A real-world cohort study to identify potential clinical practice gaps in genetic testing for homologous recombination repair gene mutations in metastatic castration -resistant prostate cancer (mCRPC)

The FDA has already approved 14 deleterious somatic or germline HRR gene mutations for the use of olaparib in mCRPC patients who have progressed following prior treatment with enzalutamide or abiraterone. Notably, the combination of talazoparib and enzalutamide was also approved for first-line treatment of HRR gene-mutant mCRPC in 2023. Compared to other BRCA-associated cancer types (ovarian cancer, pancreatic cancer, breast cancer), there is a greater need for HRR gene testing beyond BRCA1 and BRCA2 in mCRPC.

This real-world cohort study highlights the underutilization of HRR gene testing for mCRPC patients in the US. The study utilized The IntegraConnect-Precision Q Database to analyze a de-identified real-world cohort from January 1, 2020, to December 31, 2021. It enrolled 996 patients, of whom 59.2% (N=590) underwent HRRm testing. Among these, 59.8% underwent somatic mutation testing (N=353), either in somatic tissue (22.9%; N=135) or somatic liquid (36.9%; N=218), while 19.8% underwent germline testing, 4.1% underwent both somatic and germline testing, and a portion of patients had unknown testing types (16.3%).

HRR-mutant testing increased 2.2-fold after the approval of the PARP inhibitor (PARPi), with 31.7% of patients (N=187) testing positive for HRRm and 66.8% of patients (N=125) receiving a PARPi. Among the 134 patients who reported treatment failure, 37 underwent testing. Predominant HRR gene mutations were found in ATM, BRCA2, CHEK2, and CDK12. The higher frequency of ATM and CHEK mutations in somatic liquid tests could be due to clonal hematopoiesis.

In conclusion, nearly 41% of mCRPC patients did not undergo HRR gene testing, and 33.2% of HRR-mutant patients had not been treated with PARP inhibitors. Optimizing germline and somatic testing for mCRPC remains a significant unmet need. Raising awareness about implementing genetic testing and ensuring access to appropriate targeted therapies are indispensable for mCRPC patients in future clinical practice.

‍

Reference: 

1. Shore et al., poster at 2024 ASCO GU, abs. #210. 

‍