To Assess Safety and Efficacy of Agents Targeting DNA Dam... | NCT03330847

NCT03330847

ID	Type	Description	Link
2017-002361-22	EudraCT Number

Status Module

Description Module

Detailed Description

This is a prospective, open label, randomised, multi-centre Phase 2 study that will assess the efficacy and safety of olaparib monotherapy versus olaparib in combination with an inhibitor of ATR (Ceralasertib) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (adavosertib) in second or third line setting in patients with TNBC prospectively stratified by presence/absence of qualifying tumour mutation in genes involved in the HRR pathway.

Eligible patients will be randomised by a ratio 1:1:1 to treatment Arm 1: olaparib continuous in a 28-day cycle, Arm 2: Ceralasertib Days 1-7 with olaparib continuous in a 28-day cycle or Arm 3: adavosertib Days 1-3 and 8-10 with olaparib continuous in a 21-day cycle. Following the ISRC meeting on 17 April 2019 a recommendation was made to close the adavosertib+olaparib treatment arm across all biomarker strata. Following closure of this arm the randomisation ratio will be 1:1 to olaparib monotherapy or Ceralasertib+olaparib. Patients who were receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd).

The study subject population will be divided into Stratum A (patients with mutations in BRCA1 or BRCA2 (Breast cancer susceptible gene mutation (BRCAm)), Stratum B (patients with mutations in any of the other genes involved in the HRR pathway and no mutation in BRCA1 and no mutation in BRCA2), and Stratum C (patients with no detected tumour mutations in any of the HRR genes). Within each stratum A, B and C, there will be further stratification by whether the patient received prior platinum-based therapy.

In the olaparib monotherapy treatment arm as well as in the Ceralasertib+olaparib treatment arm, patients will be administered olaparib bd at 300 mg continuously. Two (2) 150 mg olaparib tablets will be taken at the same time each day, approximately 12 hours apart with one glass of water (approximately 250 mL). In the adavosertib+olaparib treatment arm, patients will be given olaparib 200 mg bd (2 x 100 mg tablets twice a day) and adavosertib 150 mg bd from Day 1 to Day 3 (inclusive) and Day 8 to Day 10 (inclusive) of every 21-day cycle. Ceralasertib will be supplied as 20 mg, 80 mg, or 100 mg film coated tablets. Patients will be administered Ceralasertib od at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle. A total of 160 mg of Ceralasertib tablets will be taken at the same time on each day of dosing with approximately 250 mL of water. Adavosertib will be supplied as capsules containing 25 mg, 50 mg, 75 mg, 100 mg, or 200 mg of drug substance. Adavosertib will be taken with approximately 250 mL of water approximately 2 hours before or 2 hours after food. Olaparib, Ceralasertib and adavosertib will be provided by AstraZeneca.

Primary outcome measures (progression free survival [PFS]) will be analysed for the 3 patient populations BRCAm, Non BRCAm HRRm (Homologous Recombination Repair gene mutation) and Non HRRm. Secondary outcome measures will be analysed in 2 patient populations HRRm and All for PFS, Objective response rate (ORR) and overall survival (OS) will be analysed in all 5 patient populations. DoR, and tumour change will be analysed in BRCAm, Non BRCAm HRRm, and Non HRRm patient populations. Tumour and germline mutation status will be analysed only in the all patient population. PK outcome measures will be analysed only in the all patient population. Blinded Independent Central Review (BICR) of radiological imaging data will be carried out using RECIST version 1.1 and Investigator assessments will also be analysed for sensitivity purposes.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Olaparib monotherapy	Active Comparator	All randomized patients will receive Olaparib monotherapy 300 mg twice daily (BD).	Drug: Olaparib Continuous (28-Day cycle) 300 mg BD.
Olaparib+Ceralasertib	Active Comparator	All randomized patients will receive Olaparib 300 mg twice daily+Ceralasertib 160 mg once daily (OD).	Drug: Ceralasertib 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).
Olaparib+adavosertib	Active Comparator	All randomized patients will receive Olaparib 200 mg BD +adavosertib 150 mg BD. Following the discontinuation of adavosertib+olaparib treatment arm on 18 April 2019, patients receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd).	Drug: Adavosertib 150 mg BD + olaparib 200 mg BD (21-day cycle).

