Ketoconazole

2024 highlights include expanded product labeling, key FDA designations and new study publications Recent developments include Phase 2 DMD Study Breakthrough Results and Vibativ China approval NASHVILLE, Tenn. , March 4, 2025 /PRNewswire/ -- Cumberland Pharmaceuticals Inc. (NASDAQ: CPIX), a specialty pharmaceutical company, announced today that its product portfolio of FDA-approved brands delivered combined net revenues of $10.4 million during the fourth quarter of 2024, an 11.6% increase over the prior year period. Net revenues for the full year 2024 were $38 million . Cumberland ended the year with $76 million in total assets – including $18 million in cash, $53 million in liabilities and $23 million of shareholders' equity. "2024 was a transformative year for our Company, marked by expanded product labeling, key FDA designations and significant new study publications that underscore our commitment to improving patient care," said Cumberland Pharmaceuticals CEO A.J. Kazimi . "As we move into 2025, we remain focused on driving growth, delivering value to our stakeholders and advancing our mission." Cumberland started 2025 with several significant developments, including: Cumberland recently announced positive top-line results following completion of its Phase II study evaluating ifetroban in patients with cardiomyopathy associated with Duchenne muscular dystrophy. This marks a breakthrough for these patients, as it is the first successful Phase II study specifically targeting the cardiac complications of their condition. The Company learned that its potent antibiotic, Vibativ®, received approval by the regulatory authorities in China – the world's second largest pharmaceutical market. This milestone adds to Cumberland's growing international business, as it also began shipping Vibativ to Saudi Arabia and completed the needed product training to launch the product there. HIGHLIGHTS FOR 2024 INCLUDE: FDA Granted Orphan Drug Designations for Ifetroban Cumberland's ifetroban product candidate received FDA Orphan Drug and Rare Pediatric Disease designations for the treatment of cardiomyopathy in Duchenne muscular dystrophy, a devastating genetic disorder affecting young boys. These designations recognize the urgent need for effective treatments and also provide vital support to accelerate research and development. They represent hope for families and a pathway to bring transformative medicines to a vulnerable patient population more quickly and efficiently. If approved, ifetroban would be the first therapy specifically indicated for DMD-related heart disease. New Study Compared Caldolor® to Ketorolac Cumberland announced the publication of new real-world outcomes research demonstrating the safety and health care resource advantages of Caldolor over its main competitor, ketorolac, in both adult and pediatric populations. The study, published in Frontiers of Pain Research , provides compelling evidence that Caldolor is associated with a significantly reduced incidence of adverse drug reactions and improved health care utilizations when compared to ketorolac. Caldolor Special Report Cumberland shared a Caldolor Special Report, which was published in Anesthesiology News , General Surgery News and Pharmacy Practice News and presented the growing amount of data supporting the use of Caldolor as a standard of care for the treatment of pain and fever. The results demonstrated that the product is a safe and effective treatment for pain and fever in adults, children and infants. FDA Approved New, Simplified Dosing Regimen for Acetadote® Cumberland announced the FDA approval of a supplemental New Drug Application for Acetadote, Cumberland's IV treatment for preventing or lessening liver injury after ingestion of potentially toxic quantities of acetaminophen. The new, streamlined approach reduces the frequency of medication errors and potentially serious non-allergic anaphylactoid reactions without compromising the effectiveness of Acetadote. By simplifying the dosing regimen, health care providers can administer the life-saving treatment more efficiently, potentially improving patient outcomes. 