To Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.

• Sponsor: AstraZeneca (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03330847
• Collaborator: (none)
• Enrollment: 273
• Locations: 141
• Arms: 3
• Anticipated Duration (Months): 57.8
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study is to assess the efficacy and safety of olaparib monotherapy versus olaparib in combination with an inhibitor of ATR (Ataxia-Telangiectasia Mutated (ATM) and Rad3-related protein kinase (Ceralasertib [AZD6738]) and olaparib monotherapy versus olaparib in combination with an inhibitor of WEE1 (adavosertib [AZD1775]) in second or third line setting in patients with Triple-negative breast cancer (TNBC) prospectively stratified by presence/absence of qualifying tumour mutation in genes involved in the homologous recombination repair (HRR) pathway. Treatment arms are olaparib monotherapy, olaparib+ Ceralasertib and olaparib+adavosertib. The study subject population will be divided into Stratum A, Stratum B, and Stratum C. Due to the different schedules of administration of each of the treatment options as well as their different toxicity profiles, the study is not blinded. Study has two stage consent process- stage 1 consent (molecular screening for HRR defects) and stage 2 consent (main study). Patients with TNBC and with known qualifying BRCAm, non BRCAm HRRm and non HRRm status will be offered the option of consenting to the main part of the study within the 28-day screening period. Following the ISRC meeting on 17 April 2019 a recommendation was made to close the adavosertib+olaparib treatment arm across all biomarker strata. Patients receiving treatment with adavosertib+olaparib treatment were offered the opportunity to continue treatment on olaparib monotherapy at the approved dose (300 mg bd). Following the closure of this arm the total number of patients randomised will be lower (approximately 350 patients). Approximately 300 patients will be randomised (using randomisation ratio 1:1) to 2 ongoing treatment arms plus an additional 47 patients to a 3rd arm (olaparib+adavosertib) prior to the arm being discontinued.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Triple Negative Breast Cancer	Drug: Olaparib Continuous (28-Day cycle) 300 mg BD.; Drug: Ceralasertib 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).; Drug: Adavosertib 150 mg BD + olaparib 200 mg BD (21-day cycle).	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 273 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Masking Description: Given the study treatment design (monotherapy and 2 different combination therapies will be employed) neither patients nor Investigators will be blinded to study treatment.
• Primary Purpose: Treatment
• Official Title: A Phase II, Open Label, Randomised, Multi-centre Study to Assess the Safety and Efficacy of Agents Targeting DNA Damage Repair in Combination With Olaparib Versus Olaparib Monotherapy in the Treatment of Metastatic Triple Negative Breast Cancer Patients Stratified by Alterations in Homologous Recombinant Repair (HRR)-Related Genes (Including BRCA1/2) (VIOLETTE).
• Actual Study Start Date: Mar 7, 2018
• Actual Primary Completion Date: Nov 13, 2020
• Anticipated Study Completion Date: Dec 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Olaparib monotherapy All randomized patients will receive Olaparib monotherapy 300 mg twice daily (BD).	Drug: Olaparib Continuous (28-Day cycle) 300 mg BD.; 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).
Active Comparator: Olaparib+Ceralasertib 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).; Patients will be administered Ceralasertib OD at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle.
Active Comparator: Olaparib+adavosertib 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).; Patients will be administered adavosertib BD at 150mg from Day 1 to Day 3 and Day 8 to Day 10.

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival Per Stratum (BICR) [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 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.

2. Progression-free Survival Per Stratum (Sensitivity Analysis) [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 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.

Secondary Outcome Measures

1. Progression-free Survival (Per BICR) [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)]

   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.

2. Number of Patients With Objective Response (Per BICR and Per Sensitivity Analysis) [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])]

   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.

3. Objective Response Rate (ORR) (Per BICR and Per Sensitivity Analysis) [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])]

   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.

4. Duration of Response (DoR) [Per BICR and Per Sensitivity Analysis] [From date of first documented response until date of first documented progression or last evaluable assessment (assessed up to 32 months)]

   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.

5. Percentage Change From Baseline in Target Lesion Tumour Size [Per BICR and Per Sensitivity Analysis] [Baseline, at Week 16]

   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.

6. Overall Survival (OS) [From the date of randomisation until time of data cut-off date or death due to any cause (assessed up to 32 months)]

   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.

7. Plasma Drug Concentrations of Olaparib [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)]

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

8. Plasma Drug Concentrations of Ceralasertib and Adavosertib [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)]

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

9. Number of Patients With Treatment Emergent Adverse Events (TEAEs) [From screening until Follow-up 30 Days after last dose of study treatment (assessed up to 32 months)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Pertinent Inclusion criteria:

1. Informed consent prior to any study specific procedures.

2. Male or female ≥18 years of age.

3. Progressive cancer at the time of study entry.

4. Histologically or cytologically confirmed TNBC at initial diagnosis with evidence of metastatic disease and HER2 negative as per ASCO-CAP HER2 guideline recommendations

6. 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.

7. Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour tissue by the Lynparza HRR assay.

8. 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.

9. Patients must have normal organ and bone marrow function measured within 28 days prior to randomization (defined in the protocol).

10. ECOG PS 0-1 within 28 days of randomisation.

11. Postmenopausal or evidence of non-childbearing status for women of childbearing potential (contraception restrictions apply to participants and their partners).

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

Pertinent Exclusion criteria:

1. 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.

2. 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).

3. Previous randomisation in the present study.

4. 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).

5. 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.

6. Patients with second primary cancer (exceptions defined in the protocol).

7. 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.

8. 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).

9. 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).

10. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy, excluding alopecia and CTCAE grade 2 peripheral neuropathy.

11. Major surgery within 2 weeks of starting study treatment: patients must have recovered from any effects of any major surgery.

12. Immunocompromised patients, eg, human immunodeficiency virus (HIV).

13. Patients with known active hepatitis (ie, hepatitis B or C).

14. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non malignant systemic disease or active, uncontrolled infection.

15. Patients with symptomatic uncontrolled brain metastases.

16. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.

17. Patients with a known hypersensitivity to olaparib, adavosertib, Ceralasertib, or any of the excipients of the products.

18. Pregnant or breast feeding women.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35205
2	Research Site	Anchorage	Alaska	United States	99508
3	Research Site	Gilbert	Arizona	United States	85234
4	Research Site	Aurora	Colorado	United States	80045
5	Research Site	New Haven	Connecticut	United States	06511
6	Research Site	Chicago	Illinois	United States	60637
7	Research Site	Munster	Indiana	United States	46321
8	Research Site	Hazard	Kentucky	United States	41701
9	Research Site	Louisville	Kentucky	United States	40207
10	Research Site	Towson	Maryland	United States	21204
11	Research Site	Brick	New Jersey	United States	08724
12	Research Site	East Setauket	New York	United States	11733
13	Research Site	Lake Success	New York	United States	11042
14	Research Site	Mineola	New York	United States	11501
15	Research Site	Mount Kisco	New York	United States	10549
16	Research Site	Stony Brook	New York	United States	11794
17	Research Site	Cincinnati	Ohio	United States	45219
18	Research Site	Knoxville	Tennessee	United States	37909
19	Research Site	Seattle	Washington	United States	98104
20	Research Site	Milwaukee	Wisconsin	United States	53212
21	Research Site	Brasschaat		Belgium	2930
22	Research Site	Brussels		Belgium	1000
23	Research Site	Bruxelles		Belgium	1200
24	Research Site	Charleroi		Belgium	6000
25	Research Site	Leuven		Belgium	3000
26	Research Site	Liège		Belgium	4000
27	Research Site	Namur		Belgium	5000
28	Research Site	Ottignies		Belgium	1340
29	Research Site	Wilrijk		Belgium	2610
30	Research Site	Calgary	Alberta	Canada	T2N 4N2
31	Research Site	Kelowna	British Columbia	Canada	V1Y 5L3
32	Research Site	Ottawa	Ontario	Canada	K1H 8L6
33	Research Site	Toronto	Ontario	Canada	M4N 3M5
34	Research Site	Brno		Czechia	625 00
35	Research Site	Olomouc		Czechia	775 20
36	Research Site	Praha 8		Czechia	180 81
37	Research Site	Angers Cedex 02		France	49055
38	Research Site	Besançon Cedex		France	25030
39	Research Site	Bordeaux		France	33076
40	Research Site	Caen Cedex 05		France	14076
41	Research Site	Lille		France	59000
42	Research Site	Lyon Cedex 08		France	69373
43	Research Site	Marseille		France	13273
44	Research Site	Montpellier		France	34298
45	Research Site	Nantes		France	44202
46	Research Site	Rennes		France	35000
