Cimadamore Alessia, Boixareu Cristina, Sharp Adam, Beltran Himisha, de Bono Johann S
Institute of Pathological Anatomy, Department of Medicine, University of Udine, Udine, Italy.
The Royal Marsden Hospital, London, UK; The Institute of Cancer Research, London, UK.
Eur Urol. 2025 Jul 19. doi: 10.1016/j.eururo.2025.06.013.
The elucidation of prostate cancer biology and genomics has led to new therapies improving disease outcomes with novel androgen receptor (AR) pathway inhibitors (ARPIs), taxanes, and targeted therapeutics that require disease molecular stratification.
We are presenting a narrative and qualitative synthesis based on a systematic search. Medline (PubMed) and Embase (OvidSP) were searched (October 1, 2024, covering 2019-2024) using keywords and Medical Subject Headings terms; ClinicalTrials.gov and ASCO/ESMO abstracts were also reviewed. The inclusion criteria were phase 1-3 studies on molecular targets or therapies for metastatic prostate cancer with posted results. The exclusion criteria included non-English articles, reviews, meta-analyses, commentaries, case reports, duplicates, nonhuman/preclinical studies, protocols, and studies lacking molecular targets.
Targeted therapies have emerged for specific molecular subtypes of advanced prostate cancer. For instance, poly(ADP)-ribose polymerase inhibitors target DNA repair defective prostate cancer (especially BRCA2 and PALB2 biallelic loss). Immune checkpoint inhibitors against PD-1/PD-L1 are effective in hypermutated prostate cancer cases, especially those with mismatch repair defective (MMRd) disease. Additionally, 177Lu-PSMA-617 impacts prostate-specific membrane antigen (folate hydrolase) expressing disease. Several other major therapeutic advances are envisioned in the near future, including targeting novel cell surface proteins with T-cell engager antibody constructs, immunoconjugates, and radiopharmaceuticals. Other rational therapeutic strategies are being pursued, targeting continued AR signalling; AR cofactors, for example, P300; PI3K/AKT signalling; the PRC2 complex protein including EZH2; as well as novel synthetic lethal strategies.
A rapidly evolving standard of care is anticipated for metastatic prostate cancer, making it imperative that rational registration trial designs incorporating multipurpose biomarkers to accelerate anticancer drug development are pursued.
对前列腺癌生物学和基因组学的阐释催生了新的疗法，这些疗法通过新型雄激素受体（AR）通路抑制剂（ARPI）、紫杉烷类药物以及需要对疾病进行分子分层的靶向治疗，改善了疾病预后。
我们基于系统检索进行了叙述性和定性综合分析。使用关键词和医学主题词检索了Medline（PubMed）和Embase（OvidSP）（截至2024年10月1日，涵盖2019 - 2024年）；还查阅了ClinicalTrials.gov以及美国临床肿瘤学会（ASCO）/欧洲肿瘤内科学会（ESMO）的摘要。纳入标准为已公布结果的关于转移性前列腺癌分子靶点或治疗方法的1 - 3期研究。排除标准包括非英文文章、综述、荟萃分析、评论、病例报告、重复文献、非人类/临床前研究、方案以及缺乏分子靶点的研究。
针对晚期前列腺癌的特定分子亚型已出现靶向治疗方法。例如，聚（ADP）-核糖聚合酶抑制剂靶向DNA修复缺陷型前列腺癌（尤其是BRCA2和PALB2双等位基因缺失的情况）。针对PD - 1/PD - L1的免疫检查点抑制剂在高突变前列腺癌病例中有效，特别是那些错配修复缺陷（MMRd）疾病患者。此外，177Lu - PSMA - 617对表达前列腺特异性膜抗原（叶酸水解酶）的疾病有影响。预计在不久的将来还会有其他几项重大治疗进展，包括使用T细胞衔接抗体构建体、免疫缀合物和放射性药物靶向新型细胞表面蛋白。正在探索其他合理的治疗策略，如靶向持续的AR信号传导；AR辅因子，例如P300；PI3K/AKT信号传导；包括EZH2在内的PRC2复合体蛋白；以及新型合成致死策略。
预计转移性前列腺癌的治疗标准将迅速演变，因此必须采用合理的注册试验设计，纳入多用途生物标志物以加速抗癌药物研发。
