Tumor heterogeneity and treatment response assessment using next generation imaging and liquid biopsy in patients with metastatic castration resistant prostate cancer receiving abiraterone (ANGELA): A single-center prospective observational trial.

Abstract

5057 Background: Metastatic castration resistant prostate cancer (mCRPC) is a disease of intra-patient tumor heterogeneity which poses obstacles in treatment and response evaluation. With the development of next generation imaging (NGI) and liquid biopsy, precise assessment of heterogeneity has entered a new era. In this study, we used longitudinal NGI (68Ga-PSMA and 18F-FDG PET/CT) and circulating tumor DNA (ctDNA) testing to assess tumor heterogeneity and treatment response in mCRPC patients receiving abiraterone. Methods: ANGELA is a single-center prospective observational trial (NCT05188911). We recruited mCRPC patients who received abiraterone as initial hormonal treatment. Eligible patients should have a life expectancy >12 months. CtDNA testing and NGI were performed at baseline and after 12 weeks of abiraterone (Week 13). Conventional imaging and PSA testing were performed at Week 1 and every 12 weeks. Primary end-point of this study is intra-patient lesion heterogeneity evaluated by 3 dimensions: (1) Imaging heterogeneity: defined as at least 1 lesion with FDG+/PSMA- phenotype at baseline and/or Week 13; (2) Genomic heterogeneity: quantified by ctDNA fraction increase and mutational changes per gene between baseline and Week 13; (3) Response heterogeneity: defined as at least 1 new tumoral lesion with either PSMA or FDG abnormal uptake at Week 13. Secondary end-points are correlations of heterogeneity with conventional-evaluated progression-free survival (PFS) and 2-year overall survival (OS). Results: Between May 20, 2020 and Feb 02, 2021, we included 33 eligible patients in our study. FDG+/PSMA- tumoral lesion was observed in 7/33 (21.2%) and 8/33 (24.2%) of patients at baseline and Week 13, respectively. Notably, 5 of 8 patients with imaging heterogeneity at Week 13 had no FDG+/PSMA- lesion at baseline. For genomic heterogeneity, we detected ctDNA fraction increase in 4/33 patients (12.1%). In addition, we found new gene mutations detected in Week 13 ctDNA testing in 5/33 patients (15.2%), 2 of 5 had ctDNA fraction increase. For response heterogeneity, we observed 15/33 patients (45.5%) patients developed at least 1 new tumoral lesion (FDG+ or PSMA+) at Week 13. We correlated heterogeneity factors with prognosis, and found that detection of new mutated genes (P=0.005 and P<0.001), new PSMA+ lesion (P<0.001 and P<0.001), and new FDG+ lesion (P=0.008 and P<0.0001) at Week 13 were significant predictors of shorter PFS and decreased 2-year OS. Detailed biomarker study for response analysis is still in process. Conclusions: Intra-patient tumor heterogeneity was common among mCRPC patients receiving abiraterone. Combining liquid biopsy with NGI can monitor changes in tumor heterogeneity and indicate early combination therapy. Clinical trial information: NCT05188911 .