Naqvi Syed Arsalan Ahmed, Riaz Irbaz Bin, Bibi Arifa, Khan Muhammad Ali, Imran Manal, Khakwani Kaneez Zahra Rubab, Raina Ammad, Anjum Muhammad Umair, Cobran Ewan K, Warner Jeremy L, Hussain Syed A, Singh Parminder, Childs Daniel S, Baca Sylvan C, Orme Jacob J, Mateo Joaquin, Agarwal Neeraj, Gillessen Silke, Murad Mohammad Hassan, Sartor Oliver, Bryce Alan H
Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Phoenix, AZ, USA.
Division of Hematology and Oncology, Department of Medicine, Mayo Clinic, Phoenix, AZ, USA.
Eur Urol. 2025 Jan 22. doi: 10.1016/j.eururo.2024.12.007.
Selection of patients harboring mutations in homologous recombination repair (HRR) genes for treatment with a PARP inhibitor (PARPi) is challenging in metastatic castration-resistant prostate cancer (mCRPC). To gain further insight, we quantitatively assessed the differential efficacy of PARPi therapy among patients with mCRPC and different HRR gene mutations.
This living meta-analysis (LMA) was conducted using the Living Interactive Evidence synthesis framework. We included clinical trials assessing PARPi as monotherapy in pretreated mCRPC or in combination with an androgen receptor pathway inhibitor (ARPI) in treatment-naïve patients. Random-effects meta-analyses were performed for a priori subgroups stratified by HRR status, BRCA status, and each gene.
This first report for our LMA includes 13 trials (4278 patients). Among patients with pretreated mCRPC receiving PARPi monotherapy, the tumor response rate per 100 person-months was numerically higher for patients with BRCA2 (50% prostate-specific antigen response [PSA50%] 3.3; objective response rate [ORR] 3.3), BRCA1 (PSA50% 1.2; ORR 2.0), or PALB2 (PSA50% 3.3; ORR 1.4) alterations than for patients with ATM (PSA50% 0.4; ORR 0.3), CDK12 (PSA50% 0.2; ORR 0.2), or CHEK2 (PSA50% 1.0; ORR 0.7) alterations. Among patients receiving PARPi + ARPI, a significant radiographic progression-free survival benefit was observed in those with BRCA (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.13-0.62) or CDK12 (HR 0.58, 95% CI 0.35-0.95) alterations, but not in patients with PALB2 (HR 0.53, 95% CI 0.21-1.32), ATM (HR 0.93, 95% CI 0.57-1.53), or CHEK2 (HR 0.92, 95% CI 0.53-1.61) alterations. An overall survival benefit was observed for patients with BRCA alterations (HR 0.47, 95% CI 0.31-0.71) after adjustment for crossover and subsequent therapy, but not for patients with PALB2 (HR 0.33, 95% CI 0.10-1.16), ATM (HR 0.97, 95% CI 0.57-1.67), CDK12 (HR 0.80, 95% CI 0.36-1.78), or CHEK2 (HR 0.81, 95% CI 0.37-1.75) alterations.
Our LMA delivers information on the effect of PARPi therapy in relation to specific gene alterations in mCRPC via an interactive web platform. The evidence suggests the greatest PARPi benefit in patients with BRCA alterations, a strong signal of benefit in patients with PALB2 or CDK12 alterations, and no benefit in patients with ATM or CHEK2 alterations.
在转移性去势抵抗性前列腺癌（mCRPC）中，选择携带同源重组修复（HRR）基因突变的患者接受聚（ADP-核糖）聚合酶抑制剂（PARPi）治疗具有挑战性。为了进一步深入了解，我们定量评估了PARPi治疗在mCRPC患者及不同HRR基因突变患者中的疗效差异。
本动态荟萃分析（LMA）采用动态交互式证据综合框架进行。我们纳入了评估PARPi作为预处理mCRPC的单药治疗或与雄激素受体途径抑制剂（ARPI）联合用于初治患者的临床试验。对按HRR状态、BRCA状态和每个基因分层的先验亚组进行随机效应荟萃分析。
我们LMA的第一份报告包括13项试验（4278例患者）。在接受PARPi单药治疗的预处理mCRPC患者中，携带BRCA2（50%前列腺特异性抗原反应率[PSA50%]为3.3；客观缓解率[ORR]为3.3）、BRCA1（PSA50%为1.2；ORR为2.0）或PALB2（PSA50%为3.3；ORR为1.4）改变的患者每100人月的肿瘤反应率在数值上高于携带ATM（PSA50%为0.4；ORR为0.3）、CDK12（PSA50%为0.2；ORR为0.2）或CHEK2（PSA50%为1.0；ORR为0.7）改变的患者。在接受PARPi + ARPI治疗的患者中，携带BRCA（风险比[HR]为0.28，95%置信区间[CI]为0.13 - 0.62）或CDK12（HR为0.58，95% CI为0.35 - 0.95）改变的患者观察到显著的影像学无进展生存获益，但携带PALB2（HR为0.53，95% CI为0.21 - 1.32）、ATM（HR为0.93，95% CI为0.57 - 1.53）或CHEK2（HR为0.92，95% CI为0.53 - 1.61）改变的患者未观察到。在对交叉和后续治疗进行调整后，携带BRCA改变的患者观察到总生存获益（HR为0.47，95% CI为0.31 - 0.71），但携带PALB2（HR为0.33，95% CI为0.10 - 1.16）、ATM（HR为0.97，95% CI为0.57 - 1.67）、CDK12（HR为0.80，95% CI为0.36 - 1.78）或CHEK2（HR为0.81，95% CI为0.37 - 1.75）改变的患者未观察到。
我们的LMA通过交互式网络平台提供了关于PARPi治疗与mCRPC中特定基因改变相关的疗效信息。证据表明，携带BRCA改变的患者从PARPi治疗中获益最大，携带PALB2或CDK12改变的患者有明显的获益信号，而携带ATM或CHEK2改变的患者无获益。
