Department of Urology, Institute of Urology, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, Sichuan, 610041, P.R. China.
BMC Cancer. 2024 Jun 8;24(1):706. doi: 10.1186/s12885-024-12388-2.
BACKGROUND: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting. METHOD: We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation. RESULTS: Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE. CONCLUSION: PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen. TRIAL REGISTRATION: CRD42023454079.
背景：聚（ADP-核糖）聚合酶抑制剂（PARPi）已越来越多地用于同源重组修复缺陷（HRD）的转移性去势抵抗性前列腺癌（mCRPC）患者。然而，在二线治疗中，哪种 PARPi 对 HRD 的 mCRPC 患者最有效尚不清楚。
方法：我们对二线治疗中基于 PARPi 的治疗 mCRPC 的试验进行了系统评价，并进行了贝叶斯网络荟萃分析（NMA）。评估影像学无进展生存期（rPFS）作为主要结局。PSA 反应和不良事件（AE）作为次要结局进行评估。根据特定基因突变进行亚组分析。
结果：纳入了四项 RCT，共纳入 1024 例患者（763 例存在同源重组修复（HRR）突变）进行定量分析。关于 rPFS，奥拉帕利单药、鲁卡帕利和西地尼布联合奥拉帕利与阿比特龙联合泼尼松相比显示出显著改善。奥拉帕利联合西地尼布在 rPFS 方面的累积排序曲线下面积（SUCRA）评分最高（87.5%），其次是鲁卡帕利、奥拉帕利和奥拉帕利联合阿比特龙。对于 BRCA1/2 突变患者，奥拉帕利与 rPFS 改善的概率最高（98.1%）相关。对于 BRCA-2 突变患者，奥拉帕利和奥拉帕利联合西地尼布具有相似的疗效。然而，在 ATM 突变患者中，奥拉帕利和鲁卡帕利均未显示出比雄激素受体轴靶向治疗（ARAT）更显著的有效性。安全性方面，奥拉帕利的≥3 级不良事件发生率明显低于西地尼布联合奥拉帕利（RR：0.72，95%CI：0.51，0.97），而奥拉帕利联合西地尼布则与全等级不良事件风险最高相关。
结论：PARPi 治疗在二线治疗中对 HRD 的 mCRPC 患者具有显著疗效。然而，应根据患者的遗传背景以及所选方案的疗效和安全性对患者进行相应治疗。
试验注册：CRD42023454079。
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