BRCA Mutated, Following Complete or Partial Response to Platinum Based Chemotherapy, Platinum Sensitive, Relapsed Ovarian Cancer
Conditions
Keywords
BRCA, Ovarian cancer, Chemotherapy, PARP Inhibitor, Platinum sensitive
Brief summary
A Phase III, randomised, double-blind, placebo-controlled, multi-centre study to assess the efficacy of olaparib maintenance monotherapy in relapsed high grade serous ovarian cancer (HGSOC) patients (including patients with primary peritoneal and / or fallopian tube cancer) or high grade endometrioid cancer with 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)) who have responded following platinum based chemotherapy.
Detailed description
Comparison of olaparib against a placebo in patients with ovarian cancer whose cancer has already improved by taking platinum based chemotherapy. The patients must also have a fault in their DNA which codes for the BRCA protein. The BRCA protein helps mend broken DNA in the cells of the body; if this protein doesn't work properly it can increase the chance of getting cancer. The aim of this study is to see whether patients taking olaparib tablets last longer until their cancer gets worse, compared to those taking the placebo tablet. The study is also looking to see if there is an overall improvement to how long the patients survive whilst taking olaparib tablets compared to the placebo tablets; and the quality of their life whilst living with ovarian cancer.
Interventions
300mg Olaparib or placebo tablets taken orally twice daily until objective radiological disease progression as per RECIST as assessed by the investigator (or as long as in the investigator's opinion they are benefiting from treatment and they do not meet any other discontinuation criteria). Dose reduction to 250mg and subsequently 200mg is permitted following confirmation of toxicity.
DRUGPlacebo to match olaparib 300mg
300mg Olaparib or placebo tablets taken orally twice daily until objective radiological disease progression as per RECIST as assessed by the investigator (or as long as in the investigator's opinion they are benefiting from treatment and they do not meet any other discontinuation criteria). Dose reduction to 250mg and subsequently 200mg is permitted following confirmation of toxicity.
Sponsors
AstraZeneca
European Network of Gynaecological Oncological Trial Groups (ENGOT)
Myriad Genetic Laboratories, Inc.
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Patients must be ≥ 18 years of age. * Female patients with histologically diagnosed relapsed high grade serous ovarian cancer (including primary peritoneal and / or fallopian tube cancer) or high grade endometrioid cancer. * 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). * Patients who have received at least 2 previous lines of platinum containing therapy prior to randomisation For the penultimate chemotherapy course prior to enrolment on the study: • Patient defined as platinum sensitive after this treatment; defined as disease progression greater than 6 months after completion of their last dose of platinum chemotherapy For the last chemotherapy course immediately prior to randomisation on the study: * Patients must be, in the opinion of the investigator, in response (partial or complete radiological response), or may have no evidence of disease (if optimal cytoreductive surgery was conducted prior to chemotherapy), and no evidence of a rising CA-125, following completion of this chemotherapy course * Patient must have received a platinum based chemotherapy regimen (e.g. carboplatin or cisplatin) and have received at least 4 cycles of treatment * Patients must be randomized within 8 weeks of their last dose of chemotherapy * Maintenance treatment is allowed at the end of the penultimate platinum regimen, including bevacizumab
Exclusion criteria
* Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). * BRCA 1 and/or BRCA2 mutations that are considered to be non detrimental (e.g., "Variants of uncertain clinical significance" or "Variant of unknown significance" or "Variant, favor polymorphism" or "benign polymorphism" etc.) * Patients who have had drainage of their ascites during the final 2 cycles of their last chemotherapy regimen prior to enrolment on the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Using Investigator Assessment According to Modified Response Evaluation Criteria In Solid Tumours (RECIST 1.1) | Radiologic scans performed at baseline then every ~12 weeks up to 72 weeks, then every ~ 24 weeks thereafter until objective radiological disease progression. Assessed until 19 Sep 2016 DCO (16 Jan 2017 DCO for China Cohort); up to a maximum of 36 months. | To determine the efficacy by progression free survival (PFS) (using investigator assessment according to modified Response Evaluation Criteria In Solid Tumours (RECIST 1.1)) of olaparib maintenance monotherapy compared to placebo in BRCA mutated relapsed ovarian cancer patients who are in complete or partial response following platinum based chemotherapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Overall Survival | Survival assessed every 4 weeks until treatment discontinues, then every 12 weeks. Assessed until 03 Feb 2020 DCO; up to a maximum of 75 months. | To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated relapsed ovarian cancer patients who are in complete or partial response following platinum based chemotherapy by assessment of overall survival (OS). |
| Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time to Earliest Progression by RECIST or Cancer Antigen (CA-125) or Death | CA-125 at baseline then every 4 wks. Radiologic scans at baseline then every ~12 wks up to 72 wks, then every ~ 24 wks until objective radiological disease progression. Assessed until 19Sep2016 DCO (16Jan2017 DCO for China Cohort); up to a max of 36 mths. | To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated relapsed ovarian cancer patients who are in complete or partial response following platinum based chemotherapy by assessment of time to earliest progression by RECIST or CA-125 or death. |
| Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time From Randomization to Second Progression | Scans at baseline then every 12 wks for 72 wks, then every 24 wks until first progression. Assessments then per local practice every 12 wks until second progression. Assessed until 19Sep2016 DCO (16Jan2017 DCO for China Cohort); up to a max of 36 mths | To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated relapsed ovarian cancer patients who are in complete response or partial response following first line platinum based chemotherapy by assessment of time from randomization up to second progression |
| Change From Baseline in Health-Related Quality of Life (HRQoL) as Assessed by the the Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O) | Questionnaires completed by patient at baseline, Day 29 and then every 12 weeks for 12 months. Assessed until 19 Sep 2016 DCO. | To compare the effects of olaparib maintenance monotherapy compared to placebo on Health-related Quality of Life (HRQoL) as assessed by the trial outcome index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O) in BRCA mutated relapsed ovarian cancer patients who are in complete or partial response following platinum based chemotherapy. The TOI ranges from 0-100 and a higher score indicates a higher HRQoL. |
| Efficacy of Olaparib by Time to First Subsequent Therapy or Death (TFST) | Time elapsed from randomization to first subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation. Assessed until 03 Feb 2020 DCO; up to a maximum of 75 months. | To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated high risk advanced ovarian cancer patients who are in clinical complete response or partial response following first line platinum based chemotherapy by assessment of time from randomization to first subsequent therapy or death (TFST). |
| Efficacy of Olaparib by Time to Second Subsequent Therapy or Death (TSST) | Time elapsed from randomization to second subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation. Assessed until 03 Feb 2020 DCO; up to a maximum of 75 months. | To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated high risk advanced ovarian cancer patients who are in clinical complete response or partial response following first line platinum based chemotherapy by assessment of time from randomization to second subsequent therapy or death (TSST). |
| Efficacy of Olaparib by Time From Randomization to Study Treatment Discontinuation or Death (TDT) | Time elapsed from randomization to study treatment discontinuation or death. Assessed until 03 Feb 2020 DCO; up to a maximum of 75 months. | To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated high risk advanced ovarian cancer patients who are in clinical complete response or partial response following first line platinum based chemotherapy by assessment of time from randomization to study treatment discontinuation or death (TDT). |
| Efficacy in Patients With a Deleterious or Suspected Deleterious Variant in Either of the BRCA Genes by Assessment of PFS. | Radiologic scans performed at baseline then every ~12 weeks for the first 72 weeks, then every ~24 weeks thereafter, assessed until disease progression. Assessed until 19 Sep 2016 DCO. | To assess efficacy of olaparib in patients identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (gene sequencing and large rearrangement analysis). |
| To Determine the Exposure to Olaparib by Pharmacokinetic Analysis | Pharmacokinetics sampling to be performed in a subset of patients. Sampling times: Day 1 pre-dose & 1 hour; Day 15 pre-dose & 1 hour; Day 29 pre-dose. Assessed until 19 Sep 2016 DCO. | To determine the exposure to olaparib in patients receiving olaparib maintenance monotherapy |
Countries
Australia, Belgium, Brazil, Canada, China, France, Germany, Israel, Italy, Japan, Netherlands, Poland, Russia, South Korea, Spain, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORProfessor E Pujade-Lauraine, MD, PhD
Universite de Paris Descartes, France
Participant flow
Recruitment details
Global Cohort: First patient screened: 03 Sep 2013; last patient screened on 21 Nov 2014. 602 patients screened across 119 centres in 16 countries; 295 were randomized. Results are reported for analysis of PFS (DCO: 19 Sep 2016) and OS (DCO: 03 Feb 2020). China Cohort: First patient enrolled: 07 Apr 2015; last patient enrolled: 30 Oct 2015. 127 patients screened across 16 sites; 32 were randomized. Results are reported for analysis of PFS (DCO: 16 Jan 2017) and OS (DCO: 03 Feb 2020).
