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

Banerjee, S.; Leary, A.; Stewart, J.R.; Dewan, M.; Lheureux, S.; Clamp, A.R.; Ray-Coquard, I.L.; Selle, F.; Gourley, C.; Glasspool, R.M.; Bowen, R.; Attygalle, A.; Vroobel, K.; Tunariu, N.; Wilkinson, K.; Toms, C.; Natrajan, R.; Bliss, J.; Lord, C.; Porta, N.

doi:10.1016/j.esmoop.2023.100814

Cited by 7 publications

(3 citation statements)

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“…Of 2 patients with protein loss, 1 responded and 1 had SD, suggesting other factors may also be involved. Durable responses have been reported in patients with ARID1A loss in ongoing clinical studies (38,39). Other components, such as ARID2, may also be associated with clinical benefit, as suggested by the durable SD in a participant with ARID2 loss.…”

Section: Discussionmentioning

confidence: 89%

Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation

Dillon,

Guevara,

Mohammed

et al. 2024

Journal of Clinical Investigation

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BACKGROUND P hase 1 study of ATR i nhibition al o ne or with radiation t herapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors. METHODS The primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20–240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle). RESULTS Intermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40–240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage–response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding. CONCLUSION Ceralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity. TRIAL REGISTRATION Clinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84. FUNDING Cancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.

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Section: Discussionmentioning

confidence: 89%

Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation

Dillon,

Guevara,

Mohammed

et al. 2024

Journal of Clinical Investigation

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“…The combination of ceralasertib and olaparib has also been evaluated in rare gynecological cancers in the open-label phase 2 ATARI trial (n = 78). In this study, outcomes were similar in patients with clear cell histology with or without AT-rich interactive domaincontaining protein 1A (ARID1A) loss (ORR: 14% vs. 14%, median PFS: 3.6 vs. 3.5 months), while the clinical activity of the combination therapy may be higher in those with non-clear cell histologies (ORR: 24%, median PFS: 5.6 months) [139].…”

Section: Gynecological Cancersmentioning

confidence: 64%

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes

Mavroeidi,

Georganta,

Panagiotou

et al. 2024

Preprint

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The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system and their interplay and therefore potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

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“…The combination of ceralasertib and olaparib has also been evaluated in rare gynecological cancers in the open-label phase 2 ATARI trial ( n = 78). In this study, outcomes were similar in patients with clear cell histology with or without AT-rich interactive domain-containing protein 1A (ARID1A) loss (ORR: 14% vs. 14%, median PFS: 3.6 vs. 3.5 months), while the clinical activity of the combination therapy may be higher in those with non-clear cell histologies (ORR: 24%, median PFS: 5.6 months) [ 139 ].…”

Section: The Atr Pathway As a Therapeutic Targetmentioning

confidence: 99%

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes

Mavroeidi,

Georganta,

Panagiotou

et al. 2024

IJMS

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The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing a reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry, and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system, and their interplay and, therefore, potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.

show abstract

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

Cited by 7 publications

References 0 publications

Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation

Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes

Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes

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