Molecular Profile Detail

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Profile Name CHEK2 D347N
Gene Variant Detail

CHEK2 D347N (loss of function)

Relevant Treatment Approaches Olaparib

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CHEK2 mutant prostate cancer not applicable N/A Guideline Risk Factor Germline CHEK2 mutations are associated with increased risk of developing prostate cancer (NCCN.org). detail...
CHEK2 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 a CHEK2 mutation presumed to be inactivating, with a radiographic partial response in 1 patient who had a co-occurring ATM alteration out of 9 evaluable patients, and PSA response rate of 16.7% (2/12), and a clinical benefit rate of 37.5% (3/8) at 6 months, with no patients remaining on treatment at 12 months (PMID: 32086346; NCT02952534). 32086346
CHEK2 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 median imaging-based progression-free survival (5.8 vs 3.5 mo, HR 0.49, p<0.001) compared to control in metastatic castration-resistant prostate cancer patients harboring deleterious or suspected deleterious mutations in homologous recombination repair genes who progressed on hormone therapy, HR for progression or death was 0.87 in CHEK2-mutant patients (PMID: 32343890; NCT02987543). detail... detail... 32343890
CHEK2 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 CHEK2 (NCCN.org). detail...
CHEK2 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 7 patients with metastatic breast cancer harboring only germline mutations in CHEK2 (PMID: 33119476; NCT03344965). 33119476
CHEK2 inact mut prostate cancer predicted - sensitive Abiraterone + Niraparib + Prednisone Phase III Actionable In a Phase III trial (MAGNITUDE), Zejula (niraparib) in combination with Zytiga (abiraterone) and Adasone (prednisone) (AAP) improved radiographic progression-free survival (HR 0.64) compared to placebo and AAP in patients with metastatic castration-resistant prostate cancer harboring inactivating mutations in the homologous recombination repair (HRR)-associated genes (CHEK2 or HDAC2), with a HR of 0.66 in patients with CHEK2 mutations (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 5020; NCT03748641). detail...
CHEK2 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 CHEK2, with an HR of 0.66 (p=0.12) in patients with non-BRCA mutations treated with Talzenna (talazoparib) (PMID: 37285865; NCT03395197). detail... 37285865
CHEK2 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 CHEK2 mutation who have not been treated in the setting of castration-resistant prostate cancer (NCCN.org). detail...
CHEK2 mutant Advanced Solid Tumor no benefit 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...
CHEK2 mutant breast cancer not applicable N/A Guideline Risk Factor Germline CHEK2 mutations are associated with increased risk of developing breast cancer (NCCN.org). detail...
CHEK2 inact mut prostate cancer no benefit unspecified PARP inhibitor Clinical Study - Meta-analysis Actionable In a combined analysis of 6 clinical trials, PARP inhibitor therapy did not benefit patients with metastatic castration-resistant prostate cancer harboring CHEK2 mutations compared to placebo, with an HR of 1.06 (14 vs 18 mo) for radiographic progression-free survival and 1.53 (26 vs 34 mo) for overall survival when combined with AR pathway inhibitors, and an objective response rate of 0% (0/17) as monotherapy (PMID: 38484203; NCT02987543, NCT03732820, NCT03395197, NCT03748641, NCT02952534, NCT03148795). 38484203