目的:确定术前6个月阿帕鲁胺治疗中危前列腺癌(IRPCa)是否能降低术后总放疗风险,并评估该研究队列中分子扰动与临床结果的相关性。
方法:在2018年5月至2020年2月之间,符合条件的IRPCa患者(格里森34或43,临床T2b-c或前列腺特异性抗原水平为10-20ng/mL)接受阿帕鲁胺240mg/天治疗6个月,然后在该单臂中进行根治性前列腺切除术(RP)。第二阶段试验。主要终点是存在盆腔放疗风险的任何不良病理特征(新辅助治疗[yp]T3或ypN1或手术切缘阳性后的病理T期)。翻译研究,包括种系和体细胞DNA改变以及RNA和蛋白质表达,在阿帕鲁胺RP后标本上进行,并评估与临床结果的相关性。
结果:共有40名患者接受了RP,只有一名患者在6个月前停用阿帕鲁胺。总之,40%在RP时出现不良病理特征,3年生化复发率(BCR)为15%,27.5%无法评估。在转移性PCas中常见的基因组改变,如雄激素受体(AR),肿瘤蛋白p53(TP53),磷酸酶和张力蛋白同源物(PTEN),或BreastCancer相关基因(BRCA1/2)在该局部队列中代表性不足。3年的不良病理特征和BCR与选定细胞周期的表达增加相关(例如,E2F目标:调整后的P值[Padj]<0.001,归一化富集评分[NES]2.47)和氧化磷酸化(Padj<0.001,NES1.62)途径。
结论:术前阿帕鲁胺并没有将未选择的IRPCa患者的术后总放射风险降低至预先指定的阈值。然而,转录组学分析确定了与不良病理结果和BCR相关的肿瘤中关键的失调通路,这需要未来的研究。对于高危PCa的男性,术前治疗的进一步研究正在进行中。
OBJECTIVE: To determine whether 6 months of preoperative apalutamide for intermediate-risk prostate cancer (IRPCa) reduces the aggregate postoperative radiotherapy risk and to evaluate associations of molecular perturbations with clinical outcomes in this study cohort.
METHODS: Between May 2018 and February 2020, eligible patients with IRPCa (Gleason 3 + 4 or 4 + 3 and clinical T2b-c or prostate-specific antigen level of 10-20 ng/mL) were treated with apalutamide 240 mg/day for 6 months followed by radical prostatectomy (RP) in this single-arm, phase II trial. The primary endpoint was presence of any adverse pathological feature at risk of pelvic radiation (pathological T stage after neoadjuvant therapy [yp]T3 or ypN1 or positive surgical margins). Translational studies, including germline and somatic DNA alterations and RNA and protein expression, were performed on post-apalutamide RP specimens, and assessed for associations with clinical outcomes.
RESULTS: A total of 40 patients underwent a RP, and only one patient discontinued apalutamide prior to 6 months. In all, 40% had adverse pathological features at time of RP, and the 3-year biochemical recurrence (BCR) rate was 15%, with 27.5% being not evaluable. Genomic alterations frequently seen in metastatic PCas, such as androgen receptor (AR), tumour protein p53 (TP53), phosphatase and tensin homologue (PTEN), or BReast CAncer associated gene (BRCA1/2) were underrepresented in this localised cohort. Adverse pathological features and BCR at 3-years were associated with increased expression of select cell cycle (e.g.,
E2F targets: adjusted P value [Padj] < 0.001, normalised enrichment score [NES] 2.47) and oxidative phosphorylation (Padj < 0.001, NES 1.62) pathways.
CONCLUSIONS: Preoperative apalutamide did not reduce the aggregate postoperative radiation risk to the pre-specified threshold in unselected men with IRPCa. However, transcriptomic analysis identified key dysregulated pathways in tumours associated with adverse pathological outcomes and BCR, which warrant future study. Further investigation of preoperative therapy is underway for men with high-risk PCa.