奥拉帕利(Olaparib) - 药物靶点：PARP1 x PARP2 x PARP3_在研适应症：晚期子宫内膜癌，复发性子宫内膜癌，BRCA突变阳性乳腺癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

4-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)phthalazin-1(2H)-one、Olaparib (JAN/USAN/INN)、奥拉帕尼

+ [14]

靶点

PARP1 x PARP2 x PARP3

作用方式

抑制剂

作用机制

PARP1抑制剂(聚腺苷二磷酸核糖聚合酶1抑制剂)、PARP2抑制剂(聚腺苷二磷酸核糖聚合酶2抑制剂)、PARP3抑制剂(聚腺苷二磷酸核糖聚合酶3抑制剂)

治疗领域

肿瘤消化系统疾病内分泌与代谢疾病+ [8]

在研适应症

晚期子宫内膜癌复发性子宫内膜癌BRCA突变阳性乳腺癌+ [135]

非在研适应症

晚期宫颈癌晚期胃癌晚期非小细胞肺癌+ [39]

原研机构

AstraZeneca PLC

在研机构

AstraZeneca AB

Merck Sharp & Dohme Corp.

AstraZeneca PLC

+ [14]

非在研机构

Novartis Pharmaceuticals Corp.

Syndax Pharmaceuticals, Inc.

Sandoz Group AG

+ [1]

权益机构

Merck & Co., Inc.

AstraZeneca PLC

Breast International Group

+ [1]

最高研发阶段批准上市

首次获批日期

欧盟 (2014-12-16),

BRCA突变去势抵抗性前列腺癌BRCA突变输卵管癌BRCA 突变卵巢癌+ [12]

最高研发阶段(中国)批准上市

特殊审评突破性疗法 (美国)、快速通道 (美国)、加速批准 (美国)、孤儿药 (美国)、附条件批准 (中国)、特殊审批 (中国)、孤儿药 (日本)、优先审评 (澳大利亚)、加速批准 (加拿大)、优先审评 (美国)、优先审评 (中国)

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结构/序列

分子式C24H23FN4O3

InChIKeyFDLYAMZZIXQODN-UHFFFAOYSA-N

CAS号763113-22-0

关联

520

项与奥拉帕利相关的临床试验

CTIS2025-522431-34-00

/ Not yet recruiting临床2期

TAILOR-PANC: Molecularly Tailored Therapy versus Standard Care in Advanced Pancreatic Cancer (DPCG-02)

开始日期2026-10-01

申办/合作机构

Region Hovedstadens Apotek

NCT05522491

/ Not yet recruiting临床2期IIT

An Open-label, Single-arm, Single-center Exploratory Clinical Study of Olaparib in the Treatment of BRCA1/2 Unmutated and BRCA1 Promoter Methylated Recurrent and Metastatic Triple-negative Breast Cancer

This is an open-label, single-arm, single-center,exploratory clinical study.

开始日期2026-09-01

申办/合作机构

河北医科大学第四医院

NCT07647653

/ Not yet recruiting临床2期IIT

A Multicenter, Randomized, Open-Label Exploratory Study of Fluzoparib Plus Bevacizumab Versus Olaparib Plus Bevacizumab for Maintenance Therapy After First-Line Platinum-Based Chemotherapy in Patients With HRD-Positive Advanced Ovarian Cancer

The PAOLA-1 trial demonstrated that for HRD-positive patients who received first-line chemotherapy combined with bevacizumab, sequential maintenance therapy with olaparib plus bevacizumab yielded a progression-free survival (PFS) of up to 46.8 months, with an olaparib-related treatment discontinuation rate of approximately 20%.
The combination of olaparib and bevacizumab has been recommended by multiple clinical guidelines as the first-line maintenance regimen for HRD-positive patients treated with first-line chemotherapy plus bevacizumab. This regimen has obtained approved indications and been covered by national medical insurance. In clinical practice, around 30% of patients receiving chemotherapy plus bevacizumab adopt olaparib combined with bevacizumab for first-line maintenance treatment.
Fluzoparib has been approved in China for first-line maintenance therapy in the overall patient population. The treatment discontinuation rate of fluzoparib plus apatinib is merely about 2%. However, there is currently no available data regarding fluzoparib combined with bevacizumab in the HRD-positive population, and the clinical value of this regimen remains to be further explored.
This study aims to generate efficacy and safety data for olaparib plus bevacizumab versus fluzoparib plus bevacizumab in HRD-positive patients who have undergone first-line chemotherapy combined with bevacizumab, so as to provide objective evidence for clinical medication decisions.

开始日期2026-06-30

申办/合作机构

山东大学

100 项与奥拉帕利相关的临床结果

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100 项与奥拉帕利相关的转化医学

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100 项与奥拉帕利相关的专利（医药）

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4,496

项与奥拉帕利相关的文献（医药）

2026-12-31·CANCER BIOLOGY & THERAPY

Evaluating carboplatin and PARP inhibitor combination efficacy using high-grade serous carcinoma spheroids and organoids

Article

作者: Tomas, Emily J. ; Davis, Jennifer ; Ramos Valdes, Yudith ; Shepherd, Trevor G.