2024 Sustainability Metrics Cumberland updated its annual sustainability metrics, detailing the Company's activities pertaining to its environmental, social and governance matters. Cumberland reported its key findings for 2024, including providing 3.9 million doses of its FDA-approved products to patients and safely disposing of nearly 12,480 pounds of damaged and expired products. Additionally, Cumberland had no products recalled and no clinical trials terminated due to failure to practice good clinical standards in 2024. Clinical Development Programs Throughout 2024, Cumberland made significant progress in advancing the Phase II clinical trials evaluating its ifetroban product candidate. The Company closed its study in patients with Duchenne muscular dystrophy, approached the conclusion of enrollment in its systemic sclerosis study and significantly progressed its study in patients suffering from pulmonary fibrosis. These programs are designed to address unmet medical needs in large potential markets. FINANCIAL RESULTS: Net Revenue: For 2024, net revenues were $38 million and included $15.3 million for Kristalose®, $9 million for Sancuso® $7.2 million for Vibativ® and $5 million for Caldolor®. Operating Expenses: Total operating expenses for 2024 were $44 million . Net Income (Loss): The net loss for the fourth quarter of 2024 was approximately $1.9 million and the year ended December 31, 2024 , was approximately $6.4 million . Adjusted Earnings (Loss): Adjusted loss for the year ended December 31, 2024 , was $1.0 million . The adjusted earnings calculation does not include the benefit of the $1.3 million of Vibativ and Sancuso cost of goods, which were received as part of each product's acquisition. Balance Sheet: At December 31, 2024 , Cumberland had $76 million in total assets, including $18 million in cash and cash equivalents. Liabilities totaled $53 million , including $15 million on the company's credit facility. Total shareholders' equity was $23 million at December 31, 2024 . EARNINGS REPORT CALL: Cumberland will report its 2024 financial results via a conference call today, March 4, 2025 , at 4:30 p.m. Eastern Time . To participate in the call, please register at https://register.vevent.com/register/BIafb49dfab9014db59440ff63e1d827b2. Registered participants can dial in from their phone using a dial-in and PIN number that will be provided to them. Alternatively, they can choose a "Call Me" option to have the system automatically call them at the start of the conference. A replay of the call will be available for one year and can be accessed via Cumberland's website or by visiting: https://edge.media-server.com/mmc/p/r4puvzy9/. ABOUT CUMBERLAND PHARMACEUTICALS : Cumberland Pharmaceuticals Inc. is the largest biopharmaceutical company founded and headquartered in Tennessee and is focused on providing unique products that improve the quality of patient care. The company develops, acquires, and commercializes products for the hospital acute care, gastroenterology and oncology market segments. The company's portfolio of FDA-approved brands includes: Acetadote® (acetylcysteine) injection, for the treatment of acetaminophen poisoning; Caldolor® (ibuprofen) injection, for the treatment of pain and fever; Kristalose® (lactulose) oral, a prescription laxative, for the treatment of constipation; Sancuso® (granisetron) transdermal, for the prevention of nausea and vomiting in patients receiving certain types of chemotherapy treatment; Vaprisol® (conivaptan) injection, to raise serum sodium levels in hospitalized patients with euvolemic and hypervolemic hyponatremia; and Vibativ® (telavancin) injection, for the treatment of certain serious bacterial infections including hospital-acquired and ventilator-associated bacterial pneumonia, as well as complicated skin and skin structure infections. The Company also has a series of Phase II clinical programs underway evaluating its ifetroban product candidate in patients with cardiomyopathy associated with Duchenne Muscular Dystrophy, Systemic Sclerosis and Idiopathic Pulmonary Fibrosis. For more information on Cumberland's approved products, including full prescribing information, please visit links to the individual product websites, which can be found on the company's website at www.cumberlandpharma.com. About Acetadote® (acetylcysteine) Injection Acetadote, administered intravenously within 8 to 10 hours after ingestion of a potentially hepatotoxic quantity of acetaminophen, is indicated to prevent or lessen hepatic injury. Used in the emergency department, Acetadote is approved in the United States to treat overdose of acetaminophen, a common ingredient in many over-the-counter medications. Acetadote is