Molecular Profile Detail

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Profile Name ATM W57*
Gene Variant Detail

ATM W57* (loss of function - predicted)

Relevant Treatment Approaches Olaparib

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM inact mut lymphoid leukemia sensitive Olaparib Preclinical - Patient cell culture Actionable In a preclinical study, lymphoblastoid cell lines with ATM inactivation derived from ataxia-telangiectasia patients demonstrated increased sensitivity to Lynparza (olaparib) in culture, compared to ATM wild-type cell lines (PMID: 20739657). 20739657
ATM mutant prostate cancer sensitive Olaparib Phase II Actionable In a Phase II clinical trial, 80% (4/5) of metastatic castration-resistant prostate cancer patients with ATM truncation mutations demonstrated response to Lynparza (olaparib) treatment (Cancer Res August 1, 2015 75:CT322). detail...
ATM inact mut Advanced Solid Tumor sensitive E7449 Preclinical Actionable In a preclinical study, E7449 inhibited proliferation of a ATM-deficient cell line in culture, which demonstrated increased sensitivity compared to cells without DNA repair pathway mutations (PMID: 26513298). 26513298
ATM inact mut mantle cell lymphoma sensitive Olaparib Preclinical - Cell line xenograft Actionable In a preclinical study, a mantle cell lymphoma cell line with ATM inactivation demonstrated sensitivity to Lynparza (olaparib) in culture and in xenograft models (PMID: 20739657). 20739657
ATM inact mut chronic lymphocytic leukemia sensitive Olaparib Preclinical - Patient cell culture Actionable In a preclinical study, patient-derived chronic lymphocytic leukemia cells with inactivating mutations in ATM, that had been induced to proliferate in culture, demonstrated increased sensitivity to growth inhibition by Lynparza (olaparib) compared to ATM wild-type cells (PMID: 20739657). 20739657
ATM inact mut mantle cell lymphoma sensitive Bendamustine + Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) sensitized a mantle cell lymphoma cell line harboring an ATM inactivating mutation to Treanda (bendamustine) in cell culture, resulting in growth inhibition (PMID: 20739657). 20739657
ATM inact mut mantle cell lymphoma sensitive Olaparib + Valproic acid Preclinical - Cell culture Actionable In a preclinical study, the combination of Lynparza (olaparib) and valproic acid worked synergistically to inhibit growth of a mantle cell lymphoma cell line harboring an ATM inactivating mutation in culture (PMID: 20739657). 20739657
ATM inact mut mantle cell lymphoma sensitive Fludarabine + Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) sensitized a mantle cell lymphoma cell line harboring an ATM inactivating mutation to Fludara (fludarabine) in cell culture, resulting in decreased cell survival (PMID: 20739657). 20739657
ATM inact mut Advanced Solid Tumor sensitive Veliparib Preclinical - Cell culture Actionable In a preclinical study, an ATM-deficient cell line demonstrated increased sensitivity to Veliparib (ABT-888) compared to an ATM-reconstituted cell line, in culture (PMID: 21300883). 21300883
ATM mutant mantle cell lymphoma predicted - sensitive Ibrutinib + Venetoclax Phase II Actionable In a Phase II trial (AIM), distinct molecular profiles were identified in mantle cell lymphoma patients responded to Imbruvica (ibrutinib) and Venclexta (venetoclax) combination therapy compared to those did not respond, with all patients harboring mutations in NSD2 (n=4), UBR5 (n=3), KMT2D (n=3), and 12 of 13 patients harboring mutations in ATM responded to the therapy, while SMARCA4 (n=4), CCND1 (n=2), and NOTCH1 (n=3) alterations were exclusively observed in nonresponders (PMID: 30455436; NCT02471391). 30455436
ATM inact mut Advanced Solid Tumor predicted - sensitive BAY1895344 Phase I Actionable In a Phase I trial, BAY1895344 treatment was tolerated and resulted in an objective response rate of 36.4% (4/11, all partial responses) and a disease control rate of 63.6% (7/11) in patients with advanced solid tumors harboring ATM inactivating mutations and/or ATM protein expression loss (PMID: 32988960; NCT03188965). 32988960