47	Research Site	Saint Herblain Cedex		France	44805
48	Research Site	Tours CEDEX		France	37044
49	Research Site	Villejuif		France	94805
50	Research Site	Dresden		Germany	1307
51	Research Site	Frankfurt am Main		Germany	60431
52	Research Site	Hamburg		Germany	20357
53	Research Site	Hannover		Germany	30559
54	Research Site	Leipzig		Germany	04103
55	Research Site	München		Germany	81675
56	Research Site	Witten		Germany	58452
57	Research Site	Cork		Ireland	T12 DV56
58	Research Site	Dublin 4		Ireland
59	Research Site	Ancona		Italy	60126
60	Research Site	Bologna		Italy	40138
61	Research Site	Brescia		Italy	25124
62	Research Site	Cona		Italy	44124
63	Research Site	Genova		Italy	16128
64	Research Site	Lecco		Italy	23900
65	Research Site	Macerata		Italy	62100
66	Research Site	Meldola		Italy	47014
67	Research Site	Messina		Italy	98125
68	Research Site	Milano		Italy	20133
69	Research Site	Milano		Italy	20141
70	Research Site	Napoli		Italy	80131
71	Research Site	Novara		Italy	28100
72	Research Site	Parma		Italy	43126
73	Research Site	Pavia		Italy	27100
74	Research Site	Pisa		Italy	56126
75	Research Site	Roma		Italy	00128
76	Research Site	Rozzano		Italy	20089
77	Research Site	Siena		Italy	53100
78	Research Site	Torino		Italy	10123
79	Research Site	Cheongju-si		Korea, Republic of	28644
80	Research Site	Daegu		Korea, Republic of	41404
81	Research Site	Goyang-si		Korea, Republic of	410-769
82	Research Site	Incheon		Korea, Republic of	405-760
83	Research Site	Seongnam-si		Korea, Republic of	13620
84	Research Site	Seoul		Korea, Republic of	02841
85	Research Site	Seoul		Korea, Republic of	03080
86	Research Site	Seoul		Korea, Republic of	03722
87	Research Site	Seoul		Korea, Republic of	05505
88	Research Site	Seoul		Korea, Republic of	06351
89	Research Site	Breda		Netherlands	4819 EV
90	Research Site	Den Haag		Netherlands	2545 CH
91	Research Site	Rotterdam		Netherlands	3015 GD
92	Research Site	Dabrowa Gornicza		Poland	41-300
93	Research Site	Gdansk		Poland	80-952
94	Research Site	Gdynia		Poland	81-519
95	Research Site	Grzepnica		Poland	72-003
96	Research Site	Kraków		Poland	31-531
97	Research Site	Lodz		Poland	91-211
98	Research Site	Olsztyn		Poland	10-228
99	Research Site	Poznań		Poland	60-192
100	Research Site	Warszawa		Poland	02-781
101	Research Site	Wroclaw		Poland	53-413
102	Research Site	Lisboa		Portugal	1400-038
103	Research Site	Lisboa		Portugal	1769-001
104	Research Site	Loures		Portugal	2674-514
105	Research Site	Porto		Portugal	4099-001
106	Research Site	Vila Nova de Gaia		Portugal	4434-502
107	Research Site	Barcelona		Spain	08035
108	Research Site	Barcelona		Spain	08036
109	Research Site	Cáceres		Spain	10003
110	Research Site	Madrid		Spain	28007
111	Research Site	Madrid		Spain	28034
112	Research Site	Madrid		Spain	28040
113	Research Site	Madrid		Spain	28046
114	Research Site	Palma de mallorca		Spain	07120
115	Research Site	San Sebastián		Spain	20014
116	Research Site	Sant Cugat del Valles		Spain	08190
117	Research Site	Sevilla		Spain	41009
118	Research Site	Sevilla		Spain	41013
119	Research Site	Valencia		Spain	46010
120	Research Site	Vigo		Spain	36312
121	Research Site	Zaragoza		Spain	50009
122	Research Site	Changhua City		Taiwan	500
123	Research Site	Kaohsiung Hsien		Taiwan	83342
124	Research Site	Taichung		Taiwan	40447
125	Research Site	Taipei		Taiwan	10048
126	Research Site	Taipei		Taiwan	10449
127	Research Site	Taipei		Taiwan	11217
128	Research Site	Taipei		Taiwan	11490
129	Research Site	Taoyuan		Taiwan	333
130	Research Site	Aberdeen		United Kingdom	AB25 2ZN
131	Research Site	Bristol		United Kingdom	BS1 2NT
132	Research Site	Cardiff		United Kingdom	CF14 2TL
133	Research Site	Durham		United Kingdom	DH1 5TW
134	Research Site	Edinburgh		United Kingdom	EH4 2XR
135	Research Site	Leicester		United Kingdom	LE1 5WW
136	Research Site	London		United Kingdom	SE1 9RT
137	Research Site	London		United Kingdom	W1G 6AD
138	Research Site	London		United Kingdom	W1T 7HA
139	Research Site	Manchester		United Kingdom	M20 4BX
140	Research Site	Nottingham		United Kingdom	NG5 1PB
141	Research Site	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Andrew Tutt, MB ChB PhD, Guy's Hospital, Great Maze Pond, London.

