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. 2021 Nov;31(11):1471-1475.
doi: 10.1136/ijgc-2021-002973. Epub 2021 Sep 13.

ATARI trial: ATR inhibitor in combination with olaparib in gynecological cancers with ARID1A loss or no loss (ENGOT/GYN1/NCRI)

Susana Banerjee  1   2 , James Stewart  3   4 , Nuria Porta  5 , Christy Toms  5 , Alexandra Leary  6 , Stephanie Lheureux  7 , Saira Khalique  3   4 , Jeremy Tai  3 , Ayoma Attygalle  3 , Katherine Vroobel  3 , Christopher J Lord  4 , Rachael Natrajan  4 , Judith Bliss  5
Affiliations

ATARI trial: ATR inhibitor in combination with olaparib in gynecological cancers with ARID1A loss or no loss (ENGOT/GYN1/NCRI)

Susana Banerjee et al. Int J Gynecol Cancer. 2021 Nov.

Abstract

Background: ARID1A (AT-rich interactive domain containing protein 1A) loss-of-function mutations have been reported in gynecological cancers, including rarer subtypes such as clear cell carcinoma. Preclinical studies indicate that ARID1A mutant cancers display sensitivity to ATR inhibition while tumors without ARID1A mutations may be sensitive to Ataxia telangiectasia and Rad3 related (ATR) inhibitors in combination with poly-ADP ribose polymerase (PARP) inhibitors.

Primary objective: To determine whether the ATR inhibitor, ceralasertib, has clinical activity as a single agent and in combination with the PARP inhibitor, olaparib, in patients with ARID1A 'loss' and 'no loss' clear cell carcinomas and other relapsed gynecological cancers.

Study hypothesis: ARID1A deficient clear cell carcinoma of the ovary or endometrium is sensitive to ATR inhibition, while the combination of ATR and PARP inhibition has activity in other gynecological tumors, irrespective of ARID1A status.

Trial design: ATARI (ENGOT/GYN1/NCRI) is a multicenter, international, proof-of-concept, phase II, parallel cohort trial assessing ceralasertib activity as a single agent and in combination with olaparib in ARID1A stratified gynecological cancers. Patients with relapsed ovarian/endometrial clear cell carcinoma with ARID1A loss will receive ceralasertib monotherapy (cohort 1A). Relapsed ovarian/endometrial clear cell carcinoma patients with no ARID1A loss (cohort 2) or patients with other histological subtypes (endometrioid, carcinosarcoma, cervical) (cohort 3) will receive combination therapy (olaparib/ceralasertib). Treatment will continue until disease progression.

Major inclusion/exclusion criteria: Patients with histologically confirmed recurrent clear cell (ovarian, endometrial, or endometriosis related), endometrioid (ovarian, endometrial, or endometriosis related), cervical (adenocarcinomas or squamous), or carcinosarcomas (ovarian or endometrial) are eligible. Patients progressing after ≥1 prior platinum with evidence of measurable (RECIST v1.1) radiological disease progression since last systemic anticancer therapy and prior to trial entry are eligible. Previous ATR or PARP inhibitor treatment is not permissible.

Primary endpoint: Best overall objective response rate (RECIST v1.1).

Sample size: A minimum of 40 and a maximum of 116.

Estimated dates for completing accrual and presenting results: Accrual is anticipated to be complete by the second quarter of 2022, with reporting of results by the fourth quarter of 2022. Overall accrual targets and reporting timelines are dependent on individual cohort progression to stage 2.

Trial registration number: NCT0405269.

Keywords: cervical cancer; endometrial neoplasms; ovarian cancer.

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Conflict of interest statement

Competing interests: SB, NP, CT, AL, SL, and JB report that their institutional departments have received grants from AstraZeneca for costs or consumables to support the research relating to this manuscript. SB reports grants and non-financial support from AstraZeneca, Tesaro, and GSK outside of this manuscript, and non-financial support from Amgen, AstraZeneca, Epsilogen, GSKm Genmab, Immunogen, Mersana, MSD, Merck Serono, Oncxerna, Pfizer, Roche, Tesaro, Clovis, and Takeda outside of this manuscript. AL reports grants and non-financial support from AstraZeneca, Tesaro, Clovis, MSD, Biocad, Ability, Merck Serono, Seattle Genetics, GSK, and Zentalis, outside of this manuscript. SL reports grants and non-financial support from AstraZeneca, GSK, Roche, Refeneron, Merck, Repare, Eisai, and Movocure outside of this manuscript. CJL reports grants and non-financial support from AstraZeneca, Merck KGaA, Artios, Suncona, Sun Pharma, Gerson Lehrman Group, Vertex, Tano, 3rd Rock, Ono Pharma, and Abingworth outside of this manuscript. CJL also reports stock in Tango, Ovibio, and is a named inventor on patents describing the use of DNA repair inhibitors. JB reports grants and non-financial support from AstraZeneca, Merck Sharp & Dohme, Puma Biotechnology, Clovis Oncology, Pfizer, Janssen-Cilag, Novartis, Roche, and Eli Lilley, outside of this manuscript.

Figures

Figure 1
Figure 1
ATARI trial design.
See this image and copyright information in PMC

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