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Olaparib

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Physician's choice single agent chemotherapy

300 mg olaparib tablets taken orally twice daily. All patients should continue to receive study treatment until objective radiological disease progression as per RECIST 1.1 as assessed by the investigator or the patient experiences unacceptable toxicity or they meet any other discontinuation criteria.

OLAPARIB

Treatment of relapsed disease with single agent chemotherapy based on physician's choice of weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine. All patients should continue to receive study treatment until objective radiological disease progression as per RECIST 1.1 as assessed by the investigator or the patient experiences unacceptable toxicity or they meet any other discontinuation criteria

Single agent chemotherapy

Richard T Penson, Associate Prof. of Medicine

Comparison of olaparib vs. physician's choice of single agent standard of care non-platinum based chemotherapy in patients with germline Breast Cancer susceptibility gene (gBRCA) mutated ovarian cancer who have progressed at least 6 months after the last platinum based chemotherapy. Patient should have received at least 2 prior lines of platinum based chemotherapy. The aim of the study is to assess the efficacy and safety of olaparib tablets.

This open label, randomised, controlled, multi-centre study will assess the efficacy and safety of single agent olaparib vs. standard of care, based on physician's choice of single agent chemotherapy ( i.e paclitaxel, or topotecan, or pegylated liposomal doxorubicin, or gemcitabine) in platinum sensitive or partially platinum sensitive relapsed ovarian cancer patients who carry germline deleterious or suspected deleterious BRCA mutation and who have received at least 2 prior lines of platinum based chemotherapy. Patients are eligible to undergo BRCA testing even if they have not yet had recurrence or progression of disease \>6 months (\>/=183 days) after completion of their last platinum therapy.

Olaparib Treatment in Relapsed Germline Breast Cancer Susceptibility Gene (BRCA) Mutated Ovarian Cancer Patients Who Have Progressed at Least 6 Months After Last Platinum Treatment and Have Received at Least 2 Prior Platinum Treatments

A Phase III, Open Label, Randomised, Controlled, Multi-centre Study to Assess the Efficacy and Safety of Olaparib Monotherapy Versus Physician's Choice Single Agent Chemotherapy in the Treatment of Platinum Sensitive Relapsed Ovarian Cancer in Patients Carrying Germline BRCA1/2 Mutations.

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.

To determine the efficacy of olaparib vs. physician's choice single agent chemotherapy by assessment of Objective Response Rate (ORR) using blinded independent central review (BICR)

Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria was used by a Blinded Independent Central Review (BICR) to assess participant response to treatment

ORR is the number of participants with Complete Response (CR) or Partial Response (PR) in the Measurable Disease Analysis Set (MDAS). Complete response is declared when all lesions have disappeared or all lesions have disappeared and all nodal disease is \< 10 mm each. Partial response is declared when there is a decrease in sum of diameters of target lesions ≥ 30%.

To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by progression free survival (PFS) using BICR assessment according to RECIST 1.1 criteria

PFS is defined as the time from randomization until the date of objective radiological disease progression according to RECIST 1.1 or death (by any cause in the absence of disease progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to disease progression (i.e., date of RECIST progression/death or censoring - date of randomization +1).

To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by second progression (PFS2).

Time from randomization to PFS2 is defined as the time from the date of randomization to the earliest of the progression events subsequent to first progression or death. The date of second progression was recorded by the investigator and defined according to local standard clinical practice, and could involve objective radiological, clinical, cancer antigen-125 (CA-125) progression or death. CA-125 progression was assessed per Gynecological Cancer Intergroup (GCIG) criteria.

To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by overall survival (OS).

Overall survival is defined as the time from the date of randomisation until death due to any cause.

To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by time to earliest progression by RECIST 1.1 or CA-125 or death.

Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria was used to assess participant response to treatment. CA-125 progression was assessed per Gynecological Cancer Intergroup (GCIG).

To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by time from randomisation to first subsequent therapy or death (TFST)

TFST is defined as the time from the date of randomisation to the earlier of first subsequent chemotherapy start date or death.

Anti-cancer treatments include chemotherapy and targeted agents.

To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by time from randomisation to second subsequent therapy or death (TSST)

TSST was defined as the time from the date of randomisation to the earlier of second subsequent chemotherapy start date or death.

Anti-cancer treatments include chemotherapy and targeted agents.

To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by time to study treatment discontinuation or death (TDT)

TDT was defined as the time from randomization to the earlier of the date of study treatment discontinuation or death.

To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by duration of response (DoR) by BICR using RECIST 1.1 criteria for evaluable patients.

Duration of response is the time from the first documentation of complete response (CR) or partial response (PR) until the date of progression or death, or the last evaluable RECIST assessment for participants that do not progress or progress after 2 missed assessments. Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria was used to assess participant response to treatment.