BACKGROUND:

PARP inhibitors (PARPis) are new targeted agents that exploit homologous recombination DNA repair deficiencies (HRDs), which are present in 50% of high-grade serous carcinoma (HGSC) cases. Currently, olaparib is approved as maintenance therapy for BRCA1/2-mutated HGSC, and niraparib is approved for platinum-sensitive recurrent disease. However, research is currently expanding their potential as front-line agents or in combination with carboplatin, a standard HGSC chemotherapeutic.

METHODS:

Immortalized ovarian cancer (iOvCa) cell lines, developed from HGSC patient ascites, were treated with carboplatin, olaparib and niraparib to determine their sensitivity. Immunofluorescence analysis of RAD51 was conducted for HRD testing of all the cell lines. The cell lines were cultured as three-dimensional organoids and spheroids to mimic tumor growth and metastasis, respectively, and then treated to assess the effects of different drug combinations.

RESULTS:

The half-maximal inhibitory concentrations of olaparib and niraparib varied across our iOvCa cell lines, with iOvCa195 BRCA1-mutant line exhibiting the expected high sensitivity to both PARPis. Direct combination of carboplatin with olaparib or niraparib enhanced cell killing, yet achieved cell viability levels to those of carboplatin alone. In sequential experiments, carboplatin followed by either PARPi or vice versa showed no significant difference in cell viability to carboplatin alone, except in iOvCa195 organoids when treated with a PARPi first.

CONCLUSIONS:

Overall, first-line carboplatin treatment remains ideal, yet there may be select utility for PARPi prior to chemotherapy. Using patient-derived tumor models such as spheroids and organoids may provide insights for on-going and future clinical trials to enhance therapeutic outcomes for HGSC patients.

2026-12-01·MOLECULAR BIOLOGY REPORTS

Targeting SRPK1 to regulate alternative splicing in prostate cancer: the roles of MALAT1 and TUG1

Article

作者: Basera, Afra ; Dlamini, Zodwa ; Alabi, Babatunde Adebola ; Gabada, Linomtha ; Marima, Rahaba

BACKGROUND:

Prostate cancer (PCa) is a leading cause of cancer-related mortality, with significant racial disparities in outcomes. Long non-coding RNAs (lncRNAs) MALAT1 and TUG1 are implicated in oncogenic pathways. Aberrant RNA splicing, a hallmark of cancer, is often driven by dysregulation of serine-arginine protein kinase 1 (SRPK1), a key spliceosome regulator. The relationship between lncRNAs of splicing factors in cancer pathways remains underexplored, and thus, this study aimed to elucidate the roles of MALAT1 and TUG1 lncRNAs in relation to the SRPK1 inhibitor SPHINX31 in PCa.

METHODS:

Bioinformatics tools were used to analyze interactions between` MALAT1, TUG1, relevant miRNAs, and target genes. A resazurin assay assessed PCa cell viability (PC-3 vs. HEK293) in response to SPHINX31 at 24 and 48 h. RT-qPCR was used to quantify MALAT1 and TUG1 lncRNAs expression levels.

RESULTS:

The Alamar Blue assay indicated a time-dependent reduction in PC3 cell viability with 3 µM SPHINX31, particularly at 48 h. RT-qPCR revealed significant regulation of MALAT1 and TUG1, highlighting SRPK1's role in RNA pathways critical for tumor survival. SPHINX31 induced similar cytotoxic effects in HEK293 cells, illustrating the need for selective tumor specificity. MALAT1 expression was upregulated at 24 h, followed by a decline at 48 h, indicating cumulative cellular stress in PC-3 cells.

DISCUSSION:

This study demonstrated that SRPK1 inhibition alters lncRNA expression and splicing-related events in PCa. These findings highlight SPHINX31's potential as a therapeutic agent, especially in combination with treatments like Olaparib, necessitating further optimization for selectivity and reduced off-target effects.

2026-07-01·BIOORGANIC CHEMISTRY

Design and synthesis of novel isatin-isoniazidhydrazone hybrid-based 1,2,3-triazoles as dual EGFR/PARP-1 inhibitors and apoptosis inducers in breast cancer cells

Article

作者: Nafie, Mohamed S ; Alshams, Muna A ; Moussa, Ziad ; Rezki, Nadjet ; Aouad, Mohamed Reda ; Ravi, Anil