Pre-assignment details
It was planned that approximately 264 women from the Global Cohort and 33 women from the China Cohort, with BRCA mutated relapsed ovarian cancer who are in complete or partial response following platinum based chemotherapy, were to receive olaparib 300 mg bd or matching placebo in a 2:1 ratio.
Participants by arm
| Arm | Count |
|---|---|
| Olaparib 300mg Tablets Taken orally twice daily | 218 |
| Placebo Tablets Taken orally twice daily | 109 |
| Total | 327 |
Baseline characteristics
| Characteristic | Olaparib 300mg Tablets | Placebo Tablets | Total |
|---|---|---|---|
| Age, Continuous China Cohort | 50.6 Years STANDARD_DEVIATION 8.42 | 47.4 Years STANDARD_DEVIATION 9.29 | 49.6 Years STANDARD_DEVIATION 8.68 |
| Age, Continuous Global Cohort | 57.0 Years STANDARD_DEVIATION 9.2 | 56.6 Years STANDARD_DEVIATION 8.9 | 56.9 Years STANDARD_DEVIATION 9.09 |
| Age, Customized China Cohort <50 | 11 Participants | 7 Participants | 18 Participants |
| Age, Customized China Cohort >=50-<65 | 10 Participants | 2 Participants | 12 Participants |
| Age, Customized China Cohort >=65 | 1 Participants | 1 Participants | 2 Participants |
| Age, Customized Global Cohort <50 | 38 Participants | 25 Participants | 63 Participants |
| Age, Customized Global Cohort >=50-<65 | 118 Participants | 52 Participants | 170 Participants |
| Age, Customized Global Cohort >=65 | 40 Participants | 22 Participants | 62 Participants |
| Ethnicity (NIH/OMB) China Cohort Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) China Cohort Not Hispanic or Latino | 22 Participants | 10 Participants | 32 Participants |
| Ethnicity (NIH/OMB) China Cohort Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Global Cohort Hispanic or Latino | 10 Participants | 1 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Global Cohort Not Hispanic or Latino | 186 Participants | 98 Participants | 284 Participants |
| Ethnicity (NIH/OMB) Global Cohort Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized China Cohort AMERICAN INDIAN OR ALASKA NATIVE | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized China Cohort ASIAN | 22 Participants | 10 Participants | 32 Participants |
| Race/Ethnicity, Customized China Cohort BLACK OR AFRICAN AMERICAN | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized China Cohort NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized China Cohort OTHER | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized China Cohort WHITE | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Global Cohort AMERICAN INDIAN OR ALASKA NATIVE | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Global Cohort ASIAN | 22 Participants | 7 Participants | 29 Participants |
| Race/Ethnicity, Customized Global Cohort BLACK OR AFRICAN AMERICAN | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Global Cohort NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Global Cohort OTHER | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Global Cohort WHITE | 173 Participants | 91 Participants | 264 Participants |
| Sex: Female, Male China Cohort Female | 22 Participants | 10 Participants | 32 Participants |
| Sex: Female, Male China Cohort Male | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Global Cohort Female | 196 Participants | 99 Participants | 295 Participants |
| Sex: Female, Male Global Cohort Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 116 / 196 | 65 / 99 | 13 / 22 | 7 / 10 |
| other Total, other adverse events | 192 / 195 | 91 / 99 | 21 / 22 | 10 / 10 |
| serious Total, serious adverse events | 50 / 195 | 8 / 99 | 5 / 22 | 1 / 10 |
Outcome results
Primary
Progression Free Survival (PFS) Using Investigator Assessment According to Modified Response Evaluation Criteria In Solid Tumours (RECIST 1.1)
To determine the efficacy by progression free survival (PFS) (using investigator assessment according to modified Response Evaluation Criteria In Solid Tumours (RECIST 1.1)) of olaparib maintenance monotherapy compared to placebo in BRCA mutated relapsed ovarian cancer patients who are in complete or partial response following platinum based chemotherapy.
Time frame: Radiologic scans performed at baseline then every ~12 weeks up to 72 weeks, then every ~ 24 weeks thereafter until objective radiological disease progression. Assessed until 19 Sep 2016 DCO (16 Jan 2017 DCO for China Cohort); up to a maximum of 36 months.
