AZD2281

To assess whether maintenance therapy with olaparib improves recurrence-free survival (RFS), as compared to observation after chemo-radiotherapy in patients with p53abn HREC

Radiological progression free survival is defined as the time from randomisation until the earlier date of radiological progression or death (by any cause in the absence of progression), regardless of whether the patient withdraws from randomised therapy or receives another anticancer therapy prior to progression. Per RECIST v1.1, progression is defined as the sum of TLs has a 20% and absolute ≥ 5mm increase from nadir, and/or unequivocal progression in any non target lesions, and/or any new lesion identified. Per PCWG3, progression on a bone scan is defined as 2 or more new lesions observed from the first visit after baseline compared to baseline, or from all other visits compared to first visit after baseline. A confirmatory scan is required.

PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by the investigator at the local site, or death due to any cause.

PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by the investigator at the local site, or death due to any cause.

Serious adverse events and adverse events of special interest reported until 30 days after the last dose of study drug.

To demonstrate the efficacy of durvalumab in combination with platinum-based chemotherapy (paclitaxel and carboplatin) followed by maintenance durvalumab or durvalumab with olaparib when compared to platinum-based chemotherapy by assessment of PFS (using investigator assessment according to Response Evaluation Criteria in Solid Tumours version 1.1 \[RECIST 1.1\]) in patients with newly diagnosed advanced or recurrent endometrial cancer

An rPFS event is defined as progression determined by Response Evaluation Criteria in Solid Tumours version 1.1 \[RECIST 1.1\] and/or Prostate Cancer Working Group 3 \[PCWG-3\] or death (by any cause in the absence of progression), regardless of whether the patient withdraws from randomised therapy or receives another anticancer therapy prior to progression. Per RECIST v1.1, progression is defined as the sum of TLs has a 20% and absolute ≥ 5mm increase from nadir, and/or unequivocal progression in any non target lesions, and/or any new lesion identified. Per PCWG3, progression on a bone scan is defined as 2 or more new lesions observed from the first visit after baseline compared to baseline, or from all other visits compared to first visit after baseline. A confirmatory scan is required.

Progression free survival (using investigator assessment) according to modified Response Evaluation Criteria In Solid Tumours (RECIST 1.1) of olaparib tablets maintenance monotherapy in platinum sensitive relapsed ovarian cancer patients who are in complete or partial response following platinum based chemotherapy

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.

The clinical effectiveness of olaparib treatment in HER2-ve metastatic breast cancer participants in a real-world setting through assessment of PFS in germline BRCA mutated patients was evaluated. PFS is defined as the time from first dose of olaparib to the date of progression or death from any cause. In this study, disease progression in gBRCAm patients will be based on Investigator assessment, i.e. radiological ( e.g. RECIST) progression, symptomatic progression, or clear progression of non-measurable disease, as long as progression can be documented.

PFS (per RECIST 1.1) was defined as the time from randomisation until the date of Investigator assessed objective radiological disease progression or death (by any cause in the absence of disease progression). Objective progression (per RECIST 1.1) is defined as at least a 20% increase in the sum of the diameters of the target lesions and an absolute increase of \>5 mm, or an overall non-target lesion assessment of progression or a new lesion. Patients who have not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment.

The time from randomisation until the date of objective radiological disease progression (determined by RECIST 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG-3) (bone)) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Progression is defined using (i) Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for soft tissue, as a \>=20% increase in the sum of diameters of target lesions and an absolute increase of \>=5mm taking as reference the smallest sum of diameters since treatment started including the baseline sum of diameters; (ii) Prostate Cancer Working Group 3 (PGWG-3) for bone as \>= 2 new bone lesions on the 1st week 8 scan compared to baseline. The confirmatory scan, \>=6 weeks later, must show \>=2 more new bone lesions (for a total of \>=4 new bone lesions since baseline).

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 olaparib maintenance monotherapy compared to placebo by PFS. The PFS was defined as the time from randomisation until the date of objective radiological disease progression according to modified RECIST v1.1 or death (by any cause in the absence of disease progression) regardless of whether the patient withdrew from randomized therapy or received another anticancer therapy prior to disease progression.

An IDFS event is defined as the first occurrence of loco-regional or distant recurrence or new cancer or death from any cause.