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Olaparib Continuous (28-Day cycle) 300 mg BD.	Drug	Two (2) 150 mg olaparib tablets should be taken at the same time each day, approximately 12 hours apart with one glass of water (approximately 250 mL).

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Progression-free Survival Per Stratum (BICR)	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.	Until date of first documented progression or censoring date or date of death from any cause, whichever came first (assessed up to 32 months)
Progression-free Survival Per Stratum (Sensitivity Analysis)	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.	Until date of first documented progression or censoring date or date of death from any cause, whichever came first (assessed up to 32 months)

Secondary Outcomes

Measure	Description	Time Frame
Progression-free Survival (Per BICR)	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 BICR using 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 presented as follows: HRRm and all enrolled patients.

Eligibility Module

Eligibility Criteria

Pertinent Inclusion criteria:

Informed consent prior to any study specific procedures.
Male or female ≥18 years of age.
Progressive cancer at the time of study entry.
Histologically or cytologically confirmed TNBC at initial diagnosis with evidence of metastatic disease and HER2 negative as per ASCO-CAP HER2 guideline recommendations 2013.
Patients must have received at least 1 and no more than 2 prior lines of treatment for metastatic disease with an anthracycline (eg, doxorubicin, epirubicin) and/or a taxane (eg, paclitaxel, docetaxel) unless contraindicated, in either the neo-adjuvant, adjuvant or metastatic setting.
Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour tissue by the Lynparza HRR assay.
At least one measurable lesion that can be accurately assessed at baseline by computed tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and is suitable for repeated assessment as per RECIST 1.1.
Patients must have normal organ and bone marrow function measured within 28 days prior to randomization (defined in the protocol).
ECOG PS 0-1 within 28 days of randomisation.
Postmenopausal or evidence of non-childbearing status for women of childbearing potential (contraception restrictions apply to participants and their partners).

13. Patient is willing to comply with the protocol requirements. 14. Life expectancy of ≥16 weeks.

Pertinent Exclusion criteria:

Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days of Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 21 or more days before Cycle 1 Day 1. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 5 days prior to study treatment.
More than 2 prior lines of cytotoxic chemotherapy for metastatic disease (prior treatments with hormonal, non-hormonal, biologics or the combination of an aromatase inhibitor and everolimus are not counted as a prior line of therapy).
Previous randomisation in the present study.
Previous treatment with a PARP inhibitor (including olaparib) or other DDR inhibitor (unless less than 3 weeks duration and at least 12 months has elapsed between the last dose and randomization).
Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer) prior to randomisation. The minimum washout period for immunotherapy shall be 42 days.
Patients with second primary cancer (exceptions defined in the protocol).
Mean resting corrected QTc interval using the Fridericia formula (QTcF) >470 msec/female patients and >450 msec for male patients (as calculated per institutional standards) obtained from 3 ECGs performed 2-5 minutes apart at study entry, or congenital long QT syndrome.
Any of the following cardiac diseases currently or within the last 6 months: unstable angina pectoris, congestive heart failure ≥ Class 2 as defined by the New York Heart Association, acute myocardial infarction, conduction abnormality not controlled with pacemaker or medication (patients with a conduction abnormality controlled with pacemaker or medication at the time of screening are eligible), significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).
Concomitant use of known strong or moderate cytochrome P (CYP) 3A inhibitors, strong or moderate CYP3A inducers, or sensitive CYP3A4 substrates or CYp3A4 substrates with a narrow therapeutic index (No longer applicable from CSPv7.0).
Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.
Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.
Immunocompromised patients, eg, human immunodeficiency virus (HIV).
Patients with known active hepatitis (ie, hepatitis B or C).
Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non malignant systemic disease or active, uncontrolled infection.
Patients with symptomatic uncontrolled brain metastases.
Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
Patients with a known hypersensitivity to olaparib, adavosertib, Ceralasertib, or any of the excipients of the products.
Pregnant or breast feeding women.

Name	Affiliation	Role
Andrew Tutt, MB ChB PhD	Guy's Hospital, Great Maze Pond, London.	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Research Site		Birmingham	Alabama	35205	United States
Research Site

PubMed Identifier	Type	Citation	Retractions
34904813	Derived	Smith G, Alholm Z, Coleman RL, Monk BJ. DNA Damage Repair Inhibitors-Combination Therapies. Cancer J. 2021 Nov-Dec 01;27(6):501-505. doi: 10.1097/PPO.0000000000000561.