Population: Full Analysis Set (FAS) consisting of all patients randomized as part of global enrolment, excluding China \[Primary analysis\] China Full Analysis Set (FAS) includes all patients who were randomised at sites in China.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300mg Tablets (Global Cohort) | Progression Free Survival (PFS) Using Investigator Assessment According to Modified Response Evaluation Criteria In Solid Tumours (RECIST 1.1) | 19.1 Months |
| Placebo Tablets (Global Cohort) | Progression Free Survival (PFS) Using Investigator Assessment According to Modified Response Evaluation Criteria In Solid Tumours (RECIST 1.1) | 5.5 Months |
| Olaparib 300mg Tablets (China Cohort) | Progression Free Survival (PFS) Using Investigator Assessment According to Modified Response Evaluation Criteria In Solid Tumours (RECIST 1.1) | 13.8 Months |
| Placebo Tablets (China Cohort) | Progression Free Survival (PFS) Using Investigator Assessment According to Modified Response Evaluation Criteria In Solid Tumours (RECIST 1.1) | 5.5 Months |
p-value: <0.000195% CI: [0.22, 0.41]Regression, Cox
95% CI: [0.17, 1.19]Regression, Cox
Secondary
Change From Baseline in Health-Related Quality of Life (HRQoL) as Assessed by the the Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O)
To compare the effects of olaparib maintenance monotherapy compared to placebo on Health-related Quality of Life (HRQoL) as assessed by the trial outcome index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O) in BRCA mutated relapsed ovarian cancer patients who are in complete or partial response following platinum based chemotherapy. The TOI ranges from 0-100 and a higher score indicates a higher HRQoL.
Time frame: Questionnaires completed by patient at baseline, Day 29 and then every 12 weeks for 12 months. Assessed until 19 Sep 2016 DCO.
Population: Full Analysis Set (FAS) consisting of all patients randomized as part of global enrolment (excluding China) with a baseline and post baseline TOI score available \[This endpoint was not assessed in the China Cohort\]
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Olaparib 300mg Tablets (Global Cohort) | Change From Baseline in Health-Related Quality of Life (HRQoL) as Assessed by the the Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O) | -2.90 Change in TOI over 12 months |
| Placebo Tablets (Global Cohort) | Change From Baseline in Health-Related Quality of Life (HRQoL) as Assessed by the the Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O) | -2.87 Change in TOI over 12 months |
p-value: 0.976595% CI: [-2.191, 2.126]Mixed Models Analysis
Secondary
Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Overall Survival
To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated relapsed ovarian cancer patients who are in complete or partial response following platinum based chemotherapy by assessment of overall survival (OS).
Time frame: Survival assessed every 4 weeks until treatment discontinues, then every 12 weeks. Assessed until 03 Feb 2020 DCO; up to a maximum of 75 months.
Population: Full Analysis Set (FAS) consisting of all patients randomized as part of global enrolment (excluding China) China Full Analysis Set (FAS) includes all patients who were randomised at sites in China.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300mg Tablets (Global Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Overall Survival | 51.7 Months |
| Placebo Tablets (Global Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Overall Survival | 38.8 Months |
| Olaparib 300mg Tablets (China Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Overall Survival | 41.7 Months |
| Placebo Tablets (China Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Overall Survival | 36.4 Months |
p-value: 0.053795% CI: [0.54, 1]Regression, Cox
95% CI: [0.38, 2.49]Regression, Cox
Secondary
Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time From Randomization to Second Progression
To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated relapsed ovarian cancer patients who are in complete response or partial response following first line platinum based chemotherapy by assessment of time from randomization up to second progression
Time frame: Scans at baseline then every 12 wks for 72 wks, then every 24 wks until first progression. Assessments then per local practice every 12 wks until second progression. Assessed until 19Sep2016 DCO (16Jan2017 DCO for China Cohort); up to a max of 36 mths
Population: Full Analysis Set (FAS) consisting of all patients randomized as part of global enrolment (excluding China).~China Full Analysis Set (FAS) includes all patients who were randomised at sites in China.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300mg Tablets (Global Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time From Randomization to Second Progression | NA Months |
| Placebo Tablets (Global Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time From Randomization to Second Progression | 18.4 Months |
| Olaparib 300mg Tablets (China Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time From Randomization to Second Progression | NA Months |
| Placebo Tablets (China Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time From Randomization to Second Progression | 17.3 Months |
p-value: 0.000295% CI: [0.34, 0.72]Regression, Cox
95% CI: [0.22, 3.97]Regression, Cox
Secondary
Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time to Earliest Progression by RECIST or Cancer Antigen (CA-125) or Death
To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated relapsed ovarian cancer patients who are in complete or partial response following platinum based chemotherapy by assessment of time to earliest progression by RECIST or CA-125 or death.
