Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
Curr Oncol Rep. 2022 Nov;24(11):1619-1631. doi: 10.1007/s11912-022-01305-0. Epub 2022 Aug 6.
We highlight the clinical development of Poly (ADP-Ribose) polymerase (PARP) inhibitors in prostate cancer.
Approximately 10 to 30% of metastatic prostate cancer patients carry germline or somatic mutations in DNA repair pathways. BRCA2 is the most commonly mutated gene in DNA damage repair pathways. Because of its critical function in homologous recombination repair (HRR) machinery, deleterious BRCA2 mutation enables synthetic lethality to a PARP inhibitor. Olaparib demonstrated clinical benefit in patients with deleterious mutations in HRR-related genes and most clearly in patients with BRCA2 mutations. Olaparib received the US FDA approval or mCRPC patients with a qualifying HRR gene mutation in May 2020. Rucaparib received an accelerated FDA approval for patients with BRCA1- or BRCA2-mutated mCRPC based on 43% objective response rate in a phase II study. To expand the application of a PARP inhibitor, several trials have evaluated various combination strategies with an androgen receptor signaling inhibitor, immunotherapy, radium-223, and others. While no PARP inhibitor combination regimen has been approved, promising data from a PARP inhibitor and an ASI combination have been reported. PARP inhibitor represents a standard treatment for patient with mCRPC with germline or somatic mutations in BRCA2 and other HRR pathway genes.
我们强调聚（ADP-核糖）聚合酶（PARP）抑制剂在前列腺癌中的临床发展。
大约 10%至 30%的转移性前列腺癌患者携带 DNA 修复途径的种系或体细胞突变。BRCA2 是 DNA 损伤修复途径中最常突变的基因。由于其在同源重组修复（HRR）机制中的关键功能，有害的 BRCA2 突变使 PARP 抑制剂产生合成致死性。奥拉帕利在具有 HRR 相关基因有害突变的患者中以及在 BRCA2 突变患者中显示出临床获益。奥拉帕利于 2020 年 5 月获得美国食品和药物管理局（FDA）批准，用于具有合格 HRR 基因突变的 mCRPC 患者。基于 II 期研究中 43%的客观缓解率，鲁卡帕利获得了 FDA 对 BRCA1 或 BRCA2 突变的 mCRPC 患者的加速批准。为了扩大 PARP 抑制剂的应用，几项试验已经评估了与雄激素受体信号抑制剂、免疫疗法、镭-223 等联合使用的各种组合策略。虽然没有 PARP 抑制剂联合方案获得批准，但已经报道了 PARP 抑制剂和 ASI 联合的有希望的数据。PARP 抑制剂是 BRCA2 和其他 HRR 途径基因种系或体细胞突变的 mCRPC 患者的标准治疗方法。
