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| Profile Name | ATM L1874F |
| Gene Variant Detail | |
| Relevant Treatment Approaches | Olaparib |
| 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 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... |