Label	URL
Related Info	View source

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.
FG001

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	May 6, 2020	Nov 10, 2021

Arm/Group Information

ID	Title	Description
BG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.
BG001	Olaparib + Ceralasertib	Randomized patients received ceralasertib 160 mg once daily (OD) from Days 1 to 7 and olaparib 300 mg twice daily (28-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met.
BG002	Olaparib + Adavosertib	Randomized patients received adavosertib 150 mg BD from days 1 to 3 and days 8 to 10 and olaparib 200 mg BD (21-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met. The adavosertib dose was reduced from 175 mg to 150 mg BD through implementation of clinical study protocol (CSP) version 5.0.
BG003	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Progression-free Survival Per Stratum (BICR)

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.

All randomized patients were analyzed according to the randomisation scheme, regardless of the treatment they actually received. Here, number analyzed reflects number of patients enrolled in each stratum per treatment arm.

Posted

Median

90% Confidence Interval

Months

Until date of first documented progression or censoring date or date of death from any cause, whichever came first (assessed up to 32 months)

ID	Title	Description
OG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.
OG001	Olaparib + Ceralasertib	Randomized patients received ceralasertib 160 mg once daily (OD) from Days 1 to 7 and olaparib 300 mg twice daily (28-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met.
OG002	Olaparib + Adavosertib	Randomized patients received adavosertib 150 mg BD from days 1 to 3 and days 8 to 10 and olaparib 200 mg BD (21-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met. The adavosertib dose was reduced from 175 mg to 150 mg BD through implementation of clinical study protocol (CSP) version 5.0.

Units	Counts
Participants	OG000114 OG001112 OG00247

Title

Denominators

Categories

BRCAm patients

- ParticipantsOG00043
- ParticipantsOG00140
- ParticipantsOG00213

Title	Measurements

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Patient Population BRCAm	Two-sided log-rank tests	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.	0.9403		Hazard Ratio (HR)	1.02			2-Sided	90	0.63	1.66			Proportional hazards models based on prior platinum-based therapy (no, yes). Hazard ratio < 1 favours respective combination treatment related with a longer PFS than olaparib monotherapy. Here, favours olaparib monotherapy.		Superiority

Primary

Progression-free Survival Per Stratum (Sensitivity Analysis)

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.

All randomized patients were analyzed according to the randomisation scheme, regardless of the treatment actually they received. Here, number analyzed reflects number of patients enrolled in each stratum per treatment arm.

Posted

Median

90% Confidence Interval

Months

Until date of first documented progression or censoring date or date of death from any cause, whichever came first (assessed up to 32 months)

ID	Title	Description
OG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.
OG001

Secondary

Progression-free Survival (Per BICR)

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 BICR using 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 presented as follows: HRRm and all enrolled patients.

All randomized patients were analyzed according to the randomization scheme, regardless of the treatment they actually received. Here, number analyzed reflects number of patients enrolled in each stratum per treatment arm.

Posted

Median

90% Confidence Interval

Months

From randomization until date of first documented progression or censoring date or date of death from any cause, whichever came first (assessed up to 32 months)

ID	Title	Description
OG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.
OG001

Secondary

Number of Patients With Objective Response (Per BICR and Per Sensitivity Analysis)

The objective response was defined as patients with at least one BICR assessed visit response of CR or PR. For sensitivity analysis, objective response was defined as the patients with at least one visit response of CR or PR based on Investigator data. These are unadjusted percentages of responders (100 * number of responders / number of patients in full analysis set). The objective response was assessed per RECIST 1.1 guidelines for: measurable lesions (measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) using CT or MRI, non-measurable lesions (all other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15mm short axis at baseline), based on target lesions [TL] (maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), non-target lesions [NTL] (lesions (or sites of disease) not recorded as TL should be identified as NTL at baseline) and any new lesions.

Posted

Count of Participants

Participants

From date of randomization until date of first documented progression or last evaluable assessment, or start of subsequent anti-cancer therapy (Whichever occurred first [assessed up to 32 months])

ID	Title	Description
OG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.

