聚腺苷二磷酸核糖聚合酶抑制剂在去势抵抗性前列腺癌转移中的差异活性。
Differential Activity of PARP Inhibitors in - Versus -Altered Metastatic Castration-Resistant Prostate Cancer.
机构信息
Johns Hopkins University School of Medicine, Baltimore, MD.
Medstar Health Georgetown University, Baltimore, MD.
出版信息
JCO Precis Oncol. 2021 Jul 22;5. doi: 10.1200/PO.21.00070. eCollection 2021.
UNLABELLED
Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring / mutations, but the relative efficacy of PARP inhibition in - versus -altered mCRPC is understudied.
METHODS
We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with /-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among - versus -altered mCRPC.
RESULTS
A total of 123 patients (13 and 110 ) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. patients were more likely to have metastatic disease at presentation (69% 37%; = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% 46%; = .78) in both groups. patients had more monoallelic (56% 41%; = .49) and concurrent (55% 36%; = .32) mutations. PSA responses in - versus -altered patients were 23% versus 63%, respectively ( = .01). patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent mutation were associated with PARP inhibitor sensitivity.
CONCLUSION
PARP inhibitor efficacy is diminished in - versus -altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent alterations in the group.
背景
两种聚 ADP-核糖聚合酶（PARP）抑制剂（奥拉帕尼和鲁卡帕尼）已获美国食品和药物管理局批准用于治疗携带 / 突变的转移性去势抵抗性前列腺癌（mCRPC）患者，但 PARP 抑制在 - 与 - 改变的 mCRPC 中的相对疗效仍在研究中。
方法
我们进行了一项涉及 12 个地点的多中心回顾性分析。我们从接受 PARP 抑制剂治疗的 123 名 /-改变的 mCRPC 患者中收集了基因组和临床数据。主要疗效终点是前列腺特异性抗原（PSA）应答率（≥50% PSA 下降）。次要终点是 PSA 无进展生存期（PSA-PFS）、临床或放射影像学无进展生存期（PFS）和总生存期。我们比较了 - 与 - 改变的 mCRPC 之间的临床结局和其他基因组特征。
结果
共纳入 123 名患者（13 名和 110 名）。使用的 PARP 抑制剂分别为奥拉帕尼（n=116）、鲁卡帕尼（n=3）、他拉唑帕尼（n=2）和 veliparib（n=2）。在诊断时，72%的患者有 Gleason 8-10 疾病。 患者更有可能在发病时出现转移性疾病（69% vs 37%； =.04）。年龄、基线 PSA、转移性分布和以前系统治疗的类型在两组之间相似。两组的种系突变比例相等（51% vs 46%； =.78）。 患者有更多的单等位基因突变（56% vs 41%； =.49）和同时存在的 突变（55% vs 36%； =.32）。- 与 - 改变的患者的 PSA 反应率分别为 23%和 63%（ =.01）。 患者获得了更长的 PSA-PFS（HR，1.94；95%CI，0.92 至 4.09； =.08）、PFS（HR，2.08；95%CI，0.99 至 4.40； =.05）和总生存期（HR，3.01；95%CI，1.32 至 6.83； =.008）。双等位基因突变（与单等位基因突变相比）、截断突变（与错义突变相比）和不存在同时存在的 突变与 PARP 抑制剂敏感性相关。
结论
PARP 抑制剂在 - 与 - 改变的 mCRPC 中的疗效降低。这不是由于种系突变的不平衡造成的，而是可能与 - 组中更多的单等位基因突变和/或同时存在的 改变有关。
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