Are PARP (Poly (ADP-ribose) polymerase) inhibitors, such as olaparib (olaparib) or talazoparib (talazoparib), effective for a patient with a CHEK2 (Checkpoint Kinase 2) c.592+3A>T mutation?

PARP Inhibitors Are Not Recommended for CHEK2 c.592+3A>T Mutations

PARP inhibitors such as olaparib and talazoparib should not be used for patients with CHEK2 mutations, including the c.592+3A>T variant, as these tumors lack homologous recombination repair deficiency and show minimal to no clinical benefit from this therapy. 1

Biological Rationale for Lack of Efficacy

• CHEK2-associated cancers do not display genomic features of homologous recombination repair deficiency, which is the fundamental mechanism required for PARP inhibitor synthetic lethality to occur. 1, 2

• Unlike BRCA1/2- or PALB2-deficient tumors that are exquisitely sensitive to PARP inhibition, CHEK2 mutations involve cell cycle checkpoint control rather than direct DNA repair pathway defects. 1

• The American College of Medical Genetics and Genomics (ACMG) explicitly states that use of PARP inhibitors is not recommended at the current time for CHEK2-associated tumors. 1

Clinical Trial Evidence

Breast Cancer Data

• A phase 2 clinical trial with olaparib in metastatic breast cancer demonstrated no responses in 10 CHEK2 heterozygotes. 1

• This complete lack of response stands in stark contrast to the 50-60% response rates seen in BRCA1/2-mutated breast cancers treated with PARP inhibitors. 1

Prostate Cancer Data

• In the PROfound trial, CHEK2 was included in Cohort B (non-BRCA1/2/ATM mutations), which failed to meet its primary endpoint for radiographic progression-free survival benefit. 3

• While the trial showed dramatic benefit in Cohort A (BRCA1/2/ATM with HR 0.34 for PFS and HR 0.69 for OS), the efficacy in CHEK2 carriers was substantially lower and not statistically significant. 1, 3

• A small subset analysis from the PROfound trial included 12 CHEK2 heterozygotes: those treated with olaparib (n=7) had numerically longer median PFS compared to controls (n=5; 5.59 months vs 3.35 months), but this was not statistically significant. 1

Critical Clinical Pitfalls

• The most dangerous pitfall is extrapolating overall PROfound trial results to CHEK2 carriers, as the trial's positive outcomes were driven almost entirely by BRCA1/2 mutations, not by genes like CHEK2 in Cohort B. 3

• Despite FDA approval of olaparib for 14 HRR genes including CHEK2, the ACMG guidelines take precedence in explicitly recommending against PARP inhibitor use for CHEK2 mutations based on lack of homologous recombination deficiency. 1

• The NCCN lists CHEK2 among genes eligible for olaparib treatment in metastatic castration-resistant prostate cancer (Category 1), but this represents regulatory approval rather than evidence of meaningful clinical benefit for this specific gene. 1, 3

Recommended Management Approach

• Base treatment decisions on standard clinical factors including tumor stage, grade, hormone receptor status, HER2 status, and established prognostic markers—not on CHEK2 mutation status. 1, 2

• For breast cancer with CHEK2 mutations, prioritize endocrine therapy for hormone receptor-positive disease and standard chemotherapy regimens based on tumor characteristics. 2

• For prostate cancer with CHEK2 mutations, use standard androgen receptor-directed therapies (abiraterone, enzalutamide) and taxane-based chemotherapy according to disease stage and prior treatments. 1

• Consider clinical trial enrollment for patients with CHEK2 mutations, as novel therapeutic strategies targeting this pathway are under investigation. 1

Nuanced Considerations

• The c.592+3A>T variant is a splice site mutation that would be expected to result in loss of function, similar to other CHEK2 pathogenic variants studied in clinical trials. 1

• While CHEK2 mutations confer increased cancer risk and may be associated with worse prognostic features (higher nodal involvement, increased risk of contralateral breast cancer), this does not translate into PARP inhibitor sensitivity. 1

• If a patient with CHEK2 mutation has already been started on a PARP inhibitor based on regulatory approval, carefully reassess the risk-benefit ratio given the lack of evidence for efficacy and the significant toxicity profile including anemia (17-31% grade ≥3), thrombocytopenia (13-29% grade ≥3), and fatigue. 4