In this study, an efficient click synthesis has been employed to combine isatin, Schiff base, and 1,2,3-triazole in a single framework. Propargylation of 5-bromoisatin, followed by condensation with isoniazid, furnished the corresponding isatin-isoniazid hydrazone-based alkyne intermediate. Subsequent CuAAC reaction with a series of aromatic azides afforded a library of 1,2,3-triazole derivatives incorporating isatin-isoniazid hydrazone conjugates. The synthesized click adducts were characterized using the appropriate spectroscopic techniques, including ¹H, ¹³C, and ¹⁹F NMR, and HRMS. They were also subjected to dual EGFR/PARP-1 inhibition and cytotoxic screening in MDA-MB-231 TNBC cells, and apoptosis induction was assessed by flow cytometry and RT-PCR. Compounds 9, 10, and 11 exhibited IC₅₀ values of 93, 64, and 78 nM, respectively, compared to Erlotinib (IC₅₀ = 80 nM); they exhibited IC₅₀ values of 76, 12, and 28 nM, respectively, compared to Olaparib (IC₅₀ = 12 nM). They showed potent cytotoxicity against MDA-MB-231 cells with IC₅₀ values of 16.3 ± 0.4, 1.27 ± 0.1, and 3.46 ± 0.1 μM, respectively. However, when tested against normal MCF-10 A cells, they showed low cytotoxicity and greater IC₅₀ values. The cell cycle was halted at the G2-phase by compound 10, which promoted apoptosis 7.16-fold. The MDA-MB-231 cancer cells' apoptosis-related genes were impacted. Molecular docking analysis revealed good binding disposition of compound 10 to the two EGFR/PARP-1 target proteins.

