Do androgen degraders work better in patients with a CHEK2 (Checkpoint Kinase 2) mutation?

Androgen Degraders and CHEK2 Mutations in Prostate Cancer

Direct Answer

There is emerging evidence that androgen degraders may work better in patients with CHEK2 mutations, though this is based on limited case report data rather than robust clinical trials. The biological rationale is compelling: CHEK2 mutations impair DNA repair mechanisms, potentially sensitizing cancer cells to the DNA damage caused by rapid hormonal cycling with androgen-based therapies 1, 2.

Biological Mechanism Supporting Enhanced Response

CHEK2 functions as a negative regulator of androgen receptor (AR) activity and prostate cancer growth. When CHEK2 is mutated or depleted:

• AR transcriptional activity increases on androgen-regulated genes 2
• Prostate cancer cells become hypersensitized to low androgen levels 2
• Cell growth dramatically increases in the absence of functional CHEK2 2
• The DNA damage response pathway (ATM-CHK2-p53) is compromised 3

This creates a therapeutic vulnerability: CHEK2-mutated tumors may be more susceptible to therapies that exploit androgen cycling or cause DNA damage 1.

Clinical Evidence

Case Report Data

A patient with germline CHEK2-mutated metastatic castration-resistant prostate cancer (mCRPC) demonstrated marked response to bipolar androgen therapy (BAT) combined with pembrolizumab after progressing through multiple standard therapies 1. Key features:

• Response duration: 13 months 1
• Patient had exhausted nearly all standard therapies over 20 years 1
• The CHEK2 mutation likely sensitized cancer cells to DNA damage caused by rapid testosterone cycling 1

Mechanistic Studies

CHEK2 depletion increases androgen sensitivity and prostate cancer proliferation through CDC25C and CDK1 signaling 2. Critical findings:

• CHEK2 physically associates with the AR 2
• CHEK2 is itself an AR-repressed gene, creating a negative feedback loop 2
• CHEK2 expression decreases in high-grade prostate tumors 2
• Loss of CHEK2 signaling occurs during progression to castration resistance 2

CHEK2 Mutations and Prostate Cancer Risk

CHEK2 truncating mutations confer moderate prostate cancer risk:

• Truncating mutations (IVS2+1G>A or 1100delC) found in 1.6% of unselected prostate cancer patients vs 0.5% controls (OR=3.4) 4
• Risk increases to 4% in familial prostate cancer cases (OR=9.0) 4
• Missense variant I157T found in 7.8% of prostate cancer patients vs 4.8% controls (OR=1.7) 4
• CHEK2 is considered a moderate penetrance cancer predisposition gene 3

Androgen Degrader Efficacy

PROTAC degraders of AR, such as ARD-69, achieve potent AR protein degradation:

• DC50 values: 0.86 nM (LNCaP), 0.76 nM (VCaP), 10.4 nM (22Rv1) 5
• Reduces AR protein levels by >95% in AR-positive prostate cancer cell lines 5

• 100 times more potent than AR antagonists at inhibiting cell growth 5

Standard androgen deprivation therapy with enzalutamide shows efficacy in non-metastatic CRPC:

• Median metastasis-free survival: 36.6 months vs 14.7 months with placebo (HR=0.29) 3
• 93% reduction in relative risk of PSA progression 3

Clinical Implications and Algorithm

When to Consider Enhanced Androgen-Based Therapy in CHEK2 Mutation Carriers:

1. Confirm CHEK2 mutation status through germline testing in patients with:

   • Family history of prostate, breast, or colorectal cancer 3, 4
   • Early-onset prostate cancer 4
   • Castration-resistant disease with limited treatment options 1

2. For CHEK2-mutated mCRPC patients who have progressed on standard therapies:

   • Consider bipolar androgen therapy (BAT) in clinical trial settings 1
   • Combination with immunotherapy (e.g., pembrolizumab) may enhance response 1
   • Monitor for DNA damage response given impaired repair mechanisms 1, 2

3. Standard first-line therapy remains unchanged:

   • Enzalutamide or abiraterone for non-metastatic CRPC at high risk 3
   • Continue ADT as backbone therapy 3

Important Caveats

The evidence for enhanced response to androgen degraders in CHEK2-mutated prostate cancer is preliminary:

• Based primarily on single case report 1
• No prospective trials specifically evaluating this population
• Loss of wild-type CHEK2 allele was NOT observed in prostate cancers from CHEK2 mutation carriers, suggesting haploinsufficiency rather than complete loss of function 4

CHEK2 mutations do not currently change standard treatment recommendations outside of clinical trials, as guidelines do not address mutation-specific therapy selection 3.

For patients with CHEK2 mutations who develop cancer, no specific targeted medical treatment is recommended at this time 3.

Monitoring Considerations

CHEK2 heterozygotes require surveillance for multiple cancer types:

• Prostate cancer surveillance based on family history assessment 3
• Increased risk for breast and colorectal cancers 3, 4
• Personalized risk estimates should guide screening intensity 3