Study Documents (Full-Text)

• Study Protocol - May 6, 2020
• Statistical Analysis Plan - Jun 14, 2019

More Information

Additional Information:

• Related Info
• Related Info
• Related Info

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03330847
• Other Study ID Numbers: D5336C00001
• First Posted: Nov 6, 2017
• Last Update Posted: Jul 12, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: Germline BRCA mutation; Human epidermal growth factor receptor 2; Olaparib; Homologous Recombinant Repair (HRR)-related Genes
• Additional relevant MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms; Olaparib; Adavosertib

Study Results

Participant Flow

Recruitment Details	The study was conducted between 21-Feb-2018 and 13-Nov-2020 in 15 countries in Asia, Europe, and North America.
Pre-assignment Detail	Participants who met the inclusion and none of the exclusion criteria were enrolled to the study. All study assessments were performed as per the schedule of assessment.

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.	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.
Period Title: Overall Study
STARTED	114	112	47
COMPLETED	52	47	32
NOT COMPLETED	62	65	15

Baseline Characteristics

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib	Total
Arm/Group Description	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.	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.	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.	Total of all reporting groups
Overall Participants	114	112	47	273
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.1 (11.55)	54.4 (10.85)	52.7 (11.29)	53.6 (11.21)
Age, Customized (Count of Participants)
<40 Years	15 13.2%	9 8%	4 8.5%	28 10.3%
>=40 to <50 Years	30 26.3%	27 24.1%	18 38.3%	75 27.5%
>=50 to <65 Years	52 45.6%	57 50.9%	16 34%	125 45.8%
>=65 to <75 Years	14 12.3%	13 11.6%	8 17%	35 12.8%
>=75 Years	3 2.6%	6 5.4%	1 2.1%	10 3.7%
Sex: Female, Male (Count of Participants)
Female	114 100%	112 100%	47 100%	273 100%
Male	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 5.3%	7 6.3%	5 10.6%	18 6.6%
Not Hispanic or Latino	92 80.7%	97 86.6%	40 85.1%	229 83.9%
Unknown or Not Reported	16 14%	8 7.1%	2 4.3%	26 9.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	14 12.3%	23 20.5%	7 14.9%	44 16.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	2 1.8%	0 0%	2 4.3%	4 1.5%
White	81 71.1%	77 68.8%	34 72.3%	192 70.3%
More than one race	5 4.4%	5 4.5%	2 4.3%	12 4.4%
Unknown or Not Reported	12 10.5%	7 6.3%	2 4.3%	21 7.7%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.	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.
Measure Participants	114	112	47
BRCAm patients	7.3	7.4	3.8
non BRCAm HRRm patients	1.9	3.9	2.1
non HRRm patients	1.9	3.6	4.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Ceralasertib
	Comments	Patient Population BRCAm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9403
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 90%; 0.63 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Adavosertib
	Comments	Patient Population BRCAm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9282
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 90%; 0.52 to 1.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Ceralasertib
	Comments	Patient Population Non BRCAm HRRm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1274
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 90%; 0.28 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	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 + ceralasertib.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Adavosertib
	Comments	Patient Population Non BRCAm HRRm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2956
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.56
	Confidence Interval	(2-Sided) 90%; 0.23 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	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 + adavosertib.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Ceralasertib
	Comments	Patient Population Non HRRm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2959
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 90%; 0.50 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	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 + ceralasertib.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Adavosertib
	Comments	Patient Population Non HRRm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0193
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.48
	Confidence Interval	(2-Sided) 90%; 0.28 to 0.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	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 + adavosertib.

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.	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.
Measure Participants	114	112	47
BRCAm patients	7.4	7.5	5.4
non BRCAm HRRm patients	3.4	3.7	2.9
non HRRm patients	1.9	3.5	2.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Ceralasertib
	Comments	Patient Population BRCAm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6147
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 90%; 0.53 to 1.39
	Parameter Dispersion	Type: Value:
	Estimation Comments	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 + ceralasertib.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Adavosertib
	Comments	Patient Population BRCAm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7879
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 90%; 0.48 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	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 + adavosertib.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Ceralasertib
	Comments	Patient Population Non BRCAm HRRm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3695
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 90%; 0.38 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	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 + ceralasertib.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Adavosertib
	Comments	Patient Population Non BRCAm HRRm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4586
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 90%; 0.29 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	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 + adavosertib.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Ceralasertib
	Comments	Patient Population Non HRRm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7452
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 90%; 0.61 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	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 + ceralasertib.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Olaparib Monotherapy, Olaparib + Adavosertib
	Comments	Patient Population Non HRRm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1185
	Comments
	Method	Two-sided log-rank tests
	Comments	Stratified for prior platinum-based therapy (no,yes) using Breslow's approach for handling of ties.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 90%; 0.37 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	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 + adavosertib.