Time from randomisation to the earliest of objective radiological progression or death by any cause in the absence of objective progression. Objective radiological progression is defined using Response Evaluation Criteria In Solid Tumours (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

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 from the date of randomization until death due to any cause

PSA response will be defined as a decline in PSA ≥ 50% compared to baseline in patients who received at least 12 weeks of treatment. Will be calculated as the percentage with 95% confidence interval (CI) of the total number of subjects that achieved a PSA response.

Assess pCR rate. pCR will be defined as no residual disease in the RP specimen by blinded central pathology review.

Assess the MRD rate. MRD will be defined as residual tumor focus in the RP specimen measuring ≤ 5 mm by blinded central pathology review.

pCR = pathological complete response pCR was defined as ypT0/Tis ypN0 (ie, no invasive residual in breast and the axillary lymph nodes on evaluation of the complete resected breast specimen and all sampled regional lymph nodes) following completion of neoadjuvant systemic therapy. Results of this outcome measure are from DCO1 (20 November 2024). The Clopper Pearson method is for the computation of the 95% confidence interval (CI).

To determine the percentage of patients with mesothelioma tumors (containing certain gene/cell mutations) that shrink or stop growing as a response to olaparib.

An event is defined as the occurrence of relapse, disease progression as defined by RECIST 1.1, or death from any cause.

The number of participants in Cohort 2 who provide both pre-treatment and post-treatment tumor specimens, allowing paired correlative analyses.

Cediranib and Olaparib single IMP, Cediranib and Olaparib in combination IMP arms, having received at least 14 days' worth of IMP

Volrustomig and Rilvegostomig, single dose of IMP

Progression-free survival was defined as time from randomization until the date of objective disease progression or death, regardless of whether the patient withdrew from randomized therapy or received another anti-cancer therapy prior to progression. Progression was determined by Blinded independent central review (BICR) using Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1). Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment. If patients had no evaluable visits or baseline data, the patient was censored at Study Day 1, unless death occurred within 17 weeks i.e., death within 17 weeks was relative to randomization. Here, the study patient population was stratified as follows: Breast cancer susceptible gene mutation (BRCAm) patients; non BRCAm homologous recombination repair gene mutation (HRRm) patients; non HRRm patients.

Progression-free survival was defined as time from randomization until the date of objective disease progression or death, regardless of whether the patient withdrew from randomized therapy or received another anti-cancer therapy prior to progression. Progression was determined by the site Investigator. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment. If patients had no evaluable visits or baseline data, the patient was censored at Study Day 1, unless death occurred within 17 weeks i.e., death within 17 weeks was relative to randomization. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients.

Time from treatment with olaparib to the date of first disease radiographic progression or death for any reason. Radiographic progression disease will be evaluated according RECIST 1.1 criteria and PCWG3

Progression free survival (PFS), measured as time from date of randomisation to RECIST-defined progression or death from any cause (whichever is first)

Evaluate the objective PFS of abiraterone/prednisone, olaparib or the combination abiraterone/prednisone + olaparib in mCRPC patients with canonical DNA repair defects in BRCA1, BRCA2, or ATM.

To determine the clinical effectiveness of olaparib treatment in each of 4 cohorts assessed using ORR according to RECIST v1.1 criteria (Investigator determined)

The safety and tolerability of olaparib in combination with abiraterone was assessed during Part A of the study. The percentage of patients experiencing AEs, including information on seriousness, severity, study treatment relationship and those leading to discontinuation for all doses of olaparib and for abiraterone are presented. Severity of AEs was assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse events (CTCAE) v4.0. AEs were assigned to a Grade from 1 through 5 as follows: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe or medically significant but not immediately life-threatening requiring hospitalisation; Grade 4: Life-threatening consequences; Grade 5: Death related to AE. 'c-r' = causally related 'discont' = discontinuation.