2,211

项与奥拉帕利相关的新闻（医药）

2026-06-22

·ioncology

国际视野丨伴BRCA突变的转移性前列腺癌的PARP抑制剂治疗策略演变

点击上方蓝字关注我们编者按：约有7%-10%的转移性前列腺癌患者携带BRCA1或BRCA2突变，这不仅预示着更为严峻的预后，也表明PARP抑制剂可能会带来良好疗效。值得关注的是，随着临床治疗策略进一步发展，ARPI已逐步成为转移性激素敏感性前列腺癌（mHSPC）的标准一线治疗方案，且应用时机不断前移。这一转变，让主要针对未接受过ARPI治疗人群的PARP抑制剂临床试验数据解读面临更多挑战，也让现有治疗方案的最优排序成为关注焦点。肿瘤瞭望-泌尿时讯特别整理相关内容，以飨读者。亮点抢先看 1 对于未接受过ARPI治疗的BRCA突变mCRPC患者，应考虑ARPI联合PARP抑制剂作为一线治疗方案。对于更广泛的HRR缺陷人群，以及既往接受过醋酸阿比特龙治疗的mHSPC患者，他拉唑帕利联合恩扎卢胺也可能适用。 2 对于既往接受过ARPI治疗的BRCA突变（以及HRR缺陷）患者，PARP抑制剂单药治疗仍然是一项关键策略，理想情况下应在紫杉烷类化疗之前进行。在转移性去势抵抗性前列腺癌（mCRPC）的治疗探索中，TALAPRO-2、PROpel和MAGNITUDE三项III期临床试验评估了PARP抑制剂联合ARPI方案一线治疗的疗效。研究结果表明：相较于ARPI单药，联合方案在BRCA突变患者群体中疗效显著，在同源重组修复（HRR）缺陷患者中也展现出一定优势，显著延长了影像学无进展生存期（rPFS）。值得一提的是，TALAPRO-2试验进一步揭示，恩扎卢胺联合他拉唑帕利，不仅在BRCA突变患者中，更在HRR缺陷人群中实现了总生存期（OS）的延长，为该联合方案获批覆盖更广泛的HRR缺陷人群提供了坚实依据。然而，临床实践与研究设计之间存在现实差异。多数研究纳入的受试者此前未接受过ARPI治疗，这与当下临床治疗中ARPI应用愈发普及的现状逐渐不符，导致mCRPC患者中符合治疗条件的人群受限。尽管醋酸阿比特龙治疗后序贯恩扎卢胺仍能保留部分疗效，但后续PARP抑制剂治疗的有效性证据仍然有限。在TALAPRO-2研究里，HRR缺陷队列中仅16例患者曾接受醋酸阿比特龙治疗，探索性分析显示联合用药在rPFS和OS上优于PARP抑制剂单药；MAGNITUDE研究纳入的ARPI经治患者同样有限，即便在BRCA突变队列观察到rPFS的积极信号，也难以充分解读疗效；PROpel研究则仅纳入1例ARPI经治患者。由此，PARP抑制剂联合ARPI在ARPI治疗进展后能否带来显著获益，仍悬而未决。正在进行的CASPAR和FUZUPRO等研究，允许mHSPC患者既往接受ARPI治疗，有望为序贯治疗方案的优化提供重要数据。现阶段，对于未接受过ARPI治疗的BRCA突变mCRPC患者，PARP抑制剂联合ARPI仍是首选的一线治疗方案；他拉唑帕利联合恩扎卢胺，也适用于更广泛的HRR缺陷人群。对于既往接受过醋酸阿比特龙治疗的BRCA突变mHSPC患者，虽疗效数据有限，但后续使用他拉唑帕利联合恩扎卢胺也可能是一个合理的选择。后线治疗：PARP抑制剂单药筑牢标准防线 PROfound和TRITON-3试验，成功奠定了奥拉帕利和卢卡帕利作为既往接受过ARPI治疗的BRCA突变（奥拉帕利同时适用于HRR缺陷）mCRPC患者标准单药治疗的地位。现有证据支持在多西他赛化疗前序贯使用PARP抑制剂，但对于侵袭性强，或已接受一线三药联合治疗的患者，这一方案需审慎对待。对于既往接受过ARPI治疗的BRCA突变mHSPC患者，PARP抑制剂单药治疗仍是重要治疗选项，尤其适用于除醋酸阿比特龙外接受过其他ARPI治疗的患者，毕竟ARPI之间转换的疗效证据相对薄弱。尽管治疗选择日益丰富，但核心原则始终明确：BRCA突变患者，无论单药还是联合，都应在疾病进程中接受PARP抑制剂治疗。早期布局：PARP抑制剂联合方案向mHSPC前移基于mCRPC中已确立的联合治疗策略，PARP抑制剂联合ARPI方案向mHSPC的早期强化治疗探索正在开展。AMPLITUDE试验聚焦尼拉帕利联合醋酸阿比特龙治疗HRR缺陷mHSPC，结果显示，相较于醋酸阿比特龙联合安慰剂，联合方案显著提升了无进展生存期（rPFS），且在BRCA突变亚组中获益尤为突出，该亚组中位rPFS尚未达到，对照组则为26个月（HR 0.52，P<0.0001），凭借这一成果，该方案成功获得监管机构批准。与此同时，TALAPRO-3和EvoPAR-PR-01等研究，正持续挖掘PARP抑制剂在mHSPC治疗中的潜力。如同众多药物从后线迈向一线的发展历程，PARP抑制剂未来有望在分子分型精准筛选的患者中，更早发挥治疗效能。在此背景下，早期开展基因组检测，精准识别HRR基因改变，成为关键之举。这不仅为当下治疗决策提供精准导航，更能顺应治疗格局的动态演变，为后续治疗的序贯方案奠定基础。随着治疗的进步，患者生存期延长，早期使用PARP抑制剂可能引发的长期或迟发性毒性，尤其是靶向放射性配体治疗时代对骨髓功能的潜在影响，亟待临床重点关注与审慎权衡。结语：精准布局，把握治疗核心脉络回顾目前的前列腺癌治疗格局，三大核心要点浮现：其一，转移性前列腺癌患者应尽早、全面开展基因组分析，为精准治疗奠基；其二，对于未接受过ARPI治疗的BRCA突变mCRPC患者，ARPI联合PARP抑制剂应作为一线优选方案，他拉唑帕利联合恩扎卢胺同样适用于更广泛的HRR缺陷人群，以及既往接受过醋酸阿比特龙治疗的mHSPC患者；其三，对于既往接受过ARPI治疗的BRCA突变患者（奥拉帕利还适用于HRR缺陷患者），PARP抑制剂单药仍是关键治疗策略，理想状态下，应在紫杉烷类化疗前启用，为患者争取更大生存获益。参考文献上下滑动查看更多内容 [1]. Valsecchi AA, Dionisio R, Panepinto O, et al. Frequency of germline and somatic BRCA1 and BRCA2 mutations in prostate cancer: an updated systematic review and meta-analysis. Cancers (Basel). 2023;15(9):2435. [2]. Fettke H, Dai C, Kwan EM, et al. BRCA-deficient metastatic prostate cancer has an adverse prognosis and distinct genomic phenotype. EBioMedicine. 2023;95:104738. [3]. Fizazi K, Azad AA, Matsubara N, et al. First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial. Nat Med. 2024;30(1):257-264. [4]. Fizazi K, Azad AA, Matsubara N, et al. Talazoparib plus enzalutamide in men with HRR-deficient metastatic castration-resistant prostate cancer: final overall survival results from the randomised, placebo-controlled, phase 3 TALAPRO-2 trial. Lancet. 2025;406(10502):461-474. [5]. Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(10):1094-1108. [6]. Chi KN, Castro E, Attard G, et al. Niraparib and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: final overall survival analysis for the phase 3 MAGNITUDE trial. Eur Urol Oncol. 2025;8(4):986-998. [7]. U.S. Food and Drug Administration. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. May 31, 2023. Accessed December 24, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration. [8]. U.S. Food and Drug Administration. FDA approves niraparib and abiraterone acetate plus prednisone for BRCA2-mutated metastatic castration-sensitive prostate cancer. FDA.gov. December 12, 2025. Accessed December 24, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-and-abiraterone-acetate-plus-prednisone-brca2-mutated-metastatic-castration. [9]. U.S. Food and Drug Administration. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. June 20, 2023. Accessed December 24, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate. [10]. AstraZeneca. Lynparza in combination with abiraterone approved in the EU as 1st-line treatment for patients with metastatic castration-resistant prostate cancer. AstraZeneca.com. December 21, 2022. Accessed December 24, 2025. https://www.astrazeneca.com/media-centre/press-releases/2022/lynparza-approved-in-eu-for-prostate-cancer.html#. [11]. Johnson & Johnson. Janssen marks first approval worldwide for AKEEGA® (niraparib and abiraterone acetate dual action tablet) with EC authorization for the treatment of patients with metastatic castration resistant prostate cancer with BRCA1/2 mutations. JnJ.com. April 21, 2023. Accessed December 24, 2025. https://www.jnj.com/media-center/press-releases/janssen-marks-first-approval-worldwide-for-akeega-niraparib-and-abiraterone-acetate-dual-action-tablet-with-ec-authorization-for-the-treatment-of-patients-with-metastatic-castration-resistant-prostate-cancer-with-brca1-2-mutations. [12]. Pfizer. European Commission approves Pfizer’s TALZENNA® in combination with XTANDI® for adult patients with metastatic castration-resistant prostate cancer. Pfizer.com. January 8, 2024. Accessed December 24, 2025. https://www.pfizer.com/news/press-release/press-release-detail/european-commission-approves-pfizers-talzennar-combination. [13]. Khalaf DJ, Annala M, Taavitsainen S, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 2019;20(12):1730-1739. [14]. Hussain M, Mateo J, Fizazi K, et al; PROfound Trial Investigators. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383(24):2345-2357. [15]. Fizazi K, Piulats JM, Reaume MN, et al; TRITON3 Investigators. Rucaparib or physician’s choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719-732. [16]. Attard G, Agarwal N, Graff JN, et al. Niraparib and abiraterone acetate plus prednisone for HRR-deficient metastatic castration-sensitive prostate cancer: a randomized phase 3 trial. Nat Med. 2025;31(12):4109-4118. （来源：《肿瘤瞭望-泌尿时讯》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

