Analytical performance of the Resolution-HRD plasma assay used to identify mCRPC patients with biallelic disruption of DNA repair genes for treatment with niraparib

Metastatic castration-resistant prostate cancer (mCRPC) patients with DNA repair gene defects (DRD) have a shorter life expectancy than patients without DRD and may benefit from treatment with PARP inhibitors. Niraparib is a highly selective PARP inhibitor, with activity against PARP-1/2 DNA-repair polymerases. Detection of DRD in cell free DNA (cfDNA) isolated from blood is minimally invasive and of special benefit to mCRPC patients, including patients without accessible lesions. The assay would also have the advantage of a shorter turnaround time (TAT) than genotyping of tissue. However, using cfDNA to identify biallelic disruption of DNA-repair genes is technically challenging. Resolution-HRD identifies patients with biallelic pathogenic alterations of the ATM, BRCA1, BRCA2, BRIP1, CHEK2, FANCA, HDAC2, or PALB2 genes, by targeted NGS sequencing of cfDNA. Analytical performance of Resolution-HRD was validated using cfDNA from mCRPC patient plasma, cfDNA from healthy donor plasma, and contrived samples with a wide spectrum of technically challenging genetic aberrations. The LOD95 at a cfDNA input level of 40 ng ranged from 0.2 to 1.37 for SNVs and indels, and 6-12 for CNL. APA for intra-run and inter-run studies at the 1X LOD was 95% and 95% respectively. No false-positives were detected in any samples from healthy donors (N=60). Resolution-HRD has been validated to give consistent results across the 10-75 ng input range. Resolution-HRD is used to identify patients for enrollment in the GALAHAD Phase 2 Efficacy and Safety Study (64091742PCR2001) of Niraparib in Men with mCRPC and DNA-Repair Anomalies. As of April 2019, over 2000 patients are tested successfully (0.88% failure rate) with a median TAT of 8.6 days (range 5-12 days). The analytical performance of the Resolution-HRD assay offers highly sensitive, specific and robust test results, and meets analytical requirements for clinical applications. This test is currently being evaluated in several clinical trials for prospective identification of mCRPC patients with DRD for treatment with niraparib.