Secondary

Objective Response Rate (ORR) (Per BICR and Per Sensitivity Analysis)

The ORR was defined using BICR data to define a visit response of CR or PR, with denominator defined as number of patients in FAS. For sensitivity analysis, ORR is defined as the percentage of patients with at least one investigator-assessed visit response of CR or PR, with denominator defined as number of patients in FAS. These are summarized using adjusted response rates, which are computed with a logistic regression including factors study treatment and prior platinum-based therapy (no, yes), i.e. these response rates are adjusted for prior platinum-based therapy, which is one of the randomisation stratification factors. The adjusted response rates have been presented as a percentage of patients.

Posted

Number

Percentage of patients

From date of randomization until date of first documented progression or last evaluable assessment, or start of subsequent anti-cancer therapy (Whichever occurred first [assessed up to 32 months])

ID	Title	Description
OG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.
OG001

Secondary

Duration of Response (DoR) [Per BICR and Per Sensitivity Analysis]

The DoR was defined as the time from the date of first documented response according to BICR data until date of documented progression according to BICR data or death in the absence of disease progression. For sensitivity analysis, DoR was defined as the time from the date of first documented response according to Investigator assessment until date of documented progression according to Investigator assessment or death in the absence of disease progression. Here, the median DoR and the 25th and 75th percentile of DoR are presented. The DoR from onset of response was calculated using Kaplan-Meier technique. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients.

Posted

Median

Inter-Quartile Range

Weeks

From date of first documented response until date of first documented progression or last evaluable assessment (assessed up to 32 months)

ID	Title	Description
OG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.
OG001	Olaparib + Ceralasertib

Secondary

Percentage Change From Baseline in Target Lesion Tumour Size [Per BICR and Per Sensitivity Analysis]

Tumour size was the sum of the longest diameters of the target lesions (TLs). The percentage change in TL tumour size at Week 16 was obtained for each patient as follows (considering a visit window around the scheduled day of the Week 16 assessment): (TL at Week 16 minus TL at baseline) divided by (TL at baseline) multiplied by 100. Here, the percentage change data have been reported as per BICR and as per sensitivity analysis per investigator assessments. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients.

All randomized patients were analyzed according to the randomization scheme, regardless of the treatment they actually received. Here, number analyzed reflects the number of patients with an observed or imputed value for the percentage change from baseline at week 16.

Posted

Mean

Standard Deviation

Percentage change

Baseline, at Week 16

ID	Title	Description
OG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.
OG001	Olaparib + Ceralasertib	Randomized patients received ceralasertib 160 mg once daily (OD) from Days 1 to 7 and olaparib 300 mg twice daily (28-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met.

Secondary

Overall Survival (OS)

Overall survival was defined as the time from the date of randomisation until death due to any cause. Any patient not known to have died at the time of data cut-off was censored based on the last recorded date on which the patient was known to be alive. Here, the study patient population was stratified as follows: BRCAm patients; non BRCAm HRRm patients; non HRRm patients.

Posted

Median

90% Confidence Interval

Months

From the date of randomisation until time of data cut-off date or death due to any cause (assessed up to 32 months)

ID	Title	Description
OG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.
OG001	Olaparib + Ceralasertib	Randomized patients received ceralasertib 160 mg once daily (OD) from Days 1 to 7 and olaparib 300 mg twice daily (28-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met.

Secondary

Plasma Drug Concentrations of Olaparib

Plasma drug concentrations of olaparib are evaluated to assess exposure to olaparib in all patients.

Pharmacokinetic (PK) analysis set included patients who have received at least one dose of study medication per the protocol and for whom there was at least one reportable PK concentration.

Posted

Mean

Standard Deviation

ug/mL

Pre-dose at Cycle 1 Day 7 [olaparib monotherapy or ceralasertib+olaparib] or Cycle 1 Day 10 [adavosertib+olaparib] (each cycle is 21 days for olaparib+adavosertib, and 28 days for olaparib monotherapy and olaparib+ceralasertib)

ID	Title	Description
OG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.
OG001	Olaparib + Ceralasertib	Randomized patients received ceralasertib 160 mg once daily (OD) from Days 1 to 7 and olaparib 300 mg twice daily (28-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met.
OG002	Olaparib + Adavosertib

Secondary

Plasma Drug Concentrations of Ceralasertib and Adavosertib

Plasma drug concentrations of ceralasertib and adavosertib are evaluated to assess exposure to ceralasertib and adavosertib in all patients.