3. Secondary Outcome

Title	Progression-free Survival (Per BICR)
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.	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.
Measure Participants	114	112	47
HRRm patients per BICR	5.6	5.6	3.7
All patients per BICR	3.6	5.3	3.8

4. Secondary Outcome

Title	Number of Patients With Objective Response (Per BICR and Per Sensitivity Analysis)
Description	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.
Time Frame	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])

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.	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.
Measure Participants	114	112	47
BRCAm patients per BICR	19 16.7%	20 17.9%	6 12.8%
non BRCAm HRRm patients per BICR	3 2.6%	4 3.6%	0 0%
non HRRm patients per BICR	2 1.8%	8 7.1%	3 6.4%
HRRm patients per BICR	22 19.3%	24 21.4%	6 12.8%
All patients per BICR	24 21.1%	32 28.6%	9 19.1%
BRCAm patients per sensitivity analysis	18 15.8%	20 17.9%	7 14.9%
non BRCAm HRRm per sensitivity analysis	3 2.6%	4 3.6%	1 2.1%
non HRRm per sensitivity analysis	1 0.9%	11 9.8%	3 6.4%

5. Secondary Outcome

Title	Objective Response Rate (ORR) (Per BICR and Per Sensitivity Analysis)
Description	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.
Time Frame	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])

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.	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.
Measure Participants	114	112	47
BRCAm patients per BICR	42.7	48.4	44.9
non BRCAm HRRm patients per BICR	15.0	20.0	0.0
non HRRm patients per BICR	3.9	15.4	11.1
HRRm patients per BICR	33.2	38.0	28.5
All patients per BICR	20.1	27.3	18.3
BRCAm patients per sensitivity analysis	41.0	49.0	53.1
non BRCAm HRRm per sensitivity analysis	15.0	20.0	14.3
non HRRm per sensitivity analysis	2.0	21.2	11.1

6. Secondary Outcome

Title	Duration of Response (DoR) [Per BICR and Per Sensitivity Analysis]
Description	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.
Time Frame	From date of first documented response until date of first documented progression or last evaluable assessment (assessed up to 32 months)

Outcome Measure Data

Analysis Population Description

All randomized patients were analyzed according to the randomization scheme, regardless of the treatment they actually received. Here, number analyzed reflects number of patients with objective response.

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.	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.
Measure Participants	114	112	47
BRCAm patients per BICR	20.0	32.0	33.4
non BRCAm HRRm patients per BICR	16.8	17.1
non HRRm patients per BICR	11.4	24.1	16.6
BRCAm patients per sensitivity analysis	20.0	32.6	41.1
non BRCAm HRRm per sensitivity analysis	16.3	16.5	48.1
non HRRm per sensitivity analysis	13.6	11.7	31.6

7. Secondary Outcome

Title	Percentage Change From Baseline in Target Lesion Tumour Size [Per BICR and Per Sensitivity Analysis]
Description	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.
Time Frame	Baseline, at Week 16

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.	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.
Measure Participants	114	112	47
BRCAm patients per BICR	-27.7 (34.33)	-33.8 (37.77)	-34.1 (42.52)
non BRCAm HRRm patients per BICR	4.9 (35.78)	4.9 (35.72)	42.3 (27.44)
non HRRm patients per BICR	40.3 (76.18)	5.7 (40.46)	9.2 (32.66)
BRCAm patients per sensitivity analysis	-21.9 (39.88)	-29.5 (35.36)	-23.7 (41.85)
non BRCAm HRRm per sensitivity analysis	6.2 (34.77)	-2.1 (40.66)	73.9 (107.94)
non HRRm per sensitivity analysis	20.1 (34.71)	3.9 (37.20)	9.3 (27.46)

8. Secondary Outcome

Title	Overall Survival (OS)
Description	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.
Time Frame	From the date of randomisation until time of data cut-off date or death due to any cause (assessed up to 32 months)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.	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.
Measure Participants	114	112	47
BRCAm patients	20.4	15.5	22.8
non BRCAm HRRm patients	8.4	12.4	8.0
non HRRm patients	9.2	10.3	10.6

9. Secondary Outcome

Title	Plasma Drug Concentrations of Olaparib
Description	Plasma drug concentrations of olaparib are evaluated to assess exposure to olaparib in all patients.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.	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.
Measure Participants	94	85	36
Mean (Standard Deviation) [ug/mL]	2.97 (2.41)	2.90 (2.68)	3.22 (3.37)

