Department Materno Infantile e Scienze Urologiche, University Sapienza, 00166 Rome, Italy.
Urologic Division, Humanitas Hospital, Rozzano, 00100 Milan, Italy.
Curr Oncol. 2023 Aug 30;30(9):8054-8067. doi: 10.3390/curroncol30090584.
The increasing diffusion of genetic analysis regarding the pathogenetic variants (PVs) of genes involved in DNA Damage Repair (DDR) mechanisms and the development of Poly ADP ribose polymerase (PARP) inhibitors (PARPis) led to the first valid precision medicine option tailored toward metastatic prostate cancer (mPC). The concept of anticipation in the systemic treatment of mPC was initially adopted for androgen receptor signaling inhibitors (ARSIs) to describe the expansion of their indications, from the setting of the late-stage second-line treatment of metastatic castration-resistant prostate cancer (mCRPC) to first-line therapy in selected cases. There is already mounting evidence in favor of the anticipation of PARPis in the first line of mCRPC therapy, and further evidence in favor of mHSPC is emerging. Many studies have demonstrated the synergism between ARSIs and PARP inhibitors. Recent discoveries regarding the crosstalk between the androgen receptor (AR) and DNA repair mechanisms are disconnecting the use of PARPis from genetic analysis. The new message emerging is that the combination of PARPis with ARSIs may work independently of DDR mutational status. As a matter of fact, most of the recent trials analyzing the combination of PARPis with abiraterone or enzalutamide as a first-line therapy enrolled mCRPC patients irrespective of their mutational status. The PROPEL trial concluded that the advantage of the combination was independent of PV status, despite a higher advantage being reported in the BRCA1/2 mutated subgroup. The MAGNITUDE trial, however, showed a significant advantage only in the DDR mutated subgroup, and the DDR non-mutated cohort was closed for further enrollment. The combination of PARPis with ARSIs represents a significant strategy with a view to the anticipation and intensification of care in mPC. However, it should not nullify the advantages of precision medicine linked to the genetic analysis of DDR genes.
基因致病性变异（PVs）在 DNA 损伤修复（DDR）机制中的扩散，以及聚 ADP 核糖聚合酶（PARP）抑制剂（PARPis）的发展，使得针对转移性前列腺癌（mPC）的精准医疗选择首次成为可能。在 mPC 的系统治疗中，最初采用预期概念来描述雄激素受体信号抑制剂（ARSIs）的适应证扩展，从晚期二线治疗转移性去势抵抗性前列腺癌（mCRPC）扩展到某些情况下的一线治疗。越来越多的证据支持在 mCRPC 治疗的一线治疗中提前使用 PARPis，并且在 mHSPC 中也有更多的证据支持。许多研究已经证明了 ARSIs 和 PARP 抑制剂之间的协同作用。最近关于雄激素受体（AR）和 DNA 修复机制之间相互作用的发现，使 PARPis 的使用与基因分析脱钩。新出现的信息是，PARPis 与 ARSIs 的联合使用可能独立于 DDR 突变状态。事实上，最近分析 PARPis 与阿比特龙或恩杂鲁胺联合作为一线治疗的大多数试验，均纳入了不论突变状态如何的 mCRPC 患者。PROPEL 试验得出的结论是，联合治疗的优势独立于 PV 状态，尽管在 BRCA1/2 突变亚组中报告的优势更高。然而，MAGNITUDE 试验仅在 DDR 突变亚组中显示出显著优势，并且 DDR 非突变队列已停止进一步入组。PARPis 与 ARSIs 的联合治疗代表了 mPC 中预期和强化治疗的重要策略。然而，它不应使与 DDR 基因的基因分析相关的精准医学的优势失效。
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