2026-06-22

·药通社

刚刚，辉瑞重磅大药，全新适应症申报！

6月22日，CDE官网显示，辉瑞的2.4类的甲苯磺酸他拉唑帕利胶囊上市申请获受理，适应症未知。甲苯磺酸他拉唑帕利胶囊是一款PARP抑制剂，2018年，他拉唑帕利首次在美国获批上市，用于治疗携带有害或疑似有害生殖细胞BRCA突变（gBRCAm）的 HER2 阴性局部晚期或转移性乳腺癌成年患者。他拉帕利最早在美国获批用于乳腺癌，但国内暂时只批了前列腺癌相关适应症。在国内，目前他拉帕利仅有1项适应症：联合恩扎卢胺用于HRR基因突变的转移性去势抵抗性前列腺癌 (mCRPC) 成人患者，于2024年11月获NMPA批准商品名：泰泽纳®。今年1月，甲苯磺酸他拉唑帕利胶囊曾有一次上市申请被发了通知件，注册分类5.1，属于境外已批准，但中国境内尚未批准的新适应症上市分类，据注册分类推测，当时报产的适应症应为胚系 BRCA 突变的 HER2 阴性乳腺癌。但该适应症上市却最终未获批准，该受理号于2025年4月16日获受理，今年1月27日收到通知件，审评时间不过7个月，不知后续是否还会重新申报。而辉瑞此番的适应症与上述适应症不同，此次注册分类为2.4类，属于国内外均未获批的适应症，暂无法推测是哪种适应症。 PARP 抑制剂是首个基于合成致死概念取得成功的药物，目前国内已批准 6 款。除他拉唑帕利外，还有奥拉帕利（阿斯利康）、帕米帕利（百济神州）、尼拉帕利（再鼎医药）、氟唑帕利（恒瑞医药）和塞纳帕利（英派药业）。他拉唑帕利是辉瑞花费140亿美金收购而来，最先由BioMarin公司研发，后来它被Medivation公司收购。直到2016年，辉瑞一眼看中了它的潜力，直接砸下重金，把Medivation整个公司都买了下来，只为把这款药攥在自己手里。奥拉帕利是最畅销的PARP抑制剂，2024年销售额为30.72亿美元，他拉唑帕利去年收入了1.17亿美元。参考：丁香园肿瘤时间 ↓⭐关注药通社，洞见行业趋势↓

2026-06-21

·今日头条

破局者EXO1：一个"叛变"的DNA修理工，意外改写抗癌药产业棋盘生物医药圈最近冒出个反常理的现象：一个本该扮演DNA保镖角色的修复蛋白，在部分癌细胞里非正常堆积，结果把自己活成了"内鬼"。宾夕法尼亚州立大学医学院刚在《Nature Communications》上发了一篇研究，讲的就是这件