contraindicated in patients with hypersensitivity or previous anaphylactoid reactions to acetylcysteine or any components of the preparation. For full prescribing and safety information, visit www.acetadote.com. About Caldolor® (ibuprofen) Injection Caldolor is indicated in adults and pediatric patients for the management of mild to moderate pain and the management of moderate to severe pain as an adjunct to opioid analgesics, as well as the reduction of fever. It was the first FDA-approved intravenous therapy for fever. Caldolor is contraindicated in patients with known hypersensitivity to ibuprofen or other non-steroidal anti-inflammatory drugs (NSAIDs) as well as patients with a history of asthma or other allergic type reactions after taking aspirin or other NSAIDs. Caldolor is contraindicated for use during the peri-operative period in the setting of coronary artery bypass graft (CABG) surgery. For full prescribing and safety information, including boxed warning, visit www.caldolor.com. About Kristalose® (lactulose) Oral Solution Kristalose is indicated for the treatment of acute and chronic constipation. It is a unique, proprietary, crystalline form of lactulose, with no restrictions on length of therapy or patient age. Kristalose is contraindicated in patients who require a low-galactose diet. Elderly, debilitated patients who receive lactulose for more than six months should have serum electrolytes (potassium, chloride, carbon dioxide) measured periodically. For full prescribing and safety information, visit www.kristalose.com. About Sancuso® (granisetron) Transdermal System Sancuso is the only skin patch approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderately and/or highly emetogenic chemotherapy. When applied 24 to 48 hours before receiving chemotherapy, the Sancuso patch slowly and continuously releases the medicine contained in the adhesive through clean and intact skin areas into the patient's bloodstream. It can prevent CINV for chemotherapy regimens of up to five consecutive days. For full prescribing and safety information, visit www.sancuso.com. About Vaprisol® (conivaptan hydrochloride) Injection Vaprisol is an intravenous treatment for hyponatremia used in the critical care setting. Hyponatremia is an electrolyte disturbance in which sodium ion concentration in blood plasma is lower than normal. This can be associated with a variety of critical care conditions including congestive heart failure, liver failure, kidney failure and pneumonia. The product is a vasopressin receptor antagonist that raises serum sodium levels and promotes free water secretion. Vaprisol is contraindicated in patients with hypovolemic hyponatremia. The coadministration of Vaprisol with potent CYP3A inhibitors, such as ketoconazole, itraconazole, clarithromycin, ritonavir and indinavir, is contraindicated. For full prescribing and safety information, including boxed warning, visit www.vaprisol.com. About Vibativ® (telavancin) for Injection Vibativ is a patented, FDA-approved injectable anti-infective for the treatment of certain serious bacterial infections including hospital-acquired and ventilator-associated bacterial pneumonia and complicated skin and skin structure infections. It addresses a range of Gram-positive bacterial pathogens, including those that are considered difficult-to-treat and multidrug-resistant. Intravenous unfractionated heparin sodium is contraindicated with Vibativ administration due to artificially prolonged activated partial thromboplastin time (aPTT) test results for up to 18 hours after Vibativ administration. Vibativ is contraindicated in patients with a known hypersensitivity to telavancin. For more information, please visit www.vibativ.com. ABOUT CUMBERLAND EMERGING TECHNOLOGIES: Cumberland Emerging Technologies, Inc. (www.cet-fund.com) is a joint initiative between Cumberland Pharmaceuticals Inc. , Vanderbilt University , LaunchTN and WinHealth. The mission of CET is to advance biomedical technologies and products conceived at Vanderbilt University and other regional research centers towards the marketplace. CET helps manage the development and commercialization process for select projects, and provides expertise on intellectual property, regulatory, manufacturing and marketing issues that are critical to successful new biomedical products. CET's Life Sciences Center provides laboratory space, equipment and infrastructure for CET's activities and