PK analysis set included patients who have received at least one dose of study medication per the protocol and for whom there was at least one reportable PK concentration.

Posted

Mean

Standard Deviation

ng/mL

Pre-dose at Cycle 1 Day 7 [ceralasertib+olaparib] or Cycle 1 Day 10 [adavosertib+olaparib] (each cycle is 21 days for olaparib+adavosertib, and 28 days for olaparib+ceralasertib)

ID	Title	Description
OG000	Olaparib + Ceralasertib	Randomized patients received ceralasertib 160 mg once daily (OD) from Days 1 to 7 and olaparib 300 mg twice daily (28-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met.
OG001	Olaparib + Adavosertib	Randomized patients received adavosertib 150 mg BD from days 1 to 3 and days 8 to 10 and olaparib 200 mg BD (21-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met. The adavosertib dose was reduced from 175 mg to 150 mg BD through implementation of clinical study protocol (CSP) version 5.0.

Secondary

Number of Patients With Treatment Emergent Adverse Events (TEAEs)

Treatment-emergent adverse events reported after treatment with olaparib monotherapy, the combination of ceralasertib and olaparib or the combination of adavosertib and olaparib. The data includes adverse events (AEs) with an onset or worsening date on or after the date of first dose and up to and including 30 days following the date of last dose of study medication.

The safety analysis set included all patients who received at least one dose of randomized treatment according to the treatment they actually received.

Posted

Count of Participants

Participants

From screening until Follow-up 30 Days after last dose of study treatment (assessed up to 32 months)

ID	Title	Description
OG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.
OG001	Olaparib + Ceralasertib	Randomized patients received ceralasertib 160 mg once daily (OD) from Days 1 to 7 and olaparib 300 mg twice daily (28-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Olaparib Monotherapy	Randomized patients received olaparib monotherapy 300 mg twice daily (BD) [28-day cycle], until objective radiological disease progression as per Response Evaluation Criteria In Solid Tumours Version (RECIST 1.1) as assessed by the Investigator or until any other discontinuation criteria were met.	42	114	21	110	99	110
EG001	Olaparib + Ceralasertib	Randomized patients received ceralasertib 160 mg once daily (OD) from Days 1 to 7 and olaparib 300 mg twice daily (28-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met.	40	112	24	109	106	109
EG002	Olaparib + Adavosertib	Randomized patients received adavosertib 150 mg BD from days 1 to 3 and days 8 to 10 and olaparib 200 mg BD (21-day cycle), until objective radiological disease progression as per RECIST 1.1 as assessed by the Investigator or until any other discontinuation criteria were met. The adavosertib dose was reduced from 175 mg to 150 mg BD through implementation of clinical study protocol (CSP) version 5.0.	26	47	17	46	46	46