破局者EXO1：一个"叛变"的DNA修理工，意外改写抗癌药产业棋盘生物医药圈最近冒出个反常理的现象：一个本该扮演DNA保镖角色的修复蛋白，在部分癌细胞里非正常堆积，结果把自己活成了"内鬼"。宾夕法尼亚州立大学医学院刚在《Nature Communications》上发了一篇研究，讲的就是这件事。那个叫EXO1的蛋白，天然功能是剪掉DNA的破损碎片，相当于基因组维修队里的剪刀手。但数据表明，一旦它在细胞里的浓度超标，这把剪刀就开始失去节制，专挑刚复制完成的新生DNA下手，把癌细胞的遗传物质拆得支离破碎。这就有意思了——癌细胞明明已经够不安分，为什么还要自毁长城？对产业观察者来说，这件事的看点不在实验室，在数据库。研究团队过了一遍美国国家癌症研究所的肿瘤数据库，EXO1过表达信号在乳腺和卵巢两类癌种里检出率最高，大约能扫到两到三成的病例。黑色素瘤、睾丸癌、宫颈癌、肝胆癌也有被波及。更耐人寻味的是，EXO1过表达的癌细胞即便BRCA基因完全正常，表现出的行为特征却和BRCA突变的癌细胞惊人地相似。产业痛点的卡位：从"先天缺陷"到"后天状态" BRCA靶向药这几年的市场热度，行业有目共睹。奥拉帕尼这类PARP抑制剂打的是"合成致死"牌——癌细胞BRCA坏了，再切断它的备用修复通路，癌细胞就扛不住。但这个策略有一个结构性的限制：BRCA突变在全部乳腺癌里的占比撑死不到一成。适应症的盘子就这么大，天花板肉眼可见。 EXO1过表达给行业提了个新思路。不用改基因，单纯靠蛋白过表达就能复刻出BRCA突变类似的细胞脆弱性。这个差异对制药企业来说意味着靶点筛选的逻辑正在发生偏移——从"找先天缺陷"转向"找后天状态"。研究团队用奥拉帕尼和顺铂做了验证实验，EXO1高表达的肿瘤对两种药都表现出敏感。对产业端而言，这抛出了一个需要认真计算的问题：现有PARP抑制剂的适应症天花板，是否被重新测量？工艺壁垒的盲区：剂量是工具，也是武器再往产业深处挖一层，EXO1过表达这件事本身折射出一个长期被低估的工艺问题——基因表达量的调控，远远比"有或无"复杂得多。研究团队的实验设计很刁钻。他们不敲除基因，而是人为拉高EXO1的表达浓度，观察蛋白"超载"后的连锁反应。结果显示，过量的EXO1通过两条路径搞破坏：扩大单链DNA间隙、降解反向复制叉。翻译成大白话就是，蛋白浓度超过系统能承受的临界点后，它的角色就从"维修工具"切换成了"拆迁武器"。这个逻辑在产业端完全成立。细胞株构建阶段、蛋白生产环节、工艺放大过程，每一步都需要精准把控目标蛋白的表达量。表达量过高，宿主细胞可能直接崩盘；表达量过低，产量又上不去。 EXO1提供的不是一个医学启示，而是一个剂量调控失控的极端样本——失控的后果不是低效，是毁灭。行业格局的变量：生物标志物池子里多了个新候选研究团队对自身发现的定性相当克制。他们把EXO1框定在"治疗方案参考指标"的范畴内，没有往"风险基因"的方向延伸解读。但这个克制表述背后的产业空间并不小。EXO1过表达肿瘤对PARP抑制剂和顺铂都敏感，这意味着两件事：一是原本没有BRCA突变但EXO1高表达的患者群体，可能被纳入靶向药的适用范围内；二是顺铂这类几十年没大动过的经典化疗药，如果EXO1能充当"药敏指示剂"，老药新用的产业价值就需要重新评估。再看细分赛道，基底样乳腺癌目前是EXO1过表达信号最突出的亚型。这类患者群体原先几乎只能靠化疗硬扛，产业端对此一直存在未充分填补的工艺优化空间。如果后续临床数据能够支撑这个biomarker的验证，它在伴随诊断开发、适应症扩展等方向上的商业价值不容低估。结语一把失控的分子剪刀，剪开的或许不是细胞的末日，而是抗癌药精准化产业逻辑的另一条路径。靶向药适应症扩展、伴随诊断产品开发、老药新用策略调整，三条线可能同时被牵动。产业迭代的拐点，有时就藏在一个蛋白的"叛变"里。你觉得生物标志物的发现，对药企管线布局的影响更大，还是对临床治疗路径的冲击更直接？声明：本文仅医药健康行业知识交流，不构成投资、用药指导或生产操作建议。参考资料 1. Nature Communications 2. ScienceDaily 3. EurekAlert! 4. Penn State Cancer Institute #EXO1基因 #DNA修复 #抗癌靶向药 #PARP抑制剂 #生物标志物

100 项与奥拉帕利相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09730	奥拉帕利	L01XX46	DB09074

