Is a CHEK2 (Checkpoint Kinase 2) mutated metastatic castration-resistant prostate cancer (mCRPC) considered a 'hot' or 'cold' tumor for immunotherapy?

CHEK2-Mutated mCRPC: Cold Tumor for Immunotherapy

CHEK2-mutated metastatic castration-resistant prostate cancer (mCRPC) is considered an immunologically "cold" tumor that does not respond well to standard immune checkpoint inhibitor monotherapy. 1, 2

Immunologic Classification of CHEK2-Mutated mCRPC

Cold Tumor Characteristics

• Prostate cancer, including CHEK2-mutated variants, is classified as a "cold tumor" or non-T-cell-inflamed cancer with low immune infiltrates and minimal response to immune checkpoint inhibitors (ICIs). 2
• The overall response rate to pembrolizumab monotherapy in unselected mCRPC is only 3-5%, demonstrating the immunologically cold nature of this disease. 1
• CHEK2 mutations do not confer the high tumor mutational burden (TMB) or microsatellite instability-high (MSI-H) phenotype that would make tumors responsive to immunotherapy. 1, 2

Distinction from Hot Tumors

• Unlike melanoma and lung cancer ("hot tumors") that demonstrate high response rates to ICIs, prostate cancer lacks the T-cell-inflamed phenotype necessary for checkpoint inhibitor efficacy. 2
• CHEK2-mutated mCRPC does not typically exhibit the high tumor-infiltrating lymphocytes (TILs) or interferon signature seen in immunotherapy-responsive cancers. 2, 3

CHEK2 Mutation Characteristics in mCRPC

Prevalence and Clinical Significance

• CHEK2 mutations occur in 2.1-13.3% of Japanese patients with mCRPC and are included among the 15 homologous recombination repair (HRR) genes tested in clinical practice. 4, 1
• CHEK2 is a cell cycle checkpoint kinase involved in DNA damage repair, but mutations in this gene do not predict response to PARP inhibitors as robustly as BRCA1/2 mutations. 1, 5

Treatment Implications

• The NCCN guidelines recommend germline and somatic tumor testing for HRR genes including CHEK2, but primarily to inform PARP inhibitor eligibility rather than immunotherapy selection. 1
• In the PROfound trial evaluating olaparib, CHEK2 was included in cohort B (12 other HRR genes), which showed less robust benefit compared to cohort A (BRCA1/2, ATM), suggesting heterogeneity in treatment response among HRR mutations. 1

Immunotherapy Considerations for CHEK2-Mutated mCRPC

Limited Role of Standard Immunotherapy

• Pembrolizumab is only recommended for mCRPC patients with MSI-H/dMMR status (prevalence 2-5%) or TMB ≥10 mutations/Mb, not based on CHEK2 mutation status alone. 1
• The KEYNOTE-199 study demonstrated objective response rates of only 3-5% with pembrolizumab in unselected mCRPC, confirming the cold tumor phenotype. 1

Emerging Combination Strategies

• One case report described a response to bipolar androgen therapy (BAT) combined with pembrolizumab in a CHEK2-mutated mCRPC patient, suggesting that DNA repair deficiency may sensitize tumors to combination approaches that convert cold tumors to hot. 6
• Combining cancer vaccines with checkpoint inhibitors may turn cold tumors hot by enabling the immune system to better recognize cancer cells, though this remains investigational in prostate cancer. 1

CDK12 Mutations: A Potential Exception

• Patients with CDK12 mutations (13.3% prevalence in Japanese cohorts) represent a distinct subset that may respond to PD-1 inhibitors, with 11-33% experiencing disease response in retrospective studies. 1, 4
• CDK12-mutated tumors tend to have aggressive disease with high metastatic rates and poor response to hormonal therapy, PARP inhibitors, and taxanes, but may have enhanced immunogenicity. 1

Recommended Treatment Approach for CHEK2-Mutated mCRPC

Standard Therapy Prioritization

• Continue ADT with LHRH agonist/antagonist to maintain castrate testosterone levels (<50 ng/dL) throughout all treatment lines. 1
• Offer standard mCRPC therapies including abiraterone, enzalutamide, docetaxel, or cabazitaxel based on prior treatment exposure and clinical factors, not CHEK2 mutation status. 1, 7
• Consider PARP inhibitors (olaparib) if CHEK2 mutation is confirmed, though efficacy is less established than for BRCA1/2 mutations. 1

Immunotherapy Testing and Selection

• Perform MSI/MMR testing and TMB assessment in all mCRPC patients to identify the small subset (2-5%) who may benefit from pembrolizumab. 1
• Reserve pembrolizumab for patients with documented MSI-H/dMMR or TMB ≥10 mutations/Mb after progression on docetaxel and/or novel hormone therapy (category 2A recommendation). 1
• Do not use pembrolizumab monotherapy based solely on CHEK2 mutation status, as this does not predict immunotherapy response. 1, 2

Clinical Trial Consideration

• Prioritize clinical trials evaluating combination immunotherapy strategies or novel approaches to convert cold tumors to hot in CHEK2-mutated mCRPC. 1, 7
• Consider trials combining PARP inhibitors with immunotherapy, as DNA repair deficiency may enhance immunogenicity through increased neoantigen burden. 6, 5

Common Pitfalls to Avoid

• Do not assume CHEK2 mutation confers immunotherapy responsiveness—this is a DNA repair gene mutation, not an immune biomarker. 1, 2
• Do not discontinue ADT when adding any systemic therapy, including immunotherapy, as maintaining castrate testosterone is essential. 1, 8
• Do not extrapolate CDK12 immunotherapy responsiveness to other HRR mutations like CHEK2, as these represent distinct biological entities. 1
• Do not use immunotherapy outside of MSI-H/dMMR or high TMB indications without clinical trial enrollment, as response rates are extremely low in unselected mCRPC. 1, 2