10. Secondary Outcome

Title	Plasma Drug Concentrations of Ceralasertib and Adavosertib
Description	Plasma drug concentrations of ceralasertib and adavosertib are evaluated to assess exposure to ceralasertib and adavosertib in all patients.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.
Measure Participants	89	39
Mean (Standard Deviation) [ng/mL]	870.05 (772.05)	290.46 (169.07)

11. Secondary Outcome

Title	Number of Patients With Treatment Emergent Adverse Events (TEAEs)
Description	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.
Time Frame	From screening until Follow-up 30 Days after last dose of study treatment (assessed up to 32 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Olaparib Monotherapy	Olaparib + Ceralasertib	Olaparib + Adavosertib
Arm/Group Description	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.	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.	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.
Measure Participants	110	109	46
Any AE	105 92.1%	107 95.5%	46 97.9%
Any AE causally related to olaparib	91 79.8%	95 84.8%	43 91.5%
Any AE causally related to non-olaparib	NA NaN	92 82.1%	45 95.7%
Any AE causally related to non-olaparib and olaparib	NA NaN	91 81.3%	42 89.4%
Any AE with outcome = death	1 0.9%	2 1.8%	1 2.1%
Any AE with outcome = death, causally related to olaparib	0 0%	0 0%	0 0%
Any AE with outcome = death, causally related to non-olaparib	NA NaN	0 0%	0 0%
Any AE with outcome = death, causally related to non-olaparib and olaparib	NA NaN	0 0%	0 0%
Any SAE	21 18.4%	24 21.4%	17 36.2%
Any SAE causally related to olaparib	4 3.5%	9 8%	9 19.1%
Any SAE causally related to non-olaparib	NA NaN	7 6.3%	14 29.8%
Any SAE causally related to non-olaparib and olaparib	NA NaN	7 6.3%	9 19.1%
Any AE leading to discontinuation of study treatment	2 1.8%	12 10.7%	9 19.1%
AEs leading to reduction of study treatment	15 13.2%	32 28.6%	19 40.4%
AEs leading to reduction of olaparib	15 13.2%	30 26.8%	11 23.4%
AEs leading to reduction of non-olaparib	NA NaN	16 14.3%	12 25.5%
AEs leading to reduction of non-olaparib and olaparib	NA NaN	11 9.8%	3 6.4%