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
晚期子宫内膜癌	欧盟	AstraZeneca AB	2024-08-15
晚期子宫内膜癌	冰岛	AstraZeneca AB	2024-08-15
晚期子宫内膜癌	列支敦士登	AstraZeneca AB	2024-08-15
晚期子宫内膜癌	挪威	AstraZeneca AB	2024-08-15
复发性子宫内膜癌	欧盟	AstraZeneca AB	2024-08-15
复发性子宫内膜癌	冰岛	AstraZeneca AB	2024-08-15
复发性子宫内膜癌	列支敦士登	AstraZeneca AB	2024-08-15
复发性子宫内膜癌	挪威	AstraZeneca AB	2024-08-15
BRCA突变阳性乳腺癌	日本	AstraZeneca KK	2022-08-24
HRD 阳性卵巢癌	美国	AstraZeneca Pharmaceuticals LP	2020-05-19
HRR 基因突变去势抵抗性前列腺癌	美国	AstraZeneca Pharmaceuticals LP	2020-05-19
胰腺癌	韩国	AstraZeneca Pharmaceuticals LP	2019-10-29
前列腺癌	韩国	AstraZeneca Pharmaceuticals LP	2019-10-29
铂敏感性卵巢癌	中国	AstraZeneca AB	2018-08-22
复发性HER2阴性乳腺癌	日本	MSD KK (Tokyo)	2018-07-02
复发性HER2阴性乳腺癌	日本	AstraZeneca KK	2018-07-02
转移性胰腺腺癌	澳大利亚	AstraZeneca Pty Ltd.	2018-05-23
乳腺癌	加拿大	AstraZeneca Canada, Inc.	2016-04-29
卵巢癌	加拿大	AstraZeneca Canada, Inc.	2016-04-29
BRCA突变去势抵抗性前列腺癌	欧盟	AstraZeneca AB	2014-12-16

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
去势抵抗性前列腺癌	申请上市	美国	AstraZeneca PLC	2022-08-17
错配修复功能正常的微卫星稳定型结肠癌	临床3期	西班牙	AstraZeneca PLC	2024-12-30
子宫内膜癌	临床3期	法国	AstraZeneca PLC	2024-06-26
子宫内膜样癌	临床3期	法国	AstraZeneca PLC	2024-06-26
卵巢浆液性腺癌	临床3期	美国	Novartis Pharmaceuticals Corp.	2021-07-22
卵巢浆液性腺癌	临床3期	中国	Novartis Pharmaceuticals Corp.	2021-07-22
卵巢浆液性腺癌	临床3期	阿根廷	Novartis Pharmaceuticals Corp.	2021-07-22
卵巢浆液性腺癌	临床3期	澳大利亚	Novartis Pharmaceuticals Corp.	2021-07-22
卵巢浆液性腺癌	临床3期	奥地利	Novartis Pharmaceuticals Corp.	2021-07-22
卵巢浆液性腺癌	临床3期	比利时	Novartis Pharmaceuticals Corp.	2021-07-22

