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Detection of Homologous Recombination Repair Gene Mutations by Tumor Tissue and Circulating Tumor DNA Testing in
Andrew J Armstrong1, Fred Saad2, Mototsugu Oya3
1Duke Cancer Institute Center for Prostate and Urologic Cancer, Duke University, Durham, NC.
Purpose:
In the PROpel study (ClinicalTrials.gov identifier: NCT03732820), olaparib plus abiraterone demonstrated statistically significant radiographic progression-free survival benefit versus placebo plus abiraterone in a first-line metastatic castration-resistant prostate cancer (mCRPC) population unselected by homologous recombination repair gene mutation (HRRm) status. From PROpel, we report exploratory biomarker analyses assessing HRRm and BRCA1 and/or BRCA2 (BRCAm) status using tumor tissue and plasma-derived circulating tumor (ct) DNA.
Methods:
Patients received (1:1) either olaparib (300 mg twice a day) or placebo in combination with abiraterone (1,000 mg once daily) plus prednisone/prednisolone (5 mg twice a day). Tumor tissue and ctDNA samples were analyzed using FoundationOne CDx and FoundationOne Liquid CDx tests, respectively. Biomarker results are presented by individual tests and as an aggregate analysis.
Results:
HRRm status was obtained for 778 of 796 (98%) patients randomly assigned. Aggregating tumor tissue and ctDNA results, 226 patients were identified as having HRRm (including 85 BRCAm). In matched tumor tissue and ctDNA samples (n = 491), and using the tumor tissue result as the reference, high concordance was observed for HRRm (overall percent agreement, 85.1%; negative predictive value, 93.7%) and BRCAm status (overall percent agreement, 93.9%; negative predictive value, 97.3%), with low ctDNA fraction being a limiting factor in rare cases where discordance was observed. Based on the observed agreement, there was a potential incidence of 1% unidentified BRCAm in aggregated non-BRCAm patients (n = 693).
Conclusion:
Aggregating tumor tissue and ctDNA analyses maximized the number of patients (98%) with known biomarker status in PROpel while limiting the number of potential false negatives. This represents the most comprehensive means for identifying biomarker-positive and biomarker-negative subgroups and demonstrates the complementary utility of ctDNA testing in mCRPC, particularly when tissue testing is unable to provide a clinically useful result.