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Bacteraemia	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Bacterial sepsis	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Catheter site infection	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Lower respiratory tract infection	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Pneumonia	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0013 events3 affected109 at risk EG0021 events1 affected46 at risk
Pneumonia staphylococcal	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Sepsis	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0021 events1 affected46 at risk
Subcutaneous abscess	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0022 events1 affected46 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Urinary tract infection	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0021 events1 affected46 at risk
Viral infection	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0021 events1 affected46 at risk
Cancer pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0004 events3 affected110 at risk EG0013 events3 affected109 at risk EG0021 events1 affected46 at risk
Febrile neutropenia	Blood and lymphatic system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0011 events1 affected109 at risk EG0026 events5 affected46 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0022 events2 affected46 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0024 events4 affected46 at risk
Normocytic anaemia	Blood and lymphatic system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0013 events1 affected109 at risk EG0020 events0 affected46 at risk
Pancytopenia	Blood and lymphatic system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0021 events1 affected46 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0023 events3 affected46 at risk
Diabetes mellitus	Metabolism and nutrition disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Glucose tolerance impaired	Metabolism and nutrition disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0021 events1 affected46 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Confusional state	Psychiatric disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Substance-induced psychotic disorder	Psychiatric disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Depressed level of consciousness	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Facial paralysis	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Headache	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Loss of consciousness	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Neuralgia	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0012 events1 affected109 at risk EG0020 events0 affected46 at risk
Partial seizures	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Presyncope	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0021 events1 affected46 at risk
Seizure	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Spinal cord compression	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Cardiac failure	Cardiac disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Tachycardia	Cardiac disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0021 events1 affected46 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0002 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0012 events2 affected109 at risk EG0020 events0 affected46 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Ascites	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0021 events1 affected46 at risk
Enteritis	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Gastrointestinal disorder	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0021 events1 affected46 at risk
Ileus	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Nausea	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0002 events2 affected110 at risk EG0010 events0 affected109 at risk EG0022 events1 affected46 at risk
Vomiting	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0023 events2 affected46 at risk
Peau d'orange	Skin and subcutaneous tissue disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Urticaria	Skin and subcutaneous tissue disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Death	General disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0021 events1 affected46 at risk
General physical health deterioration	General disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0020 events0 affected46 at risk
Non-cardiac chest pain	General disorders	MedDRA version 23.1	Non-systematic Assessment	EG0002 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk
Pyrexia	General disorders	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0021 events1 affected46 at risk
Platelet count decreased	Investigations	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0011 events1 affected109 at risk EG0021 events1 affected46 at risk
White blood cell count decreased	Investigations	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0021 events1 affected46 at risk
Spinal fracture	Injury, poisoning and procedural complications	MedDRA version 23.1	Non-systematic Assessment	EG0001 events1 affected110 at risk EG0010 events0 affected109 at risk EG0020 events0 affected46 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Upper respiratory tract infection	Infections and infestations	MedDRA version 23.1	Non-systematic Assessment	EG0002 events2 affected110 at risk EG0012 events2 affected109 at risk EG0026 events5 affected46 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA version 23.1	Non-systematic Assessment	EG00051 events36 affected110 at risk EG00199 events56 affected109 at risk EG00245 events23 affected46 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0007 events5 affected110 at risk EG00112 events7 affected109 at risk EG00215 events8 affected46 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA version 23.1	Non-systematic Assessment	EG00018 events10 affected110 at risk EG00129 events20 affected109 at risk EG00239 events19 affected46 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0003 events3 affected110 at risk EG00116 events12 affected109 at risk EG00223 events9 affected46 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA version 23.1	Non-systematic Assessment	EG00023 events19 affected110 at risk EG00122 events22 affected109 at risk EG00213 events10 affected46 at risk
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0025 events3 affected46 at risk
Dizziness	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0009 events8 affected110 at risk EG00112 events11 affected109 at risk EG0027 events3 affected46 at risk