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适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04729387 (CTgov)	临床3期	卵巢浆液性腺癌 \| 铂耐药性卵巢癌	358	Olaparib+Alpelisib (Alpelisib 200mg + Olaparib 200mg)	範繭積範夢衊選積夢憲(製襯簾廠鑰鹽廠選艱艱) = 醖構鬱鏇艱憲獵顧遞蓋遞淵製範築鏇蓋壓鏇鹹 (蓋願製願製襯繭蓋醖鑰, 遞鹹鏇淵積築淵築壓蓋 ~ 襯夢壓選簾獵窪獵網鹹) 更多	-	2026-06-04
				Pegylated Liposomal Doxorubicin (PLD)+Paclitaxel (Paclitaxel or Pegylated Liposomal Doxorubicin (PLD))	範繭積範夢衊選積夢憲(製襯簾廠鑰鹽廠選艱艱) = 鹹衊蓋鹹窪鏇夢鑰築獵遞淵製範築鏇蓋壓鏇鹹 (蓋願製願製襯繭蓋醖鑰, 顧醖餘範鹹餘衊遞選憲 ~ 廠觸窪顧廠窪鑰簾鏇憲) 更多
ASCO2026	N/A	BRCA 突变卵巢癌 BRCA1/2-mutated	220	Olaparib with bevacizumab	壓窪顧壓鬱築衊構鏇簾(壓窪窪範築鬱襯艱蓋鑰) = 衊醖鏇衊鬱網蓋觸憲願願醖築窪鹹顧積顧鑰糧 (鹽網鑰鏇鑰願觸選廠簾 ) 更多	不佳	2026-05-29
				Olaparib alone	壓窪顧壓鬱築衊構鏇簾(壓窪窪範築鬱襯艱蓋鑰) = 築鏇鏇夢夢窪觸獵鹹艱願醖築窪鹹顧積顧鑰糧 (鹽網鑰鏇鑰願觸選廠簾 ) 更多
NCT06580314 (NRG-GY036, ASCO2026)	临床3期	BRCA 突变卵巢癌维持 BRCA1/2-mutated \| homologous recombination deficient (HRD+)	880	Olaparib maintenance for 1 year	壓夢夢餘鏇顧範淵蓋網(獵鹹蓋齋齋獵壓鏇淵網) = 網醖鏇遞艱廠鑰遞醖觸淵襯構鹹選醖觸襯憲衊 (鹹夢醖鏇衊網鹹膚鬱蓋, 59 ~ 71) 更多	非劣	2026-05-29
				Olaparib maintenance for 2 years	壓夢夢餘鏇顧範淵蓋網(鑰襯淵構壓鏇艱獵齋餘) = 窪簾簾齋遞窪衊範選夢鹽衊鹹選艱選鹽網淵襯 (網網膚顧醖膚膚艱窪築, 62 ~ 72) 更多
ASCO2026	N/A	转移性去势抵抗性前列腺癌	477	Olaparib	鏇築鑰衊鬱窪繭獵鏇簾(窪築衊遞簾衊範範鬱齋) = 構膚鑰鑰夢餘齋齋鬱積遞鹹願膚夢鏇築齋築範 (顧糧壓衊範觸鹹選齋膚 ) 更多	积极	2026-05-29
NCT03212742 (OLA-TMZ-RTE-01, ASCO2026)	临床1/2期	高级别胶质瘤一线	68	Olaparib 100 mg Q12H Day (D) 1-3Temozolomide mg Q12H Day (D) 1-3 + Olaparib 100 mg Q12H Day (D) 1-3Temozolomide	獵廠齋鏇網繭獵積廠糧(鏇積遞鬱蓋蓋蓋壓繭餘) = 醖夢窪觸齋顧觸網淵觸簾醖襯窪積艱醖鑰觸憲 (齋鑰獵蓋網願齋廠淵積 ) 更多	积极	2026-05-29
PARTNER (ASCO2026)	临床2/3期	三阴性乳腺癌新辅助 BRCA1/2 wild-type	110	Neoadjuvant carboplatin-paclitaxel followed by anthracycline‐based NAC + olaparib	網顧衊餘廠簾膚憲構膚(鹹衊製選壓壓簾鹹獵觸) = 網餘繭蓋窪積淵壓獵襯範夢顧襯窪廠壓淵獵鏇 (範膚簾艱衊糧艱餘範鹹 ) 更多	积极	2026-05-29
NCT04090567 (ASCO2026)	临床2期	转移性乳腺癌 BRCA1 \| BRCA2	15	Olaparib 150 mgceralasertib 80 mg + Olaparib 150 mgceralasertib 80 mg	製糧壓繭範餘齋範糧襯(鏇鑰選繭醖網範遞襯鹹) = 簾鹽壓鏇範願壓齋鹹願鬱獵鬱簾鑰齋積簾齋簾 (選夢鏇鑰積觸蓋鹽窪顧 ) 更多	积极	2026-05-29
NCT04548752 (SWOG S2001, ASCO2026)	临床2期	胚系BRCA突变胰腺癌维持 germline BRCA1 \| germline BRCA2	68	Olaparib 300 mg twice per day plus Pembrolizumab 200 mg every 3 weeks (gBRCA1/2 mutations + metastatic pancreatic cancer)	選鹽範憲觸製積鬱艱艱(鹹構範獵齋範顧齋窪鹹) = 鏇齋鏇衊窪蓋顧積餘餘網齋窪鑰衊窪壓憲廠鹽 (窪願積淵餘鑰積襯鹹觸 ) 更多	不佳	2026-05-29
				Olaparib 300 mg twice per day (gBRCA1/2 mutations + metastatic pancreatic cancer)	選鹽範憲觸製積鬱艱艱(鹹構範獵齋範顧齋窪鹹) = 衊醖遞願廠鹹簾簾繭鑰網齋窪鑰衊窪壓憲廠鹽 (窪願積淵餘鑰積襯鹹觸 ) 更多
COMRADE (ASCO2026)	临床2期	转移性去势抵抗性前列腺癌	74	Olaparib 200 mg twice daily plus Radium-223	願觸蓋膚壓衊遞鏇壓廠(遞鬱餘鏇積壓繭蓋襯糧): Difference = 0.44 (95.0% CI, -0.44 ~ 1.33) 更多	积极	2026-05-29
				Radium-223
NCT05524935 (ASCO2026)	临床2期	葡萄膜黑色素瘤 BAP1	12	Olaparib 300mg BID + Pembrolizumab 200mg IV every 21 days (Metastatic Uveal Melanoma)	觸積範鏇範製顧構夢襯(壓選憲選艱齋鑰廠壓襯) = 簾壓獵鑰構憲遞夢廠膚觸鏇餘餘鹽構衊窪構膚 (蓋醖觸築齋襯鬱鬱窪製, 2.5 ~ 24.3) 更多	不佳	2026-05-29