In this paper, physics-based numerical simulation (PBS) is employed to render a broad-band (0–10 Hz) realization of the near-field seismic response of the experimental nuclear site of Cadarache, located nearby the active Middle Durance Fault (southeastern France). The sensitivity of the earthquake numerical model to geological features is investigated by comparison with geophysical measurements and past aftershock and by highlighting the amplification induced by the soft sediments below Cadarache. The blind prediction of an MW6 target earthquake is approached by synthesizing four different finite-fault scenarios. The outcome is compared to the standard ground motion prediction equations (GMPEs), unveiling a possible GMPE overestimation of the pseudospectral acceleration ordinates at short natural periods, supporting the actual need to integrate synthetic and empirical predictions when direct observations are not available.