To determine the efficacy of single agent olaparib vs. physician's choice single agent chemotherapy by time to response (TTR) by BICR using RECIST 1.1 criteria for evaluable patients.

TTR was defined as the time from randomization until the date of first documented response by Blinded independent central review (BICR) assessment.

To compare the efficacy of single agent olaparib versus physician's choice single agent chemotherapy on the Health-related Quality of Life (HRQoL) as measured by the trial outcome index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O)

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. TOI score ranges from 0 to 100, a higher score indicates a higher HRQoL. A negative change in score from baseline indicated a worsening in symptoms.

To compare the efficacy of single agent olaparib versus physician's choice single agent chemotherapy on the Health-related Quality of Life (HRQoL) as measured by the trial outcome index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O)

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. TOI score ranges from 0 to 100, a higher score indicates a higher health-related quality of life (HRQoL). A change in at least 10 points was considered clinically relevant.

BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis).

The number of participants with complete or partial response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Partial response is declared when there is a decrease in sum of target disease ≥ 30%. Complete response is declared when all lesions have disappeared or all lesions have disappeared and all nodal disease is \< 10 mm each.

BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis).

Progressive disease was defined as at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis).

BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis).

OS in BRCA gene population was measured by the number of participants who died due to any cause.

BRCA gene population includes participants 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 (eg, gene sequencing and large rearrangement analysis).

Anti-cancer treatments include chemotherapy and targeted agents.

Summary of plasma concentrations (ug/mL) of olaparib

An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.

Myriad Genetic Laboratories, Inc.

Merck Sharp & Dohme LLC

AstraZeneca

All-Cause Mortality was collected for the Full Analysis Set (FAS).

Serious Adverse Events and Other Adverse Events were collected for the Safety Analysis Set (SAS), which includes patients who received at least 1 dose of the randomised study treatment.

Participants received olaparib twice daily as a 300 mg tablet.

Olaparib 300 mg bd

Participants received physician's choice of chemotherapy, out of weekly paclitaxel, topotecan, pegylated liposomal doxorubicin, or gemcitabine.

Single Agent Chemotherapy

Olaparib 300mg BID

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

White

Black Or African American

Asian

American Indian Or Alaska Native

Other

Race/Ethnicity, Customized

Baseline characteristics are displayed for all participants who started the study. This includes the 12 participants who did not receive treatment in the 'Single Agent Chemotherapy' arm.

Global Clinical Leader

Olaparib 300 mg BID

The Measurable Disease Analysis Set (MDAS) includes all participants in the Full Analysis Set (FAS) with measurable disease at baseline (as per RECIST 1.1), determined using Blinded Independent Central Review.

Objective Response Rate (ORR)

The Full Analysis Set (FAS) includes all randomized participants and compares the treatment groups on the basis of randomized treatment, regardless of the treatment actually received. Participants who were randomized but did not subsequently go on to receive study treatment were included in the FAS.

Progression Free Survival (PFS)

Time From Randomisation to Second Progression (PFS2)

Overall Survival (OS)

Time To Earliest Progression By RECIST 1.1 Or Cancer Antigen (CA) -125 Or Death

Time From Randomization To First Subsequent Therapy Or Death (TFST)

Time From Randomization To Second Subsequent Therapy Or Death (TSST)

Time From Randomization To Study Treatment Discontinuation Or Death (TDT)

Duration of Response (DoR)

Time to Response (TTR)

Selected Chemotherapy

Mean Change From Baseline In Trial Outcome Index (TOI) Score

Number of Participants Who Show an Improvement in TOI Score

Objective Response Rate (ORR) in Breast Cancer Susceptibility (BRCA) Gene Population by Blinded Independent Central Review (BICR)

Number of Participants Who Experienced Disease Progression or Death in BRCA Gene Population by Blinded Independent Central Review (BICR)

Number of Participants Who Experienced Second Progression or Death (PFS2) in BRCA Gene Population

Overall Survival (OS) in BRCA Gene Population

Number of Participants Who Discontinued Study Treatment or Died in BRCA Gene Population

Number of Participants Who Received Subsequent Chemotherapy or Died in BRCA Gene Population

Number of Participants Who Received Second Subsequent Chemotherapy or Died in BRCA Gene Population

Day 1, 1 hour post-dose

Day 29, pre-dose

The pharmacokinetic (PK) analysis set includes all participants who received an olaparib dose and provided evaluable plasma concentration data.

Geometric Mean Plasma Concentration of Olaparib

The safety analysis set includes all participants who received at least 1 dose of randomized study treatment, olaparib or chemotherapy.

Spots Global Cancer Trial Database for brca, ovarian, platinum, chemotherapy,