DLTs were assessed by a Safety Review Committee (SRC) after a minimum of 3 patients had received at least 14 days of treatment in Part A. A DLT was defined as any toxicity which was not a recognised AE of abiraterone or prednisolone, and was not attributable to the disease or disease-related processes under investigation, which occurred during a minimum period of 14 days treatment and which included: 1. haematological toxicity CTCAE v4.0 Grade 4 or higher present for more than 4 days (except anaemia); 2. non-haematological toxicity CTCAE v4.0 Grade 3 or higher including infection, corrected QT interval prolongation; 3. any other toxicity that was greater than that at baseline, was clinically significant and/or unacceptable, did not respond to supportive care, resulted in a disruption of dosing schedule of 7 days or more, or was judged to be a DLT by the SRC. A DLT excluded alopecia and isolated laboratory changes of any grade without clinical sequelae or clinical significance.

The efficacy of olaparib when given in combination with abiraterone was assessed by rPFS, defined as the time from randomisation to disease progression using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (for soft tissue disease) and Prostate Cancer Working Group 2 (PCWG-2) (for bone disease) criteria, or death. Progression using RECIST 1.1 criteria was defined as at least 20% increase from baseline in the sum of diameters of target lesions, progression of existing non-target lesions, or the appearance of at least 1 new lesion. Progression using PCWG-2 criteria was determined if 2 or more new metastatic bone lesions were observed (with a total of at least 4 new lesions since baseline assessment if observed at the 12 week scan, or persistence of or increase in number of lesions if observed after the 12 week scan as determined by a confirmatory scan at least 6 weeks later or at next scheduled visit).

The efficacy of olaparib when given in combination with abiraterone was assessed by rPFS, defined as the time from randomisation to disease progression using RECIST version 1.1 (for soft tissue disease) and PCWG-2 (for bone disease) criteria, or death. Progression using RECIST 1.1 criteria was defined as at least 20% increase from baseline in the sum of diameters of target lesions, progression of existing non-target lesions, or the appearance of at least 1 new lesion. Progression using PCWG-2 criteria was determined if 2 or more new metastatic bone lesions were observed (with a total of at least 4 new lesions since baseline assessment if observed at the 12 week scan, or persistence of or increase in number of lesions if observed after the 12 week scan as determined by a confirmatory scan at least 6 weeks later or at next scheduled visit). The percentage of patients with progression events is presented overall and according to RECIST 1.1 and/or PCWG-2 criteria, or death.

Tumour response rate is the proportion of patients who experienced complete or partial response at least once during the assessment period, according to the definitions of Response Evaluation Criteria In Solid Tumours (RECIST version 1.1).

PFS is defined as the time from randomisation till objective progression or death. In absence of progression or death, the time is calculated from randomisation till last evaluable scanning visit.

PFS is defined as the time from randomisation till objective progression or death. In absence of progression or death, the time is calculated from randomisation till last evaluable scanning visit.

Tumour response is the number of patients who experienced complete or partial response at least once during the assessment period, according to the definitions of Response Evaluation Criteria In Solid Tumours (RECIST version 1.1)

PFS was defined as the time from randomisation to the earlier date of radiological progression (per RECIST criteria) or death by any cause in the absence of objective progression. \[Full analysis set (FAS)\]

Percentage of participants with confirmed best RECIST response of complete response (CR) or partial response (PR). Patients with a best RECIST response of CR or PR had to have a confirmed response at least 28 days later.

The ORR is the percentage of participants whose best tumor response is either complete response (CR) or partial response (PR), according to the RECIST v1.0 criteria. The CR is defined as disappearance of all target lesions (TLs). The PR is defined as at least a 30% decrease in the sum of longest diameters (LD) taking as reference the baseline sum of LD. Percentage of participants with ORR is reported.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease from baseline in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Phase I: frequency and severity of adverse events will be measured using common toxicity criteria for adverse events version 5.

Phase II: Intracranial disease control rate will be defined as the percentage of subjects with \[complete response (CR) + partial response (PR) + stable disease\] per RANO-BM criteria at 6 months after study treatment initiation.

The incidence of dose limiting toxicities occuring during the DLT evaluation period (from start of study treatment until 3 months after the last radiation day). This endpoint will be used to determine the maximal tolerated dose of Olaparib in combination with radiotherapy with and without low dose Cisplatin.

DLT - Dose limiting toxicity

Number of patients with adverse events

The DCR at 12 weeks was defined as the percentage of participants who had complete response (CR) + partial response (PR) + stable disease (SD) at 12 weeks. Participants demonstrated SD for a minimum interval of 11 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 77 days) following the start of treatment. The DCR was determined using Investigator assessments according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).