ATM inact mut prostate cancer sensitive Olaparib Phase II Actionable In a Phase II trial (TOPARP-B), Lynparza (olaparib) treatment resulted in a composite overall response rate of 36.8% (7/19) and a RECIST objective response rate of 8.3% (1/12) in patients with castration-resistant prostate cancer harboring deleterious ATM mutations (PMID: 31806540; NCT01682772). 31806540
ATM inact mut prostate cancer no benefit Rucaparib Phase II Actionable In a Phase II trial (TRITON2), activity of Rubraca (rucaparib) was limited in the cohort of patients with metastatic castrate-resistant prostate cancer harboring an ATM mutation presumed to be inactivating, with a radiographic response rate of 10.5% (2/19, including 1 patient with co-occurring CHEK2 alteration) and PSA response rate of 4.1% (2/49), and no radiographic responses in 11 patients with biallelic alterations in ATM or 11 patients with germline ATM alterations (PMID: 32086346; NCT02952534). 32086346
ATM inact mut prostate cancer sensitive Olaparib FDA approved - On Companion Diagnostic Actionable In a Phase III trial (PROfound) that supported FDA approval, Lynparza (olaparib) improved progression-free survival (7.4 vs 3.6 mo, HR 0.34, p<0.001), objective response rate (33% vs 2%, OR 20.86, p<0.001), and median overall survival (18.5 vs 15.1 mo, HR 0.64, p=0.02) compared to control in metastatic castration-resistant prostate cancer patients harboring deleterious or suspected deleterious BRCA or ATM mutations, HR for progression or death was 1.04 in ATM-mutant patients (PMID: 32343890; NCT02987543). detail... 32343890 detail...
ATM inact mut prostate cancer sensitive Olaparib Guideline Actionable Lynparza (olaparib) is included in guidelines as second-line therapy post androgen receptor-directed therapy for patients with metastatic castration-resistant prostate cancer harboring pathogenic mutations in ATM (NCCN.org). detail...
ATM inact mut Advanced Solid Tumor predicted - sensitive Radiotherapy Clinical Study Actionable In a clinical study, treatment with radiotherapy resulted in greater therapeutic efficacy in advanced solid tumor patients harboring an ATM inactivating mutation (n=177) compared to those who harbored an ATM variant of unknown significance (n=180), demonstrating a significantly decreased 2-year cumulative incidence of irradiated progression, 13.2% versus 27.5% (p=0.001), respectively, and the greatest clinical benefit was observed in tumors with bi-allelic ATM inactivating mutations (PMID: 32726432). 32726432
ATM mutant breast cancer no benefit Olaparib Case Reports/Case Series Actionable In a Phase II trial (TBCRC 048), Lynparza (olaparib) treatment did not result in an objective response in 4 patients with metastatic breast cancer harboring only germline mutations in ATM (PMID: 33119476; NCT03344965). 33119476
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 inact mut Advanced Solid Tumor predicted - sensitive RP-3500 Case Reports/Case Series Actionable In a Phase I/II trial (TRESR), RP-3500 treatment resulted in a response rate of 12% (13/113), clinical benefit rate (CBR) of 42% (47/113) and median progression-free survival (mPFS) of 15 weeks in advanced solid tumor patients with inactivating mutations in DNA damage repair genes, including ATM with a CBR of 44.1% (15/34) and CBR was 54% (7/13) with biallelic vs 11% (1/9) with monoallelic ATM inactivation, and CBR of 75% and mPFS of 35 weeks in 20 ovarian cancer patients (PMID: 37277454; NCT04497116). 37277454
ATM mutant Advanced Solid Tumor conflicting Olaparib Phase II Actionable In a Phase II trial (TAPUR), Lynparza (olaparib) treatment resulted in an objective response rate of 8% and a disease control rate of 25% (9/36, 1 complete response, 2 partial responses, 6 stable disease at 16+ weeks) in patients with advanced solid tumors harboring ATM mutations (Cancer Res 2022;82(12_Suppl):Abstract nr CT110; NCT02693535). detail...