other early-stage life sciences ventures. FORWARD LOOKING STATEMENTS: This press release contains forward-looking statements, which are subject to certain risks and reflect Cumberland's current views on future events based on what it believes are reasonable assumptions. No assurance can be given that these events will occur. Forward-looking statements include, among other things, statements regarding the Company's intent, belief or expectations, and can be identified by the use of terminology such as "may," "will," "expect," "believe," "intend," "plan," "estimate," "should," "seek," "anticipate," "look forward" and other comparable terms or the negative thereof. As with any business, all phases of Cumberland's operations are subject to factors outside of its control, and any one or combination of these factors could materially affect Cumberland's operation results. These factors include macroeconomic conditions, including rising interest rates and inflation, competition, an inability of manufacturers to produce Cumberland's products on a timely basis, failure of manufacturers to comply with regulations applicable to pharmaceutical manufacturers, natural disasters, public health epidemics, maintaining an effective sales and marketing infrastructure, and other events beyond the Company's control as more fully discussed in its most recent annual report on Form 10-K as filed with the U.S. Securities and Exchange Commission (" SEC "), as well as the Company's other filings with the SEC from time to time. There can be no assurance that results anticipated by the company will be realized or that they will have the expected effects. Readers are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date hereof. The Company does not undertake any obligation to publicly revise these statements to reflect events after the date hereof. CUMBERLAND PHARMACEUTICALS INC. AND SUBSIDIARIES Consolidated Balance Sheets December 31, 2024 and 2023 (Unaudited) 2024 2023 ASSETS Current assets: Cash and cash equivalents $ 17,964,184 $ 18,321,624 Accounts receivable, net 11,701,466 9,758,176 Inventories, net 3,999,995 4,609,362 Prepaid and other current assets 2,786,513 3,025,248 Total current assets 36,452,158 35,714,410 Non-current inventories 11,005,499 12,804,529 Property and equipment, net 277,365 367,903 Intangible assets, net 17,973,449 22,607,918 Goodwill 914,000 914,000 Operating lease right-of-use assets 6,176,923 6,674,394 Other assets 2,784,016 2,692,921 Total assets $ 75,583,410 $ 81,776,075 LIABILITIES AND EQUITY Current liabilities: Accounts payable $ 13,914,266 $ 14,037,629 Operating lease current liabilities 356,508 348,092 Current portion of long-term debt 5,100,000 — Other current liabilities 12,250,955 13,596,528 Total current liabilities 31,621,729 27,982,249 Revolving line of credit - long term 10,176,170 12,784,144 Operating lease non-current liabilities 4,939,739 5,296,247 Other long-term liabilities 6,299,795 6,453,566 Total liabilities 53,037,433 52,516,206 Equity: Shareholders' equity: Common stock – no par value; 100,000,000 shares authorized; 13,952,624 and 14,121,833 shares issued and outstanding as of December 31, 2024 and 2023, respectively 46,821,425 47,091,602 Accumulated deficit (23,967,931) (17,488,161) Total shareholders' equity 22,853,494 29,603,441 Noncontrolling interests (307,517) (343,572) Total equity 22,545,977 29,259,869 Total liabilities and equity $ 75,583,410 $ 81,776,075 CUMBERLAND PHARMACEUTICALS INC. AND SUBSIDIARIES Consolidated Statements of Operations (Unaudited) Three months ended December 31 , Years ended December 31 , 2024 2023 2024 2023 Net revenues $ 10,435,569 $ 9,353,066 $ 37,867,945 $ 39,552,507 Costs and expenses: Cost of products sold 1,976,473 1,529,983 6,585,972 6,066,611 Selling and marketing 4,222,554 4,759,230 17,023,023 18,451,765 Research and development 1,292,671 1,264,753 4,816,206 5,834,229 General and administrative 3,326,466 3,439,184 11,126,901 10,651,915 Amortization and impairment 1,459,444 4,539,155 4,748,252 8,102,648 Total costs and expenses 12,277,608 15,532,305 44,300,354 49,107,168 Operating loss (1,842,039) (6,179,239) (6,432,409) (9,554,661) Interest income 106,667 81,000 334,444 286,854 Other income — — 2,828,871 Other income - settlement — — 475,000 Other income - gain on insurance proceeds — 237,089 346,800 Interest expense (223,261) (178,792) (605,508) (667,861) Loss before income taxes (1,958,633) (6,277,031) (6,466,384) (6,284,997) Income