The ORR (based on RECIST 1.1 as assessed by the Investigator) was defined as the percentage of participants with at least 1 visit response of CR or PR prior to PD or last evaluable assessment in the absence of progression. The 95% confidence interval (CI) were calculated using Exact Clopper-Pearson confidence limits for the binomial proportion.

The DCR at 24 weeks was defined as the percentage of participants who had CR + PR + SD at 24 weeks. Participants demonstrated SD for a minimum interval of 23 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 days) following the start of treatment. The DCR was determined using Investigator assessments according to RECIST v1.1.

Single dose PK parameter summary for olaparib in monotherapy by dose - Cmax (PK analysis set)

Single dose PK parameter summary for olaparib in monotherapy by dose - AUC (PK analysis set)

Single dose PK parameter summary for olaparib in monotherapy by dose - tmax (PK analysis set)

Single dose PK parameter summary for olaparib in monotherapy by dose - t1/2, λz (PK analysis set)

Single dose PK parameter summary for olaparib in monotherapy by dose - Vz/F (PK analysis set)

Single dose PK parameter summary for olaparib in monotherapy by dose - CL/F (PK analysis set)

Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - Cmax, ss and Cmin, ss (PK analysis set)

Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - AUC (PK analysis set)

Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - tmax, ss (PK analysis set)

Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - RAC and TCP (PK analysis set)

Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - Cmax, ss and Cmin, ss (PK analysis set)

Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - AUC (PK analysis set)

Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - tmax, ss (PK analysis set)

Steady state pharmacokinetic parameter summary for olaparib by dose and visit after multiple doses - CLss/F (PK analysis set)

Tamoxifen, N-desmethyl tamoxifen (N-DMT) and endoxifen Cmax ss in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios

Olaparib Cmax ss in the presence and absence of co-administered tamoxifen, and associated Cmax ss treatment ratios

Anastrozole maximum plasma concentration at steady state (Cmax ss) in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios

Olaparib Cmax ss in the presence and absence of co-administered anastrozole, and associated Cmax ss treatment ratios

Letrozole Cmax ss in the presence and absence of co-administered olaparib, and associated Cmax ss treatment ratios

Olaparib Cmax ss in the presence and absence of co-administered letrozole, and associated Cmax ss treatment ratios

Tamoxifen, N-DMT and endoxifen AUC0-τ, in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios

Olaparib AUC0-τ, in the presence and absence of co-administered tamoxifen, and associated AUC0-τ treatment ratios

Anastrozole Area under plasma concentration-time curve over the dosing interval at steady state (AUC0-τ), in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios

Olaparib AUC0-τ, in the presence and absence of co-administered anastrozole, and associated AUC0-τ treatment ratios

Letrozole AUC0-τ, in the presence and absence of co-administered olaparib, and associated AUC0-τ treatment ratios

Olaparib AUC0-τ, in the presence and absence of co-administered letrozole, and associated AUC0-τ treatment ratios

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to infinity (AUC)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of maximum plasma olaparib concentration (Cmax)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of area under the plasma concentration time curve from zero to the last measurable time point (AUC0-t), if AUC is not adequately estimable.

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of time to reach maximum plasma concentration for olaparib (tmax)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib apparent clearance (CL/F)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib apparent volume of distribution (Vz/F)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of terminal rate constant (λz)

Rate and extent of absorption of olaparib following single (Part A) and multiple (Part B) oral doses of olaparib tablet formulation by assessment of olaparib terminal half-life (t1/2).

Rate and extent of absorption of olaparib following single-dose olaparib by assessment of maximum plasma olaparib concentration (Cmax) and time to reach maximum plasma concentration (tmax)

Rate and extent of absorption of olaparib following single-dose olaparib by assessment of area under the plasma concentration time curve from zero to the last measurable time point (AUC0-t)

Rate and extent of absorption of olaparib following single-dose olaparib by assessment of area under the plasma concentration time curve from zero to infinity (AUC)

Rate and extent of absorption of olaparib following single-dose olaparib by assessment of apparent clearance following oral administration (CL/F), apparent volume of distribution (Vz/F), terminal rate constant (λz), and terminal half-life (t½)

An adverse event 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. This was recorded if it happend from the start dose to 30 days after the last of study drug.