Time frame: CA-125 at baseline then every 4 wks. Radiologic scans at baseline then every ~12 wks up to 72 wks, then every ~ 24 wks until objective radiological disease progression. Assessed until 19Sep2016 DCO (16Jan2017 DCO for China Cohort); up to a max of 36 mths.
Population: Full Analysis Set (FAS) consisting of all patients randomized as part of global enrolment (excluding China).~China Full Analysis Set (FAS) includes all patients who were randomised at sites in China.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300mg Tablets (Global Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time to Earliest Progression by RECIST or Cancer Antigen (CA-125) or Death | 16.9 Months |
| Placebo Tablets (Global Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time to Earliest Progression by RECIST or Cancer Antigen (CA-125) or Death | 4.9 Months |
| Olaparib 300mg Tablets (China Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time to Earliest Progression by RECIST or Cancer Antigen (CA-125) or Death | 12.9 Months |
| Placebo Tablets (China Cohort) | Efficacy in Patients Following Platinum Based Chemotherapy by Assessment of Time to Earliest Progression by RECIST or Cancer Antigen (CA-125) or Death | 3.7 Months |
p-value: <0.000195% CI: [0.23, 0.41]Regression, Cox
95% CI: [0.18, 1.03]Regression, Cox
Secondary
Efficacy in Patients With a Deleterious or Suspected Deleterious Variant in Either of the BRCA Genes by Assessment of PFS.
To assess efficacy of olaparib in patients identified as having a deleterious or suspected deleterious variant in either of the BRCA genes using variants identified with current and future BRCA mutation assays (gene sequencing and large rearrangement analysis).
Time frame: Radiologic scans performed at baseline then every ~12 weeks for the first 72 weeks, then every ~24 weeks thereafter, assessed until disease progression. Assessed until 19 Sep 2016 DCO.
Population: Full Analysis Set (FAS) consisting of all patients randomized as part of global enrolment (excluding China) and confirmed as Myriad gBRCAm \[This endpoint was not assessed in the China Cohort\]
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300mg Tablets (Global Cohort) | Efficacy in Patients With a Deleterious or Suspected Deleterious Variant in Either of the BRCA Genes by Assessment of PFS. | 19.3 Months |
| Placebo Tablets (Global Cohort) | Efficacy in Patients With a Deleterious or Suspected Deleterious Variant in Either of the BRCA Genes by Assessment of PFS. | 5.5 Months |
p-value: <0.000195% CI: [0.22, 0.4]Regression, Cox
Secondary
Efficacy of Olaparib by Time From Randomization to Study Treatment Discontinuation or Death (TDT)
To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated high risk advanced ovarian cancer patients who are in clinical complete response or partial response following first line platinum based chemotherapy by assessment of time from randomization to study treatment discontinuation or death (TDT).
Time frame: Time elapsed from randomization to study treatment discontinuation or death. Assessed until 03 Feb 2020 DCO; up to a maximum of 75 months.
Population: Full Analysis Set (FAS) consisting of all patients randomized as part of global enrolment (excluding China).~China Full Analysis Set (FAS) includes all patients who were randomised at sites in China.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300mg Tablets (Global Cohort) | Efficacy of Olaparib by Time From Randomization to Study Treatment Discontinuation or Death (TDT) | 19.4 Months |
| Placebo Tablets (Global Cohort) | Efficacy of Olaparib by Time From Randomization to Study Treatment Discontinuation or Death (TDT) | 5.6 Months |
| Olaparib 300mg Tablets (China Cohort) | Efficacy of Olaparib by Time From Randomization to Study Treatment Discontinuation or Death (TDT) | 13.4 Months |
| Placebo Tablets (China Cohort) | Efficacy of Olaparib by Time From Randomization to Study Treatment Discontinuation or Death (TDT) | 4.7 Months |
p-value: <0.000195% CI: [0.28, 0.49]Regression, Cox
95% CI: [0.2, 1.04]Regression, Cox
Secondary
Efficacy of Olaparib by Time to First Subsequent Therapy or Death (TFST)
To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated high risk advanced ovarian cancer patients who are in clinical complete response or partial response following first line platinum based chemotherapy by assessment of time from randomization to first subsequent therapy or death (TFST).
