Abstract 5580: Circulating tumor DNA (ctDNA) identifies genomic alterations associated with resistance to Nivolumab in combination with other agents in metastatic castration-resistant prostate cancer from the CheckMate 9KD trial
Authors: Wang Yu , Li Jun , Baden Jonathan , Gupta Saurabh , David Justin M. 
Published: April 2023

Introduction: Metastatic castration-resistant prostate cancer (mCRPC) is characterized by an immunosuppressive tumor microenvironment resulting in resistance to single agent immunotherapy, and several combination strategies are being clinically evaluated to address this resistance. CheckMate 9KD (NCT03338790) was a nonrandomized, open-label, multicohort, phase 2 trial of nivolumab combined with rucaparib, docetaxel, or enzalutamide for mCRPC, which showed encouraging clinical activity for the nivolumab plus docetaxel combination. To identify genetic factors potentially associated with response or resistance in this trial, we conducted a retrospective analysis of the tumor genomic alteration landscape utilizing circulating tumor DNA (ctDNA) from plasma samples.

Methods: We performed integrated analyses of sequence and structural alterations identified through comprehensive genomic profiling of cell-free DNA (cfDNA) obtained from plasma at baseline using the GuardantOMNI™ assay (500 genes). The analysis was performed on 253 unique samples across all cohorts for which both clinical and OMNI datasets were available. Variant prevalence in ctDNA was compared to that of matched tumor tissue using the FoundationONE® assay (395 genes). Hazard ratios with corresponding two-sided 95% CI were estimated via unstratified multivariable Cox modeling adjusted by subject age and homologous recombination repair deficiency (HRD) status. Odds ratios with corresponding two-sided 95% CI were estimated via unstratified logistic regression modeling adjusted by subject age and HRD status.

Results: Most patients (239/253; 94.5%) were ctDNA(+), with a substantially higher prevalence of most gene variants detected in cfDNA compared to patient-matched tumor tissue. Mutations in the AR, TERT, DNMT3A, HNF1A, and TP53 genes had the highest frequency. Amplifications in a number of genes detected in ctDNA including the androgen receptor (AR), PI3K/Akt pathway regulators (PIK3CA, PIK3CB, PREX2), and epigenetic regulators (DNMT3A, EZH2, KDM6A), were positively associated with poorer clinical outcomes (rPFS and/or OS) in the nivolumab + docetaxel arm.

Conclusions: This investigation highlights the utility of liquid biopsy for evaluating tumor genomic alterations in late-stage mCRPC trials and provides translational insights into potential resistance mechanisms to inform patient selection and combination strategies for future clinical development.

Acknowledgements: We acknowledge the patients and families, clinical study teams, and investigators who made the CheckMate 9KD study possible, and acknowledge Guardant Health and Foundation Medicine for the collaborative development and validation of the GuardantOMNI™ and FoundationOne®CDx assays, respectively.

Citation Format: Yu Wang, Jun Li, Jonathan Baden, Saurabh Gupta, Justin M. David. Circulating tumor DNA (ctDNA) identifies genomic alterations associated with resistance to Nivolumab in combination with other agents in metastatic castration-resistant prostate cancer from the CheckMate 9KD trial. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5580.