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Ref Type Journal Article
PMID (34527850)
Authors Mahdi H, Hafez N, Doroshow D, Sohal D, Keedy V, Do KT, LoRusso P, Jürgensmeier J, Avedissian M, Sklar J, Glover C, Felicetti B, Dean E, Mortimer P, Shapiro GI, Eder JP
Title Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations).
Journal JCO precision oncology
Vol 5
Issue
Date 2021
URL
Abstract Text Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapy in cancers with homologous recombination repair deficiency. However, efficacy is limited by both intrinsic and acquired resistance. The Olaparib Combinations basket trial explored olaparib alone and in combination with other homologous recombination-directed targeted therapies. Here, we report the results of the arm in which olaparib was combined with the orally bioavailable ataxia telangiectasia and RAD3-related inhibitor ceralasertib in patients with relapsed or refractory cancers harboring DNA damage response and repair alterations, including patients with BRCA-mutated PARP inhibitor-resistant high-grade serous ovarian cancer (HGSOC).Germline and somatic mutations had to be deleterious by COSMIC or ClinVar for eligibility. Olaparib was administered at 300 mg twice daily and ceralasertib at 160 mg daily on days 1-7 in 28-day cycles until progression or unacceptable toxicities. Primary end points were confirmed complete response (CR) or partial response (PR) rates and clinical benefit rate (CBR; CR + PR + stable disease [SD] at 16 weeks).Twenty-five patients were enrolled, with median four prior therapies. Five patients required dose reductions for myelosuppression. Overall response rate was 8.3% and CBR was 62.5% among the entire cohort. Two of five patients with tumor harboring ATM mutation achieved CR or SD ongoing at 24+ months, respectively (CBR 40%). Of seven patients with PARP inhibitor-resistant HGSOC, one achieved PR (-90%) and five had SD ranging 16-72 weeks (CBR 86%).Olaparib with ceralasertib demonstrated preliminary activity in ATM-mutated tumors and in PARP inhibitor-resistant BRCA1/2-mutated HGSOC. These data warrant additional studies to further confirm activity in these settings.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM LOH ATM inact mut estrogen-receptor positive breast cancer predicted - sensitive Ceralasertib + Olaparib Case Reports/Case Series Actionable In a Phase II trial (OLAPCO), Ceralasertib (AZD6738) and Lynparza (olaparib) combination treatment resulted in an ongoing complete response for over 26 months in a patient with estrogen receptor–positive metastatic breast cancer harboring germline ATM mutation with accompanying loss of heterozygosity (LOH) (PMID: 34527850; NCT02576444). 34527850
ATM inact mut Advanced Solid Tumor predicted - sensitive Ceralasertib + Olaparib Case Reports/Case Series Actionable In a Phase II trial (OLAPCO), Ceralasertib (AZD6738) and Lynparza (olaparib) combination treatment resulted in an overall response rate of 20% (1/5) and a clinical benefit rate of 40% (2/5) in patients with advanced solid tumors harboring ATM inactivating mutations, including a durable complete response in a patient with breast cancer and a durable stable disease in a patient with adenoid cystic carcinoma of minor salivary gland (PMID: 34527850; NCT02576444). 34527850
ATM P1069fs ATM LOH salivary gland adenoid cystic carcinoma predicted - sensitive Ceralasertib + Olaparib Case Reports/Case Series Actionable In a Phase II trial (OLAPCO), Ceralasertib (AZD6738) and Lynparza (olaparib) combination treatment resulted in an ongoing 22% reduction in target lesions in a patient with adenoid cystic carcinoma of minor salivary gland harboring germline ATM P1069fs with accompanying loss of heterozygosity (LOH), who remained on treatment for over 26 months (PMID: 34527850; NCT02576444). 34527850