Adverse Events

Time Frame	From screening until Follow-up 30 Days after last dose of study treatment (assessed up to 32 months)
Adverse Event Reporting Description	Full analysis set population is used for All-cause Mortality as death formed part of efficacy. However, safety analysis set is used for serious adverse events and non-serious adverse event as the adverse events form part of safety and not efficacy.
Arm/Group Title	Olaparib Monotherapy		Olaparib + Ceralasertib		Olaparib + Adavosertib
Arm/Group Description	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.		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.		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.
All Cause Mortality
	Olaparib Monotherapy		Olaparib + Ceralasertib		Olaparib + Adavosertib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/114 (36.8%)		40/112 (35.7%)		26/47 (55.3%)
Serious Adverse Events
	Olaparib Monotherapy		Olaparib + Ceralasertib		Olaparib + Adavosertib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/110 (19.1%)		24/109 (22%)		17/46 (37%)
Blood and lymphatic system disorders
Anaemia	3/110 (2.7%)	4	3/109 (2.8%)	3	1/46 (2.2%)	1
Febrile neutropenia	1/110 (0.9%)	1	1/109 (0.9%)	1	5/46 (10.9%)	6
Leukopenia	0/110 (0%)	0	0/109 (0%)	0	2/46 (4.3%)	2
Neutropenia	0/110 (0%)	0	0/109 (0%)	0	4/46 (8.7%)	4
Normocytic anaemia	0/110 (0%)	0	1/109 (0.9%)	3	0/46 (0%)	0
Pancytopenia	0/110 (0%)	0	0/109 (0%)	0	1/46 (2.2%)	1
Thrombocytopenia	0/110 (0%)	0	0/109 (0%)	0	3/46 (6.5%)	3
Cardiac disorders
Cardiac failure	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Tachycardia	0/110 (0%)	0	0/109 (0%)	0	1/46 (2.2%)	1
Gastrointestinal disorders
Ascites	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Diarrhoea	0/110 (0%)	0	0/109 (0%)	0	1/46 (2.2%)	1
Enteritis	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Gastrointestinal disorder	0/110 (0%)	0	0/109 (0%)	0	1/46 (2.2%)	1
Ileus	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Nausea	2/110 (1.8%)	2	0/109 (0%)	0	1/46 (2.2%)	2
Vomiting	1/110 (0.9%)	1	0/109 (0%)	0	2/46 (4.3%)	3
General disorders
Death	0/110 (0%)	0	0/109 (0%)	0	1/46 (2.2%)	1
General physical health deterioration	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Non-cardiac chest pain	1/110 (0.9%)	2	0/109 (0%)	0	0/46 (0%)	0
Pyrexia	1/110 (0.9%)	1	0/109 (0%)	0	1/46 (2.2%)	1
Infections and infestations
Bacteraemia	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Bacterial sepsis	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Catheter site infection	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Lower respiratory tract infection	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Pneumonia	0/110 (0%)	0	3/109 (2.8%)	3	1/46 (2.2%)	1
Pneumonia staphylococcal	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Sepsis	1/110 (0.9%)	1	0/109 (0%)	0	1/46 (2.2%)	1
Subcutaneous abscess	0/110 (0%)	0	0/109 (0%)	0	1/46 (2.2%)	2
Upper respiratory tract infection	1/110 (0.9%)	1	1/109 (0.9%)	1	0/46 (0%)	0
Urinary tract infection	0/110 (0%)	0	1/109 (0.9%)	1	1/46 (2.2%)	1
Viral infection	0/110 (0%)	0	0/109 (0%)	0	1/46 (2.2%)	1
Injury, poisoning and procedural complications
Spinal fracture	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Investigations
Platelet count decreased	0/110 (0%)	0	1/109 (0.9%)	1	1/46 (2.2%)	1
White blood cell count decreased	0/110 (0%)	0	0/109 (0%)	0	1/46 (2.2%)	1
Metabolism and nutrition disorders
Diabetes mellitus	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Glucose tolerance impaired	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Hyperglycaemia	0/110 (0%)	0	0/109 (0%)	0	1/46 (2.2%)	1
Hyponatraemia	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/110 (0.9%)	1	1/109 (0.9%)	1	0/46 (0%)	0
Back pain	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Musculoskeletal pain	1/110 (0.9%)	1	1/109 (0.9%)	1	0/46 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Nervous system disorders
Depressed level of consciousness	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Facial paralysis	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Headache	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Loss of consciousness	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Neuralgia	0/110 (0%)	0	1/109 (0.9%)	2	0/46 (0%)	0
Partial seizures	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Presyncope	0/110 (0%)	0	0/109 (0%)	0	1/46 (2.2%)	1
Seizure	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Spinal cord compression	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Psychiatric disorders
