What is the efficacy of Poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib (olaparib), in treating metastatic castration-resistant prostate cancer (mCRPC) in a Checkpoint Kinase 2 (CHEK2) carrier?

PARP Inhibitor Efficacy in mCRPC with CHEK2 Mutations

Olaparib is FDA-approved and NCCN-recommended (Category 1) for mCRPC patients with CHEK2 mutations who have progressed on prior androgen receptor-directed therapy, though efficacy data specific to CHEK2 carriers is limited and appears substantially lower than for BRCA1/2 mutations. 1

Regulatory Approval and Guideline Recommendations

Olaparib (300 mg twice daily) received FDA approval in May 2020 for mCRPC patients with deleterious or suspected deleterious germline or somatic HRR gene mutations in 14 genes, including CHEK2, following progression on enzalutamide or abiraterone. 1 The NCCN guidelines provide a Category 1 recommendation for olaparib in patients with CHEK2 mutations (along with BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L). 1

Critical Efficacy Considerations for CHEK2

Heterogeneity of Response by Gene

The PROfound trial demonstrated significant heterogeneity in PARP inhibitor response based on specific HRR gene mutations, with CHEK2 showing substantially less benefit than BRCA1/2 mutations. 1 The trial stratified patients into two cohorts:

• Cohort A (BRCA1/2, ATM): Radiographic PFS HR 0.34 (95% CI, 0.25-0.47; P<0.001) and OS HR 0.69 (95% CI, 0.50-0.97; P=0.02) 1
• Cohort B (12 other genes including CHEK2): The primary endpoint was negative, with statistical interaction indicating these genes are "less likely overall to indicate response to PARP inhibition" 1

CHEK2 was included in Cohort B, which failed to meet its primary endpoint for radiographic PFS benefit. 1 The PROfound trial reported "minimal activity" in patients with non-BRCA1/2 mutations in Cohort B. 1

Gene-Specific Response Data

Early phase II data (TOPARP-A) showed that among 16 patients with DNA-repair gene defects (including CHEK2), 14 (88%) responded to olaparib, but the response was driven primarily by BRCA2 (100% response in 7 patients) and ATM mutations. 2 The specificity of the biomarker suite was 94%, but CHEK2-specific response rates were not separately reported. 2

The NCCN guidelines explicitly note that "there may be further heterogeneity of response to olaparib based on which gene has a mutation" and that efficacy "appears to be driven by the cohort of patients with at least one alteration in BRCA2, BRCA1, or ATM." 1

Clinical Decision Algorithm for CHEK2 Carriers

When to Consider Olaparib in CHEK2 Carriers:

1. Prior therapy requirement: Patient must have received prior enzalutamide or abiraterone 1
2. Confirmed mutation: Use commercially available analytically and clinically validated somatic tumor, ctDNA, or germline assays 1
3. Timing: Can be used before or after docetaxel (taxane therapy not mandated) 1
4. Realistic expectations: Counsel patients that CHEK2 mutations show lower response rates than BRCA1/2 mutations 1

Alternative Considerations:

Rucaparib should NOT be used in CHEK2 carriers, as it is FDA-approved only for BRCA1/2 mutations and showed "minimal to no responses in patients with ATM and CDK12 mutations" in TRITON2. 1 The NCCN explicitly states "Rucaparib should not be used in patients with HRRm other than BRCA1/2." 1

Monitoring and Safety Profile

Close monitoring with complete blood counts and hepatic/renal function is mandatory, with transfusion support and dose reductions as needed for severe anemia. 1, 3 Specific monitoring includes:

• CBC every 2-4 weeks in patients with significant cytopenias 3
• Weekly blood counts during first 4-6 weeks, then every 2 weeks until month 3, then every 3 months 3

Common adverse events include anemia (20% grade 3/4), fatigue (12% grade 3/4), nausea, vomiting, anorexia, weight loss, diarrhea, and thrombocytopenia. 1, 2 Rare but serious adverse events include thromboembolic events (including pulmonary emboli), drug-induced pneumonitis (~2%), and theoretical risk of myelodysplasia or acute myeloid leukemia (≤2%). 1, 4

Clinical Pitfalls

The most critical pitfall is overestimating efficacy in CHEK2 carriers based on the overall PROfound trial results, which were driven by BRCA1/2 mutations. 1 While olaparib is FDA-approved for CHEK2 mutations, the evidence suggests substantially lower benefit compared to BRCA1/2 carriers. 1

Do not use PPP2R2A mutation status to guide olaparib therapy, as these patients experienced an unfavorable risk-benefit profile in PROfound. 1