Dev Harveer, Linch Mark, Narahari Krishna, Milne-Clark Toby, Cheung Melissa, Warren Anne, Malaviya Alopa, Gnanapragasam Vincent, Hernandez Tatiana, Bullock Nicholas, Machin Andrea, Dayimu Alimu, Robb Tamsin, Cromwell Elizabeth, Freeman Alex, Harrington Elizabeth A, Camacho Niedzika, Glont Silvia, Squatrito Massimo, Rotem Asaf, Moore Luiza, Hanson Robert, Dodd Marc, Anand Shubha, Kynaston Howard, Shaw Greg, Shah Nimish, Pacey Simon
Early Cancer Institute, University of Cambridge, Cambridge, United Kingdom.
University College London Cancer Institute, London, United Kingdom.
Clin Cancer Res. 2025 Jun 13;31(12):2347-2357. doi: 10.1158/1078-0432.CCR-24-1304.
The purpose was to investigate combined PARP and androgen inhibition in primary prostate cancer and understand the biological mechanisms underlying clinical efficacy, especially in the absence of mutations in homologous recombination (HR) repair pathways.
The primary objective was to measure PARP inhibition, and the secondary objectives were to assess safety and feasibility. Participants received olaparib for 2 weeks before prostatectomy and were randomly assigned or not assigned (1:1) to degarelix. We analyzed diagnostic biopsy and radical prostatectomy samples for PARylated protein expression using IHC. Exploratory analyses included tumor gene sequencing, mutation analysis, and RNA sequencing (RNA-seq) using both bulk and single-cell RNA-seq performed on pretreatment and posttreatment tissues.
PARylated protein expression was significantly reduced in both cohorts, with no drug-related delays in radical prostatectomy. The gene set enrichment analysis identified distinct treatment response signatures related to olaparib in both cohorts and showed downregulation of androgen response genes after olaparib + degarelix treatment.Transcript profiling revealed an upregulation of the p53 hallmark, which was more pronounced with the combination treatment. Canonical cell-cycle progression hallmarks, including E2F targets and the G2-M checkpoint, were suppressed across all cases, correlating with a HR-deficient transcriptional signature. Single-nuclear RNA-seq indicated a greater increase in inflammatory response pathway activity within tumor epithelia after combination treatment.
Transcriptomic analysis identified common hallmark alterations reflecting the combined impact of PARP inhibitor and androgen blockade on cell-cycle progression. We observed a shared phenotypic response to combination therapy across prostate cancers without known HR repair gene alterations. This suggests alternative mechanisms rather than antiandrogen-induced HR deficiency.
本研究旨在探讨PARP抑制剂与雄激素抑制联合应用于原发性前列腺癌的效果，并了解其临床疗效背后的生物学机制，尤其是在同源重组（HR）修复途径无突变的情况下。
主要目标是测量PARP抑制情况，次要目标是评估安全性和可行性。参与者在前列腺切除术前接受2周的奥拉帕利治疗，并随机（1:1）分配或不分配至地加瑞克。我们使用免疫组化分析诊断性活检和根治性前列腺切除标本中PAR化蛋白的表达。探索性分析包括肿瘤基因测序、突变分析以及使用对治疗前和治疗后组织进行的批量和单细胞RNA测序（RNA-seq）。
两个队列中PAR化蛋白表达均显著降低，根治性前列腺切除术未出现与药物相关的延迟。基因集富集分析在两个队列中均鉴定出与奥拉帕利相关的不同治疗反应特征，并显示奥拉帕利+地加瑞克治疗后雄激素反应基因下调。转录谱分析显示p53特征上调，联合治疗时更为明显。所有病例中包括E2F靶点和G2-M检查点在内的经典细胞周期进展特征均受到抑制，与HR缺陷转录特征相关。单核RNA-seq表明联合治疗后肿瘤上皮内炎症反应途径活性增加更为显著。
转录组分析确定了共同的特征改变，反映了PARP抑制剂和雄激素阻断对细胞周期进展的联合影响。我们观察到在无已知HR修复基因改变的前列腺癌中，联合治疗有共同的表型反应。这提示存在替代机制而非抗雄激素诱导的HR缺陷。
