The Institute of Cancer Research.
The Royal Marsden NHS Foundation Trust, Sutton, U.K.
Curr Opin Oncol. 2020 Sep;32(5):503-509. doi: 10.1097/CCO.0000000000000654.
Prostate cancer is the second leading cause of cancer death in men. Characterization of the genomic landscape of prostate cancer has demonstrated frequent aberrations in DNA repair pathways, identifiable in up to 25% patients with metastatic disease, which may sensitize to novel therapies, including PARP inhibitors and immunotherapy. Here, we summarize the current clinical landscape and future horizons for targeting defective DNA repair pathways in PC.
Several clinical trials have demonstrated efficacy of different PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC), most pronounced in those with BRCA mutations. The PROfound trial is the first positive phase 3 biomarker-selected trial to demonstrate improved outcomes with a targeted treatment, Olaparib, in mCRPC. Whilst the Keynote-199 trial failed to demonstrate efficacy of immune-checkpoint inhibitor pembrolizumab in unselected mCRPC patients, there was evidence of response in those harbouring DNA repair defects.
These landmark trials represent a significant advance towards personalization of PC therapy. However, resistance remains inevitable and there is a lack of reliable predictive biomarkers to select patients for treatment. Characterization of resistance mechanisms, and validation of novel biomarkers is critical to maximize clinical benefit and inform novel treatment combinations to improve outcomes.
目的综述：前列腺癌是男性癌症死亡的第二大主要原因。对前列腺癌基因组图谱的特征分析表明，多达 25%的转移性疾病患者存在 DNA 修复途径的频繁异常，这可能对包括 PARP 抑制剂和免疫疗法在内的新型疗法敏感。在此，我们总结了针对 PC 中缺陷 DNA 修复途径的当前临床现状和未来前景。
最新发现：几项临床试验表明，不同的 PARP 抑制剂在转移性去势抵抗性前列腺癌（mCRPC）中具有疗效，在存在 BRCA 突变的患者中效果最为显著。PROfound 试验是首个阳性的基于生物标志物选择的 III 期临床试验，证明了靶向治疗奥拉帕利在 mCRPC 中的改善结局。虽然 Keynote-199 试验未能证明免疫检查点抑制剂 pembrolizumab 在未选择的 mCRPC 患者中的疗效，但在存在 DNA 修复缺陷的患者中存在有反应的证据。
总结：这些具有里程碑意义的试验代表了前列腺癌治疗个体化的重大进展。然而，耐药性仍然不可避免，并且缺乏可靠的预测性生物标志物来选择接受治疗的患者。因此，明确耐药机制并验证新型生物标志物对于最大限度地提高临床获益和为改善结果提供新的治疗组合至关重要。
