Cross-resistance and drug sequence in prostate cancer

The treatment landscape of advanced prostate cancer has widely expanded over the past years with androgen receptor signaling inhibitors (ARSIs) and taxane chemotherapy moving to earlier disease stages in the treatment of prostate cancer. With the increasing use of ARSIs in earlier disease stages, cross-resistance between treatments has emerged, which is a dominant impediment in current clinical practice. To overcome cross-resistance in the treatment of prostate cancer, it is of paramount importance to decipher the mechanisms of cross-resistance between ARSIs and between ARSIs and chemotherapy. Here, molecular mechanisms of resistance to the available therapies including androgen receptor (AR) splice variants, AR overexpression, AR mutations and glucocorticoid receptor upregulation are described. Based on these underlying mechanisms, clinical data of cross-resistance between ARSIs and chemotherapy have been reported. Only recently these data have been confirmed in prospective randomized trials. From these studies, it has become clear that sequential ARSI treatment has no place in the treatment of advanced prostate cancer due to emerging drug resistance. In addition, based on prospective evidence, we argue that it is worth considering an early switch to cabazitaxel treatment in case of lack of benefit on docetaxel regimen after an ARSI treatment. Based on these new insights from randomized trials, several recommendations for treatment sequence are proposed.