Pty Ltd
Myriad Genetics, Inc.
Covance
Theradex
Parexel
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open
Intervention model description
Single arm study
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 95 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Female patients with histologically diagnosed relapsed HGSOC (including primary peritoneal and / or fallopian tube cancer) or high grade endometrioid ovarian cancer * Documented gBRCA1/2 mutation status * Patients must have completed at least 2 previous courses of platinum containing therapy * Patients must have normal organ and bone marrow function measured within 28 days of starting study treatment * ECOG performance status 0-1 (see Appendix E) * Patients must have a life expectancy ≥16 weeks * Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1 * At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for repeated assessment OR No evidence of disease following a complete response to chemotherapy * An appropriately prepared tumour sample from the cancer, of sufficient quantity and quality (as specified in the Central Laboratory Services Manual) must be available for future central testing of tumour genetic status
Exclusion criteria
* Patients receiving any systemic hormonal therapy, chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to start of study treatment * Any previous treatment with PARP inhibitor, including olaparib * Patients with a germline BRCA mutation that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function) * Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma. * Concomitant use of known strong CYP3A inhibitors and strong (or moderate CYP3A inducers * Persistent toxicities (≥ Grade 2 Common Terminology Criteria for Adverse Event (CTCAE) adverse event) caused by previous cancer therapy, excluding alopecia * Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML * Patients with symptomatic uncontrolled brain metastases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Up to maximum of 32 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Treatment Discontinuation or Death (TDT) | Up to a maximum of 43 months | 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. |
| PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status | Up to maximum of 32 months | 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. |
| Chemotherapy-free Interval (CT-FI) | Up to a maximum of 43 months | 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 to First Subsequent Therapy or Death (TFST) | Up to a maximum of 43 months | 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. |
| Percentage of Patients With Any Improvement From Baseline in Trial Outcome Index (TOI) Score at Any Point During the Treatment Period | Baseline up to a maximum of 32 months | 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 With a 10-Point Deterioration From Baseline in TOI Score at Any Point During the Treatment Period | Baseline up to a maximum of 32 months | 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. |
| Overall Survival (OS) | Up to a maximum of 43 months | 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. |
Countries
Austria, Belgium, Bulgaria, Canada, Czechia, Denmark, Finland, Israel, Italy, Netherlands, Norway, Poland, Portugal, Romania, Slovenia, Spain, Sweden, Switzerland, United Kingdom
Participant flow
Recruitment details
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.
Pre-assignment details
Olaparib was administered to all patients at a starting dose of 300 milligrams (mg) twice daily. Dose reductions were required in patients experiencing toxicities or due to concomitant medication (CM).
Participants by arm
| Arm | Count |
|---|---|
| Olaparib Olaparib was administered to all patients at a starting dose of 300 mg twice daily. Dose reductions were required in patients experiencing toxicities or due to CM.
Patients continued with olaparib until documented disease progression as assessed by the Investigator or unacceptable toxicity or for as long as they did not meet any other discontinuation criteria. | 279 |
| Total | 279 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 146 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Olaparib |
|---|---|
| Age, Continuous | 64.0 years STANDARD_DEVIATION 9.19 |
| Age, Customized >=50 - <65 years | 110 Participants |
| Age, Customized <50 years | 22 Participants |
| Age, Customized >=65 - <75 years | 113 Participants |
| Age, Customized >=75 years | 34 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 7 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 271 Participants |
| Race/Ethnicity, Customized Unspecified | 2 Participants |
| Race/Ethnicity, Customized White | 273 Participants |
| Sex: Female, Male Female | 279 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 146 / 279 |
| other Total, other adverse events | 268 / 279 |
| serious Total, serious adverse events | 58 / 279 |
Outcome results
Primary
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
Population: The FAS included all enrolled patients assigned to olaparib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib | Progression Free Survival (PFS) | 9.2 months |
Secondary
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
Population: The FAS included all enrolled patients assigned to olaparib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib | Chemotherapy-free Interval (CT-FI) | 17.9 months |
Secondary
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
Population: The FAS included all enrolled patients assigned to olaparib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib | Overall Survival (OS) | 32.7 months |
Secondary
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
Population: The FACT-O set consisted of all FAS patients with at least a baseline and a post-baseline assessment (excluding the end of treatment and 30-day follow up assessments).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olaparib | Percentage of Patients With a 10-Point Deterioration From Baseline in TOI Score at Any Point During the Treatment Period | 42.6 percentage of patients |
Secondary
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
Population: The FACT-O set consisted of all FAS patients with at least a baseline and a post-baseline assessment (excluding the end of treatment and 30-day follow up assessments).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Olaparib | Percentage of Patients With Any Improvement From Baseline in Trial Outcome Index (TOI) Score at Any Point During the Treatment Period | 64.3 percentage of patients |
Secondary
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
Population: The FAS included all enrolled patients assigned to Olaparib. Only FAS patients with available central assessment are reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Olaparib | PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status | HRD status positive and/or sBRCAm subgroup | 11.1 months |
| Olaparib | PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status | HRD status positive, non-BRCAm subgroup | 9.7 months |
| Olaparib | PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status | HRD status negative subgroup | 7.3 months |
| Olaparib | PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status | sBRCAm subgroup | 16.4 months |
| Olaparib | PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status | gBRCAm subgroup | 12.1 months |
Secondary
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
Population: The FAS included all enrolled patients assigned to olaparib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib | Time to First Subsequent Therapy or Death (TFST) | 13.9 months |
Secondary
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
Population: The FAS included all enrolled patients assigned to olaparib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib | Time to Treatment Discontinuation or Death (TDT) | 9.6 months |