Elevated driver mutational burden or number of perturbed pathways and poor response to abiraterone or enzalutamide in metastatic castration-resistant prostate cancer

Abstract

Abstract Background Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease with rare driver gene alteration combinations in most men, requiring large sample sizes for stratified evaluations. We therefore hypothesized that the number of driver genes or pathways would affect prognosis in patients initiating androgen receptor signalling inhibitors (ARSi, i.e abiraterone acetate or enzalutamide). Methods We performed a post hoc analysis of the circulating tumor DNA (ctDNA) mutational landscape in ARSi-treated men with mCRPC (n\xa0=\xa0342), recruited in our prospective, non-interventional, cohort study (n\xa0=\xa0142) and the prospective NCT02125357 trial (n\xa0=\xa0200). The driver gene mutational burden was defined as the number of detectable hotspot, pathogenic and/or function-affecting perturbations in 39 overlapping genes, which in turn were associated with 13 pathways. Progression-free survival (PFS) estimates were inferred by Kaplan-Meier analysis and multivariable Cox regression models, including the following covariates: PSA and ctDNA levels, prior chemotherapy, prior ARSi exposure, and presence of visceral metastases. Results Driver gene perturbations were detectedin 192/342 (56.1%) evaluable patients at baseline, with 152/192 (79.2%) and 40/192 (20.8%) perturbed patients having 1-3 and ≥ 4 significant events, respectively. PFS decreased as the driver mutational burden increased (0, 1-3, ≥ 4 drivers, median PFS 12.5 vs 5.6 vs 2.7 months, p\xa0 Conclusions We demonstrate for the first time that the elevated driver mutational burden or number of affected pathways is independently associated with poor prognosis in mCRPC patients starting ARSi. Legal entity responsible for the study CORE-ARV-CTC and ProBio Investigators. Funding The Belgian Foundation Against Cancer, Kom op tegen Kanker (the Flemish Cancer Society), Royal College of Surgeons/Cancer Research UK, The Erling-Persson Family Foundation, the Swedish Research Council, and the Swedish Cancer Foundation. Disclosure All authors have declared no conflicts of interest.