Headache	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG00019 events13 affected110 at risk EG00118 events16 affected109 at risk EG0027 events4 affected46 at risk
Neuropathy peripheral	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0012 events2 affected109 at risk EG0025 events3 affected46 at risk
Taste disorder	Nervous system disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0010 events0 affected109 at risk EG0023 events3 affected46 at risk
Palpitations	Cardiac disorders	MedDRA version 23.1	Non-systematic Assessment	EG0002 events2 affected110 at risk EG0013 events3 affected109 at risk EG0024 events4 affected46 at risk
Hot flush	Vascular disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0013 events3 affected109 at risk EG0023 events3 affected46 at risk
Hypertension	Vascular disorders	MedDRA version 23.1	Non-systematic Assessment	EG0002 events2 affected110 at risk EG0019 events5 affected109 at risk EG0023 events3 affected46 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG00012 events10 affected110 at risk EG00111 events10 affected109 at risk EG0026 events5 affected46 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0009 events7 affected110 at risk EG00112 events11 affected109 at risk EG00211 events8 affected46 at risk
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0002 events2 affected110 at risk EG0010 events0 affected109 at risk EG0024 events3 affected46 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0003 events2 affected110 at risk EG00110 events7 affected109 at risk EG0029 events6 affected46 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0009 events7 affected110 at risk EG0018 events7 affected109 at risk EG0023 events2 affected46 at risk
Constipation	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG00015 events12 affected110 at risk EG00119 events17 affected109 at risk EG00213 events10 affected46 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG00020 events16 affected110 at risk EG00144 events24 affected109 at risk EG00259 events25 affected46 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0007 events7 affected110 at risk EG0016 events6 affected109 at risk EG0024 events3 affected46 at risk
Nausea	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG00075 events55 affected110 at risk EG001102 events64 affected109 at risk EG00242 events26 affected46 at risk
Stomatitis	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG0003 events3 affected110 at risk EG0019 events8 affected109 at risk EG0022 events2 affected46 at risk
Vomiting	Gastrointestinal disorders	MedDRA version 23.1	Non-systematic Assessment	EG00049 events34 affected110 at risk EG00149 events31 affected109 at risk EG00232 events15 affected46 at risk
Erythema	Skin and subcutaneous tissue disorders	MedDRA version 23.1	Non-systematic Assessment	EG0004 events3 affected110 at risk EG0014 events3 affected109 at risk EG0023 events3 affected46 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA version 23.1	Non-systematic Assessment	EG0008 events7 affected110 at risk EG00112 events9 affected109 at risk EG0028 events6 affected46 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA version 23.1	Non-systematic Assessment	EG00012 events11 affected110 at risk EG00111 events9 affected109 at risk EG0028 events5 affected46 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA version 23.1	Non-systematic Assessment	EG0002 events2 affected110 at risk EG0018 events6 affected109 at risk EG0025 events4 affected46 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA version 23.1	Non-systematic Assessment	EG0007 events7 affected110 at risk EG0016 events6 affected109 at risk EG0023 events3 affected46 at risk
Asthenia	General disorders	MedDRA version 23.1	Non-systematic Assessment	EG00034 events26 affected110 at risk EG00141 events33 affected109 at risk EG00210 events7 affected46 at risk
Fatigue	General disorders	MedDRA version 23.1	Non-systematic Assessment	EG00036 events30 affected110 at risk EG00152 events32 affected109 at risk EG00226 events16 affected46 at risk
Influenza like illness	General disorders	MedDRA version 23.1	Non-systematic Assessment	EG0000 events0 affected110 at risk EG0012 events2 affected109 at risk EG0023 events3 affected46 at risk
Oedema peripheral	General disorders	MedDRA version 23.1	Non-systematic Assessment	EG0004 events4 affected110 at risk EG0016 events6 affected109 at risk EG0023 events3 affected46 at risk
Pyrexia	General disorders	MedDRA version 23.1	Non-systematic Assessment	EG0006 events6 affected110 at risk EG00110 events7 affected109 at risk EG0027 events6 affected46 at risk
Alanine aminotransferase increased	Investigations	MedDRA version 23.1	Non-systematic Assessment	EG0009 events8 affected110 at risk EG0018 events7 affected109 at risk EG0028 events7 affected46 at risk
Aspartate aminotransferase increased	Investigations	MedDRA version 23.1	Non-systematic Assessment	EG0003 events3 affected110 at risk EG0016 events5 affected109 at risk EG0027 events7 affected46 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA version 23.1	Non-systematic Assessment	EG0004 events4 affected110 at risk EG0012 events2 affected109 at risk EG0026 events4 affected46 at risk
C-reactive protein increased	Investigations	MedDRA version 23.1	Non-systematic Assessment	EG0003 events3 affected110 at risk EG0014 events4 affected109 at risk EG0024 events4 affected46 at risk
Lymphocyte count decreased	Investigations	MedDRA version 23.1	Non-systematic Assessment	EG0005 events5 affected110 at risk EG0014 events3 affected109 at risk EG0024 events3 affected46 at risk
Neutrophil count decreased	Investigations	MedDRA version 23.1	Non-systematic Assessment	EG0006 events5 affected110 at risk EG00117 events8 affected109 at risk EG00212 events6 affected46 at risk
Platelet count decreased	Investigations	MedDRA version 23.1	Non-systematic Assessment	EG0006 events2 affected110 at risk EG00119 events10 affected109 at risk EG00216 events8 affected46 at risk
Weight decreased	Investigations	MedDRA version 23.1	Non-systematic Assessment	EG0003 events3 affected110 at risk EG0014 events3 affected109 at risk EG0025 events5 affected46 at risk
White blood cell count decreased	Investigations	MedDRA version 23.1	Non-systematic Assessment	EG0003 events3 affected110 at risk EG00115 events9 affected109 at risk EG00210 events8 affected46 at risk

ID	Term
D001943	Breast Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D001941	Breast Diseases
D012871	Skin Diseases
D017437	Skin and Connective Tissue Diseases