34O - ATR inhibitor alone (ceralasertib) or in combination with olaparib in gynaecological cancers with ARID1A loss or no loss - results from the ENGOT/GYN1/NCRI ATARI trial

Background

Clinical outcomes for rare subtypes of relapsed gynaecological cancers (GC) including ovarian clear cell carcinomas (CCC) and carcinosarcomas (CS) are poor with limited treatment options. Preclinical data demonstrate GC with deleterious ARID1A mutations (and thus ARID1A-protein loss) display increased sensitivity to ATR inhibition. In the absence of ARID1A mutations, ATR inhibitor sensitivity can be enhanced by combination with PARP inhibitors. ATARI is an academic, international, parallel cohort platform phase II trial assessing ceralasertib (CERA) in ARID1A stratified GC.

Methods

Relapsed CCC (ovarian OCCC/endometrial ECCC) patients (pts) with ARID1A loss received CERA alone (160 mg BD day (D) 1-14 of 28D cycle) (Cohort 1A); CCC with ARID1A no loss (Cohort 2) and other non-CCC histological subtypes (endometrioid, CS, cervical) CERA (160 mg OD D1-7) and olaparib (300 mg BD, D1-28) (Cohort 3). Primary endpoint is best overall objective response rate (ORR, RECIST v1.1); key secondary endpoints include disease control rate (DCR) and progression free survival (PFS). Each cohort recruited 29 pts under a Simon 2-stage design (p0=0.1, p1=0.3, alpha=5%, power=80%, 6+ responses to be observed).

Results

We report efficacy results of the first 29 evaluable pts per cohort. Grade 3+ toxicities (safety population) were 47% (1A n=36), 41% (2 n=32), 39% (3 n=33); most common anaemia (1A 36%, 2 19%,3 27%) & any other <10%. Discontinuation rates due to AEs were ≤10% in all cohorts. Preliminary translational results will be presented. Table: 34O

Antitumour activity results

FU: follow-up; wk: weeks; yr: years; DOR: duration OR; SD: stable disease; P25-P75: 1^st& 3^rdquartiles; CI: confidence interval

Conclusions

Celarasertib alone or in combination with olaparib has relevant clinical activity in rare gynae cancers. Demonstrable activity for combination in the non-clear cell ‘basket’ cohort, including carcinosarcoma, provides hypothesis-generating evidence for further investigation.

Clinical trial identification

NCT04065269.

Legal entity responsible for the study

The Institute of Cancer Research.

Funding

AstraZeneca UK Limited.

Disclosure

S. Banerjee: Financial Interests, Personal, Advisory Board: Amgen, Immunogen, Mersana, Merck Sereno, MSD, Roche, AstraZeneca, GSK, Oncxerna, Shattuck Labs, Novartis, Epsilogen, Seagen, Eisai; Financial Interests, Personal, Invited Speaker: Clovis, Pfizer, AstraZeneca, GSK, Takeda, Amgen, Medscape, Research to Practice, Peerview; Financial Interests, Personal, Stocks/Shares: PerciHealth; Financial Interests, Institutional, Research Grant: AstraZeneca, GSK; Non-Financial Interests, Personal, Principal Investigator, Phase II clinical trial Global lead, ENGOTov60/GOG3052/RAMP201: Verastem; Non-Financial Interests, Personal, Principal Investigator, ENGOT-GYN1/ATARI phase II international trial (academic sponsored): AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, Academic sponsored trial PI (MONITOR-UK): GSK; Non-Financial Interests, Personal, Other, Member of membership committee: ESGO; Non-Financial Interests, Personal, Advisory Role, Medical advisor to UK ovarian cancer charity: Ovacome Charity. A. Leary: Financial Interests, Personal, Advisory Board: Zentalis; Financial Interests, Personal, Invited Speaker, Educational: GSK, Medscape, Onko+; Financial Interests, Institutional, Other, Steering committee: MSD; Financial Interests, Institutional, Advisory Board: GSK, AstraZeneca, Clovis, Ability Pharma, MSD, Tesaro, Merck Serono, Apmonia, Blueprint; Financial Interests, Institutional, Invited Speaker, Educational: Kephren publishing; Financial Interests, Institutional, Other, Consultancy: Orion; Financial Interests, Institutional, Invited Speaker: Tesaro, AstraZeneca, Clovis; Financial Interests, Personal, Other, Consultancy: GLG; Financial Interests, Institutional, Research Grant, PI translational research: ARCAGY-GINECO, Sanofi, AstraZeneca; Financial Interests, Institutional, Funding, CI clinical trial: AstraZeneca; Financial Interests, Institutional, Research Grant, Int CI clinical trial: OSE immuno; Financial Interests, Institutional, Funding, PI clinical trial: Agenus, BMS, Iovance, GSK; Financial Interests, Institutional, Funding, PI 5 clinical trials: Roche; Financial Interests, Institutional, Funding, PI 2 clinical trials: AstraZeneca; Financial Interests, Institutional, Funding, PI 3 clinical trials and steering committee: MSD; Non-Financial Interests, Institutional, Other, Academic research project: Owkin, LXRepair; Non-Financial Interests, Personal, Proprietary Information, IDMC member: Clovis; Non-Financial Interests, Personal, Proprietary Information, IDMC chair: Pfizer. S. Lheureux: Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Eisai, Merck, Novartis; Financial Interests, Personal, Invited Speaker: GSK, Roche; Financial Interests, Institutional, Research Grant, Academic trial: GSK; Financial Interests, Institutional, Invited Speaker: Repare Therapeutics, Merck, AstraZeneca, Regeneron, GSK, Roche, Seagen; Financial Interests, Institutional, Research Grant: Roche. A.R. Clamp: Financial Interests, Personal, Invited Speaker: Clovis Oncology, AstraZeneca; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Merck, Verastem, Novartis, Advenchen Laboratories, AstraZeneca; Non-Financial Interests, Personal, Advisory Role: National Institute of Health and Care Excellence. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, Adaptimmune, Eisai, SUTRO, BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Personal, Principal Investigator: PAOLA1; Non-Financial Interests, Personal, Other, President: GINECO. C. Gourley: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board, Both personal and institutional: AstraZeneca, MSD, GlaxoSmithKline; Financial Interests, Personal, Invited Speaker, Both personal and institutional: AstraZeneca, MSD, GSK, Clovis, Chugai, Takeda; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis, Aprea, Nucana, Medannexin; Financial Interests, Institutional, Invited Speaker: GlaxoSmithKline, BerGenBio. R.M. Glasspool: Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Clovis Oncology, MSD, Immunogen, Sotio; Financial Interests, Institutional, Other, Institutional Consultancy fees: Novartis; Financial Interests, Institutional, Research Grant: Clovis Ongocology, Lilly/Ignyta, Boehringer Ingelheim; Financial Interests, Personal, Other, Conference fees for medical conferences: GSK; Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca, GSK, Novartis, Oncology Venture, Clovis Oncology. R. Natrajan: Financial Interests, Institutional, Research Grant: Pfizer. C. Lord: Financial Interests, Institutional, Research Grant: AstraZeneca, Merck KGaA; Financial Interests, Personal, Advisory Board: Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, Artios, Abingworth, Tesselate, Dark Blue Therapeutics, Pontifax, Astex, Neophore, GSK; Financial Interests, Personal, Stocks/Shares: Tango, Ovibio, Hysplex, Tesselate; Financial Interests, Personal and Institutional, Proprietary Information, Rewards to Inventors scheme: Institute of Cancer Research. All other authors have declared no conflicts of interest.