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).
We performed a post hoc analysis of the circulating tumor DNA (ctDNA) mutational landscape in ARSi-treated men with mCRPC (n = 342), recruited in our prospective, non-interventional, cohort study (n = 142) and the prospective NCT02125357 trial (n = 200). 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.
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 < 0.0001). In multivariate analysis the driver burden reached significance once ≥ 4 driver hits were detected (HR 1.85, 95%CI 1.06-3.23, p = 0.03). The number of perturbed pathways reached independent prognostic value once ≥ 3 pathway or gene classes were affected (HR 1.7, 95%CI 1.02-2.84, p = 0.04). Additionally, in both models the presence of visceral metastases (p < 0.0001) and increasing PSA (p < 0.001) and plasma ctDNA (p < 0.001) levels were also independently associated with inferior outcome.
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.
CORE-ARV-CTC and ProBio Investigators.
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.
All authors have declared no conflicts of interest.