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Olaparib

Mitogens

Adavosertib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

All randomized patients will receive Olaparib monotherapy 300 mg twice daily (BD).

All randomized patients will receive Olaparib 300 mg twice daily+Ceralasertib 160 mg once daily (OD).

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).

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).

Olaparib Continuous (28-Day cycle) 300 mg BD.

Patients will be administered Ceralasertib OD at 160 mg from Day 1 to Day 7 (inclusive) of every 28-day cycle.

Ceralasertib 160 mg OD + olaparib continuous 300 mg BD (28-day cycle).

Patients will be administered adavosertib BD at 150mg from Day 1 to Day 3 and Day 8 to Day 10.

Adavosertib 150 mg BD + olaparib 200 mg BD (21-day cycle).

Andrew Tutt, MB ChB PhD

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.

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.

Given the study treatment design (monotherapy and 2 different combination therapies will be employed) neither patients nor Investigators will be blinded to study treatment.

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

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).

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

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

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

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.

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.

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.

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.

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.

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.

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

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

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.

AstraZeneca

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.

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.

Olaparib Monotherapy

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.

Olaparib + Ceralasertib

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.

Olaparib + Adavosertib

Total

Age, Continuous

<40 Years

>=40 to <50 Years

>=50 to <65 Years

>=65 to <75 Years

>=75 Years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Full analysis set: All randomized patients were analyzed according to the randomization scheme, regardless of the treatment they actually received.

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.

Global Clinical Lead

BRCAm patients

non BRCAm 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.

Progression-free Survival Per Stratum (BICR)

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.

Progression-free Survival Per Stratum (Sensitivity Analysis)

HRRm patients per BICR

All patients per BICR

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.

Progression-free Survival (Per BICR)

BRCAm patients per BICR

non BRCAm HRRm patients per BICR

non HRRm patients per BICR

BRCAm patients per sensitivity analysis

non BRCAm HRRm per sensitivity analysis

non HRRm per sensitivity analysis

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

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

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.

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

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.

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

Overall Survival (OS)

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.

Plasma Drug Concentrations of Olaparib

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.

Plasma Drug Concentrations of Ceralasertib and Adavosertib

Any AE

Any AE causally related to olaparib

Any AE causally related to non-olaparib

Any AE causally related to non-olaparib and olaparib

Any AE with outcome = death

Any AE with outcome = death, causally related to olaparib

Any AE with outcome = death, causally related to non-olaparib

Any AE with outcome = death, causally related to non-olaparib and olaparib

Any SAE

Any SAE causally related to olaparib

Any SAE causally related to non-olaparib

Any SAE causally related to non-olaparib and olaparib

Any AE leading to discontinuation of study treatment

AEs leading to reduction of study treatment

AEs leading to reduction of olaparib

AEs leading to reduction of non-olaparib

AEs leading to reduction of non-olaparib and olaparib

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

Number of Patients With Treatment Emergent Adverse Events (TEAEs)

Overall Study

Patients With Deleterious Germline Mutation in BRCA 1/2 and HER2-negative, Metastatic or Locally Advanced Breast Cancer.

For each included patient, tumor biopsy specimen and blood samples will be collected at baseline visit (before the first dose of PARPi treatment).

During the treatment period: blood samples will be scheduled every 8 weeks (i.e. 2 cycles).

At the time of progression: tumor biopsy and blood samples will be collected.

Main study:

For each included patient, tumor biopsy specimen and blood samples will be collected as soon as possible after progression (before initiation of the post PARPi anti-tumoral treatment).

Sub-study:

Florence DALENC

Monica ARNEDOS

Georges EMILE

Xavier DURANDO

Sylvain LADOIRE

Frank PRIOU

Nawale HAJJAJI

Elise DELUCHE

Olivier TREDAN

Anthony GONCALVES

Cristian VILLANUEVA

William JACOT

Frédéric FITENI

Jean-Philippe SPANO

Luis TEIXEIRA

Joseph GLIGOROV

Juliette MAINGUENE

Anne-Claire HARDY-BESSARD

Nicolas ISAMBERT

Thibault DE LA MOTTE ROUGE

Jean-Sébastien FRENEL

Gilles FREYER

Hélène VEGAS

Anne KIEFFER

Suzette DELALOGE

The purpose of this study is to assess whether expression of not only POLQ/Polθ, but also Shieldin complex and/or 53BP1 are correlated with primary and/or acquired resistance to PARPi (Poly(ADP-Ribose) Polymerases inhibitors) in a sub-population of locally advanced or metastatic breast cancer patients and vary regarding type and location of gBRCA1/2 mutations.

This translational research program is composed of two multicentric, non-randomized prospective studies in patients with HER2-negative locally advanced or metastatic breast cancer:

* The main study concerns 80 patients eligible for PARPi (according to the investigators).PARPi treatments (talazoparib or olaparib) will be administered and dosed according to the standard of care administration.
* The sub-study concerns 40 patients in progression disease under PARPi alone.

For each included patient in the main study or sub-study, tumor biopsy specimen and blood samples will be collected at different times during the study.

Study Evaluating DNA Double-strand Breaks (DSBs) REpair Factors (POLQ, Shieldin Complex and 53BP1) Expression as Biomarker of PARP Inhibitor Resistance in Patients With Deleterious Germline Mutation in BRCA 1/2 and HER2-negative, Metastatic or Locally Advanced Breast Cancer.

Prospective and Multicentric Study Evaluating DNA Double-strand Breaks (DSBs) REpair Factors (POLQ, Shieldin Complex and 53BP1) Expression as Biomarker of PARP Inhibitor Resistance in Patients With Deleterious Germline Mutation in BRCA 1/2 and HER2-negative, Metastatic or Locally Advanced Breast Cancer.

Progression will be determined using RECIST v1.1 criteria.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
To Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.	NCT03330847	Metastatic Trip...	Olaparib Contin... Ceralasertib 16... Adavosertib 150...	18 Years - 130 Years	AstraZeneca
Study Evaluating DNA Double-strand Breaks (DSBs) REpair Factors (POLQ, Shieldin Complex and 53BP1) Expression as Biomarker of PARP Inhibitor Resistance in Patients With Deleterious Germline Mutation in BRCA 1/2 and HER2-negative, Metastatic or Locally Advanced Breast Cancer.	NCT05378204	Breast Cancer	Main study: Sub-study:	18 Years -	Institut Claudius Regaud

Spots Global Cancer Trial Database for germline brca mutation