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.

在过去几年中，随着雄激素受体信号传导抑制剂 (ARSI) 和紫杉​​烷化学疗法在前列腺癌的治疗中进入早期疾病阶段，晚期前列腺癌的治疗前景得到了广泛扩展。随着在疾病早期阶段越来越多地使用 ARSI，治疗之间出现了交叉耐药性，这是当前临床实践中的主要障碍。为了克服前列腺癌治疗中的交叉耐药性，破译 ARSI 之间以及 ARSI 与化疗之间的交叉耐药机制至关重要。在这里，描述了对包括雄激素受体 (AR) 剪接变体、AR 过表达、AR 突变和糖皮质激素受体上调在内的可用疗法产生抗性的分子机制。基于这些底层机制，ARSI 与化疗之间交叉耐药的临床数据已有报道。直到最近，这些数据才在前瞻性随机试验中得到证实。从这些研究中可以清楚地看出，由于新出现的耐药性，顺序 ARSI 治疗在晚期前列腺癌的治疗中没有地位。此外，基于前瞻性证据，我们认为，如果 ARSI 治疗后多西他赛方案缺乏益处，值得考虑尽早改用卡巴他赛治疗。基于随机试验的这些新见解，提出了一些治疗顺序的建议。很明显，由于新出现的耐药性，序贯 ARSI 治疗在晚期前列腺癌的治疗中没有地位。此外，基于前瞻性证据，我们认为，如果 ARSI 治疗后多西他赛方案缺乏益处，值得考虑尽早改用卡巴他赛治疗。基于随机试验的这些新见解，提出了一些治疗顺序的建议。很明显，由于新出现的耐药性，序贯 ARSI 治疗在晚期前列腺癌的治疗中没有地位。此外，基于前瞻性证据，我们认为，如果 ARSI 治疗后多西他赛方案缺乏益处，值得考虑尽早改用卡巴他赛治疗。基于随机试验的这些新见解，提出了一些治疗顺序的建议。