ATM inact mut transitional cell carcinoma predicted - sensitive Durvalumab + Olaparib Case Reports/Case Series Actionable In a Phase II trial (BAYOU), Lynparza (olaparib) and Imfinzi (durvalumab) improved median progression-free survival (5.6 vs 1.8 mo, HR 0.18) compared to Imfinzi (durvalumab) and placebo in a subgroup of patients with metastatic urothelial carcinoma harboring inactivating mutations in DNA damage repair genes (n=17), with 8.5% of the tumors harboring ATM inactivating mutations (PMID: 35737919; NCT03459846). 35737919
ATM inact mut Advanced Solid Tumor no benefit Avelumab + Talazoparib Phase II Actionable In a Phase II trial (JAVELIN), Talzenna (talazoparib) and Bavencio (avelumab) combination therapy did not meet the prespecified futility requirement with a confirmed objective response rate of 4.9% (2/41, 2 partial responses) in patients with advanced solid tumors harboring ATM inactivating mutations, and subsequently, enrollment to the cohort was discontinued (PMID: 36394867; NCT03565991). 36394867
ATM inact mut prostate cancer no benefit Rucaparib Phase III Actionable In a Phase III trial (TRITON3), Rubraca (rucaparib) treatment demonstrated limited efficacy compared to control treatment with Taxotere (docetaxel) in patients with metastatic castration-resistant prostate cancer harboring deleterious ATM mutations, with a median imaging-based progression-free survival of 8.1 months vs. 6.8 months (HR=0.95), a median overall survival of 21.1 months vs. 21.7 months of patients (PMID: 36795891; NCT02975934). 36795891
ATM inact mut prostate cancer sensitive Enzalutamide + Talazoparib FDA approved Actionable In a Phase III trial (TALAPRO-2) that supported FDA approval, Talzenna (talazoparib) plus Xtandi (enzalutamide) improved median radiographic progression-free survival compared to enzalutamide plus placebo (27.9 vs 16.4 mo, HR 0.46, p=0.0003) in patients with metastatic castration-resistant prostate cancer harboring deficient homologous recombination repair genes including ATM, with an HR of 0.66 (p=0.12) in patients with non-BRCA mutations treated with Talzenna (talazoparib) (PMID: 37285865; NCT03395197). detail... 37285865
ATM inact mut prostate cancer sensitive Enzalutamide + Talazoparib Guideline Actionable Talzenna (talazoparib) plus Xtandi (enzalutamide) is included in guidelines as systemic therapy for patients with metastatic castration-resistant prostate cancer harboring a pathogenic germline or somatic ATM mutation who have not been treated in the setting of castration-resistant prostate cancer (NCCN.org). detail...
ATM mutant Advanced Solid Tumor conflicting Olaparib Phase II Actionable In a Phase II trial, Lynparza (olaparib) treatment did not demonstrate clinical activity in patients with advanced solid tumors harboring ATM (n=13) or CHEK2 (n=14) mutations (Ann Oncol (2023) 34 (suppl_2): S242; NCT03967938). detail...
ATM inact mut Advanced Solid Tumor no benefit Ipilimumab + Nivolumab Phase II Actionable In a Phase II trial (TAPUR), Opdivo (nivolumab) and Yervoy (ipilimumab) combination treatment did not meet predetermined efficacy criteria in patients with advanced solid tumors harboring ATM mutations, resulting in an objective response rate of 14% (4/29, 1 complete and 3 partial responses), a disease control rate of 24% (7/29), with stable disease of at least 16 weeks in 3 patients, a median progression-free survival of 9 weeks, and median overall survival of 28 weeks (PMID: 38039429; NCT02693535). 38039429
ATM inact mut lung non-small cell carcinoma predicted - sensitive Ceralasertib + Durvalumab Phase II Actionable In a Phase II trial (HUDSON), treatment with the combination of Imfinzi (durvalumab) and Ceralasertib (AZD6738) demonstrated efficacy in patients with advanced non-small cell lung cancer harboring inactivating ATM mutations, with an objective response rate of 26.1% (6/23, all partial responses), a median progression-free survival of 8.4 months, and a median overall survival of 22.8 months (PMID: 38351187; NCT03334617). 38351187
ATM inact mut Advanced Solid Tumor predicted - sensitive Radiotherapy + RP-3500 Case Reports/Case Series Actionable In a Phase I trial, the addition of RP-3500 to radiotherapy treatment resulted in metabolic complete responses in two patients with advanced solid tumors harboring ATM inactivating mutations (Cancer Res (2024) 84 (1_Supplement): A002, NCT05566574). detail...
ATM mutant prostate cancer not applicable N/A Guideline Risk Factor Germline ATM mutations are associated with increased risk of developing prostate cancer (NCCN.org). detail...