Confusional state	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Substance-induced psychotic disorder	0/110 (0%)	0	1/109 (0.9%)	1	0/46 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/110 (0.9%)	2	0/109 (0%)	0	0/46 (0%)	0
Pleural effusion	1/110 (0.9%)	1	2/109 (1.8%)	2	0/46 (0%)	0
Pulmonary embolism	1/110 (0.9%)	1	1/109 (0.9%)	1	0/46 (0%)	0
Skin and subcutaneous tissue disorders
Peau d'orange	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Urticaria	1/110 (0.9%)	1	0/109 (0%)	0	0/46 (0%)	0
Other (Not Including Serious) Adverse Events
	Olaparib Monotherapy		Olaparib + Ceralasertib		Olaparib + Adavosertib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	99/110 (90%)		106/109 (97.2%)		46/46 (100%)
Blood and lymphatic system disorders
Anaemia	36/110 (32.7%)	51	56/109 (51.4%)	99	23/46 (50%)	45
Leukopenia	5/110 (4.5%)	7	7/109 (6.4%)	12	8/46 (17.4%)	15
Neutropenia	10/110 (9.1%)	18	20/109 (18.3%)	29	19/46 (41.3%)	39
Thrombocytopenia	3/110 (2.7%)	3	12/109 (11%)	16	9/46 (19.6%)	23
Cardiac disorders
Palpitations	2/110 (1.8%)	2	3/109 (2.8%)	3	4/46 (8.7%)	4
Gastrointestinal disorders
Abdominal pain	2/110 (1.8%)	3	7/109 (6.4%)	10	6/46 (13%)	9
Abdominal pain upper	7/110 (6.4%)	9	7/109 (6.4%)	8	2/46 (4.3%)	3
Constipation	12/110 (10.9%)	15	17/109 (15.6%)	19	10/46 (21.7%)	13
Diarrhoea	16/110 (14.5%)	20	24/109 (22%)	44	25/46 (54.3%)	59
Dyspepsia	7/110 (6.4%)	7	6/109 (5.5%)	6	3/46 (6.5%)	4
Nausea	55/110 (50%)	75	64/109 (58.7%)	102	26/46 (56.5%)	42
Stomatitis	3/110 (2.7%)	3	8/109 (7.3%)	9	2/46 (4.3%)	2
Vomiting	34/110 (30.9%)	49	31/109 (28.4%)	49	15/46 (32.6%)	32
General disorders
Asthenia	26/110 (23.6%)	34	33/109 (30.3%)	41	7/46 (15.2%)	10
Fatigue	30/110 (27.3%)	36	32/109 (29.4%)	52	16/46 (34.8%)	26
Influenza like illness	0/110 (0%)	0	2/109 (1.8%)	2	3/46 (6.5%)	3
Oedema peripheral	4/110 (3.6%)	4	6/109 (5.5%)	6	3/46 (6.5%)	3
Pyrexia	6/110 (5.5%)	6	7/109 (6.4%)	10	6/46 (13%)	7
Infections and infestations
Upper respiratory tract infection	2/110 (1.8%)	2	2/109 (1.8%)	2	5/46 (10.9%)	6
Investigations
Alanine aminotransferase increased	8/110 (7.3%)	9	7/109 (6.4%)	8	7/46 (15.2%)	8
Aspartate aminotransferase increased	3/110 (2.7%)	3	5/109 (4.6%)	6	7/46 (15.2%)	7
Blood alkaline phosphatase increased	4/110 (3.6%)	4	2/109 (1.8%)	2	4/46 (8.7%)	6
C-reactive protein increased	3/110 (2.7%)	3	4/109 (3.7%)	4	4/46 (8.7%)	4
Lymphocyte count decreased	5/110 (4.5%)	5	3/109 (2.8%)	4	3/46 (6.5%)	4
Neutrophil count decreased	5/110 (4.5%)	6	8/109 (7.3%)	17	6/46 (13%)	12
Platelet count decreased	2/110 (1.8%)	6	10/109 (9.2%)	19	8/46 (17.4%)	16
Weight decreased	3/110 (2.7%)	3	3/109 (2.8%)	4	5/46 (10.9%)	5
White blood cell count decreased	3/110 (2.7%)	3	9/109 (8.3%)	15	8/46 (17.4%)	10
Metabolism and nutrition disorders
Decreased appetite	19/110 (17.3%)	23	22/109 (20.2%)	22	10/46 (21.7%)	13
Hypoalbuminaemia	0/110 (0%)	0	0/109 (0%)	0	3/46 (6.5%)	5
Musculoskeletal and connective tissue disorders
Arthralgia	7/110 (6.4%)	8	9/109 (8.3%)	12	6/46 (13%)	8
Back pain	11/110 (10%)	12	9/109 (8.3%)	11	5/46 (10.9%)	8
Myalgia	2/110 (1.8%)	2	6/109 (5.5%)	8	4/46 (8.7%)	5
Pain in extremity	7/110 (6.4%)	7	6/109 (5.5%)	6	3/46 (6.5%)	3
Nervous system disorders
Dizziness	8/110 (7.3%)	9	11/109 (10.1%)	12	3/46 (6.5%)	7
Headache	13/110 (11.8%)	19	16/109 (14.7%)	18	4/46 (8.7%)	7
Neuropathy peripheral	0/110 (0%)	0	2/109 (1.8%)	2	3/46 (6.5%)	5
Taste disorder	0/110 (0%)	0	0/109 (0%)	0	3/46 (6.5%)	3
Respiratory, thoracic and mediastinal disorders
Cough	10/110 (9.1%)	12	10/109 (9.2%)	11	5/46 (10.9%)	6
Dyspnoea	7/110 (6.4%)	9	11/109 (10.1%)	12	8/46 (17.4%)	11
Dyspnoea exertional	2/110 (1.8%)	2	0/109 (0%)	0	3/46 (6.5%)	4
Skin and subcutaneous tissue disorders
Erythema	3/110 (2.7%)	4	3/109 (2.8%)	4	3/46 (6.5%)	3
Vascular disorders
Hot flush	0/110 (0%)	0	3/109 (2.8%)	3	3/46 (6.5%)	3
Hypertension	2/110 (1.8%)	2	5/109 (4.6%)	9	3/46 (6.5%)	3

Limitations/Caveats

The interpretation of efficacy results of the adavosertib + olaparib arm and comparison with the olaparib monotherapy arm and ceralasertib + olaparib arm is limited due to the lower number of patients with available data in the adavosertib + olaparib arm, the nature of the analysis (intent-to-treat), and the fact that some of the patients switched from adavosertib + olaparib treatment to olaparib monotherapy.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Disclosure of which is prohibited without providing advance notice to AstraZeneca and opportunity to object.