Time frame: Time elapsed from randomization to first subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation. Assessed until 03 Feb 2020 DCO; up to a maximum of 75 months.
Population: Full Analysis Set (FAS) consisting of all patients randomized as part of global enrolment (excluding China).~China Full Analysis Set (FAS) includes all patients who were randomised at sites in China.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300mg Tablets (Global Cohort) | Efficacy of Olaparib by Time to First Subsequent Therapy or Death (TFST) | 27.4 Months |
| Placebo Tablets (Global Cohort) | Efficacy of Olaparib by Time to First Subsequent Therapy or Death (TFST) | 7.2 Months |
| Olaparib 300mg Tablets (China Cohort) | Efficacy of Olaparib by Time to First Subsequent Therapy or Death (TFST) | 13.9 Months |
| Placebo Tablets (China Cohort) | Efficacy of Olaparib by Time to First Subsequent Therapy or Death (TFST) | 5.5 Months |
p-value: <0.000195% CI: [0.28, 0.48]Regression, Cox
95% CI: [0.21, 1.08]Regression, Cox
Secondary
Efficacy of Olaparib by Time to Second Subsequent Therapy or Death (TSST)
To determine the efficacy of olaparib maintenance monotherapy compared to placebo in BRCA mutated high risk advanced ovarian cancer patients who are in clinical complete response or partial response following first line platinum based chemotherapy by assessment of time from randomization to second subsequent therapy or death (TSST).
Time frame: Time elapsed from randomization to second subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation. Assessed until 03 Feb 2020 DCO; up to a maximum of 75 months.
Population: Full Analysis Set (FAS) consisting of all patients randomized as part of global enrolment (excluding China).~China Full Analysis Set (FAS) includes all patients who were randomised at sites in China.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Olaparib 300mg Tablets (Global Cohort) | Efficacy of Olaparib by Time to Second Subsequent Therapy or Death (TSST) | 35.8 Months |
| Placebo Tablets (Global Cohort) | Efficacy of Olaparib by Time to Second Subsequent Therapy or Death (TSST) | 18.9 Months |
| Olaparib 300mg Tablets (China Cohort) | Efficacy of Olaparib by Time to Second Subsequent Therapy or Death (TSST) | 19.0 Months |
| Placebo Tablets (China Cohort) | Efficacy of Olaparib by Time to Second Subsequent Therapy or Death (TSST) | 26.4 Months |
p-value: <0.000195% CI: [0.39, 0.68]Regression, Cox
95% CI: [0.37, 1.85]Regression, Cox
Secondary
To Determine the Exposure to Olaparib by Pharmacokinetic Analysis
To determine the exposure to olaparib in patients receiving olaparib maintenance monotherapy
Time frame: Pharmacokinetics sampling to be performed in a subset of patients. Sampling times: Day 1 pre-dose & 1 hour; Day 15 pre-dose & 1 hour; Day 29 pre-dose. Assessed until 19 Sep 2016 DCO.
Population: Pharmacokinetic (PK) Analysis Set - all patients who receive study treatment as per protocol, do not violate or deviate from the protocol in ways that would significantly affect the PK analyses and have valid PK data.~The PK Analysis Set is a subset of the Global FAS; PK analysis was not performed in the China Cohort.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Olaparib 300mg Tablets (Global Cohort) | To Determine the Exposure to Olaparib by Pharmacokinetic Analysis | Day 1 - Pre-dose | NA mcg/mL | — |
| Olaparib 300mg Tablets (Global Cohort) | To Determine the Exposure to Olaparib by Pharmacokinetic Analysis | Day 1 - 1 hour | 3.26 mcg/mL | Geometric Coefficient of Variation 312.2 |
| Olaparib 300mg Tablets (Global Cohort) | To Determine the Exposure to Olaparib by Pharmacokinetic Analysis | Day 15 - Pre-dose | 0.92 mcg/mL | Geometric Coefficient of Variation 95.5 |
| Olaparib 300mg Tablets (Global Cohort) | To Determine the Exposure to Olaparib by Pharmacokinetic Analysis | Day 15 - 1 hour | 5.12 mcg/mL | Geometric Coefficient of Variation 61.8 |
| Olaparib 300mg Tablets (Global Cohort) | To Determine the Exposure to Olaparib by Pharmacokinetic Analysis | Day 29 - Pre-dose | 0.94 mcg/mL | Geometric Coefficient of Variation 179 |