tax benefit (expense) 56,996 (24,956) 22,669 (45,769) Net loss (1,901,637) (6,301,987) (6,443,715) (6,330,766) Net (income) loss at subsidiary attributable to noncontrolling interests (2,177) 10,967 (36,055) 51,446 Net loss attributable to common shareholders $ (1,903,814) $ (6,291,020) $ (6,479,770) $ (6,279,320) Loss per share attributable to common shareholders: Basic $ (0.14) $ (0.44) $ (0.46) $ (0.44) Diluted (0.14) (0.44) (0.46) (0.44) Weighted-average common shares outstanding: Basic 13,971,228 14,164,270 14,060,272 14,298,774 Diluted 13,971,228 14,164,270 14,060,272 14,298,774 CUMBERLAND PHARMACEUTICALS INC. AND SUBSIDIARIES Condensed Consolidated Statements of Cash Flows Years ended December 31, 2024 and 2023 (Unaudited) 2024 2023 Cash flows from operating activities: Net loss $ (6,443,715) $ (6,330,766) Adjustments to reconcile net loss to net cash flows provided by (used in) operating activities: Depreciation and amortization expense 4,902,560 4,935,954 Impairment loss on intangible assets — 3,343,842 Amortization of operating lease right-of-use asset 1,140,738 834,500 Disposal of assets 2,691 20,256 Stock-based compensation 301,895 365,040 Decrease in non-cash contingent consideration (1,460,804) (1,253,840) Increase in cash surrender value of life insurance policies over premiums paid (139,953) (124,736) Noncash interest expense 28,313 15,523 Life insurance proceeds (237,089) (346,800) Net changes in assets and liabilities affecting operating activities: Accounts receivable (1,943,290) 3,404,949 Inventories, net 2,408,397 (23,143) Other current assets and other assets 189,112 65,684 Operating lease liabilities 1,784,089 (1,405,363) Accounts payable and other current liabilities (991,359) 3,724,174 Other long-term liabilities (153,771) (1,131,453) Net cash provided by (used in) operating activities (612,186) 6,093,821 Cash flows from investing activities: Additions to property and equipment (66,461) (281,268) Additions to intangible assets (113,253) (171,783) Life insurance policy proceeds received 237,556 347,356 Net cash provided by (used in) investing activities 57,842 (105,695) Cash flows from financing activities: Borrowings on line of credit 38,488,920 31,475,000 Payments on line of credit (35,996,894) (34,890,856) Payments made in connection with repurchase of common shares (579,049) (740,533) Cash settlement of contingent consideration (1,716,073) (3,268,083) Net cash provided by (used in) financing activities 196,904 (7,424,472) Net decrease in cash and cash equivalents (357,440) (1,436,346) Cash and cash equivalents, beginning of year 18,321,624 19,757,970 Cash and cash equivalents, end of year $ 17,964,184 $ 18,321,624 CUMBERLAND PHARMACEUTICALS INC. AND SUBSIDIARIES Reconciliation of Net Income (Loss) Attributable to Common Shareholders to Adjusted Earnings (Loss) and Adjusted Diluted Earnings (Loss) Per Share (Unaudited) Three months ended December 31 , Three months ended December 31 , 2024 2024 2023 2023 Earnings impact Earnings pershare impact Earnings impact Earnings per share impact Net loss attributable to common shareholders $ (1,903,814) $ (0.14) $ (6,291,020) $ (0.44) Less: Net loss at subsidiary attributable to noncontrolling interests (2,177) — 10,967 — Net loss (1,901,637) (0.14) (6,301,987) (0.44) Adjustments to net loss Income tax (benefit) expense (56,996) — 24,956 — Depreciation and amortization 1,496,394 0.11 4,577,109 0.32 Share-based compensation (a) 74,812 0.01 93,894 0.01 Interest income (106,667) (0.01) (81,000) (0.01) Interest expense 223,261 0.02 178,792 0.01 Adjusted loss and Adjusted Diluted loss Per Share $ (270,833) $ (0.02) $ (1,508,236) $ (0.11) Diluted weighted-average common shares outstanding: 13,971,228 14,164,270 Year ended December 31 , Year ended December 31 , 2024 2024 2023 2023 Earnings impact Earnings per share impact Earnings impact Earnings per share impact Net loss attributable to common shareholders $ (6,479,770) $ (0.46) $ (6,279,320) $ (0.43) Less: Net income at subsidiary attributable to noncontrolling interests (36,055) — 51,446 — Net loss (6,443,715) (0.46) (6,330,766) (0.43) Adjustments to net loss Income tax (benefit) expense (22,669) — 45,769 $ — Depreciation and amortization 4,902,560 0.35 8,279,796 $ 0.57 Share-based compensation (a) 301,895 0.02 365,040 $ 0.03 Interest income (334,444) (0.02) (286,854) $ (0.02) Interest expense 605,508 0.04 667,861 $ 0.04 Adjusted Earnings (loss) and Adjusted Diluted Earnings (loss) Per Share $ (990,865) $ (0.07) $ 2,740,846 $ 0.20 Diluted weighted-average common shares outstanding: 14,060,272 14,526,400 The Company provided the above adjusted supplemental financial performance measures, which are considered "non-GAAP" financial measures under applicable SEC rules and regulations. These financial measures should be considered supplemental to, and not as a substitute for, financial information prepared in accordance with Generally Accepted Accounting Principles ("GAAP"). The definition of these supplemental measures may differ from similarly titled measures used by others. Because these supplemental financial measures exclude the effect of items that will increase or decrease the Company's reported results of operations, management encourages investors to review the Company's consolidated financial statements and publicly filed reports in their entirety. A reconciliation of the supplemental financial measures to the most directly comparable GAAP financial measures is included in the tables accompanying this release. Cumberland's management believes these supplemental financial performance measures are important as they are used by management, along with financial measures in accordance with GAAP, to evaluate the Company's operating performance. In addition, Cumberland believes that they will be used by certain investors to measure the Company's operating results. Management believes that presenting these supplemental measures provides useful information about the Company's underlying performance across reporting periods on a consistent basis by excluding items that Cumberland does not believe are indicative of its core business performance or reflect long-term strategic activities. Certain of these items are not settled through cash payments and include: depreciation, amortization, share-based compensation expense and income taxes. Cumberland utilizes its net operating loss carryforwards to pay minimal income taxes. In addition, the use of these financial measures provides greater transparency to investors of supplemental information used by management in its financial and operational decision-making, including the evaluation of the Company's operating performance. The Company defines these supplemental financial measures as follows: Adjusted Earnings: Net loss adjusted for the impact of income taxes, depreciation and amortization expense, share-based compensation, interest income and interest expense. The financial information presented for the year ended December 31, 2023 , has been adjusted to be consistent with the current year presentation. (a) Represents the share-based compensation of Cumberland. Adjusted Diluted Earnings Per Share: Adjusted loss divided by diluted weighted-average common shares outstanding. View original content to download multimedia:https://www.prnewswire.com/news-releases/cumberland-pharmaceuticals-reports-11-6-fourth-quarter-2024-revenue-growth-302391883.html SOURCE Cumberland Pharmaceuticals Inc. Investor Contact: Shayla Simpson, Cumberland Pharmaceuticals Inc., (615) 255-0068; Media Contact: Molly Aggas, Dalton Agency, (704) 641-6641

本文刊登于《现代妇产科进展》2025年第34卷第2期 引用本文： 中华医学会妇科肿瘤学分会.卵巢癌PARP抑制剂临床应用指南（2025版）[J].现代妇产科进展,2025,34 (2):81-94 DOI： 10.13283/j.cnki.xdfckjz.2025.02.001 通信作者: 孔北华,刘继红,向阳 ,马丁 原文下载: 卵巢癌 PARP 抑制剂临床应用指南(2025 版).pdf 摘  要 卵巢癌是病死率最高的妇科恶性肿瘤，5年生存率长期徘徊在40%左右。近年来，多腺苷二磷酸核糖聚合酶（poly ADP ribose polymerase，PARP）抑制剂的问世改变了卵巢癌的治疗模式，患者生存获益显著。PARP抑制剂业已广泛应用于我国临床，为规范此类药物的应用，中华医学会妇科肿瘤学分会先后制定了《卵巢癌PARP抑制剂临床应用指南》2020版和2022版，随着临床研究数据的不断更新和临床实践经验的积累，有必要对其进行修订，经中华医学会妇科肿瘤学分会编写组专家充分讨论和投票表决，形成《卵巢癌PARP抑制剂临床应用指南（2025版）》（以下简称“本指南”）。 本指南采用中华医学会妇科肿瘤学分会临床诊疗指南推荐类别，见表1。 本指南中，卵巢癌包括输卵管癌和原发性腹膜癌。本指南不涉及国内未上市的PARP抑制剂。本指南临床研究中乳腺癌易感基因（breast cancer susceptibility gene，BRCA）突变为致病性或可能致病性突变。 1  PARP抑制剂及其作用机制 1963年Chambon等［1］首次发现PARP，后经证实其参与单链DNA损伤后的修复过程。1980年Durkacz等［2］证明烟酰胺类似物可以抑制DNA修复，并可增强DNA损伤剂硫酸二甲酯的细胞毒性，提示其有可能作为增敏剂与细胞毒性药物联合用于肿瘤治疗。2005年Nature同期发表的2项研究首次证实了PARP抑制剂与BRCA1/2突变之间存在“合成致死”效应［3-4］。目前已知PARP家族包括17个成员，其中PARP1和PARP2主要通过碱基切除修复（base excision repair，BER）途径在DNA单链断裂（single strand break，SSB）修复中发挥重要作用。 PARP抑制剂经历了3次更新换代，第3代PARP抑制剂以复合物单晶结构为基础，具有活性高、选择性好等优点。多项研究表明晚期卵巢上皮性癌患者应用PARP抑制剂进行维持治疗获益显著。 1.1  作用机制  BRCA1/2基因是抑癌基因，在DNA损伤修复、细胞正常生长等方面均具有重要作用。该基因突变可抑制DNA损伤后正常修复能力，引起同源重组缺陷（homologous recombination deficiency，HRD），即BRCA功能缺失或其他同源重组相关基因发生突变或功能缺失，使双链断裂的DNA修复不能通过同源重组修复（homologous recombinant repair，HRR），最终导致癌变。PARP在DNA单链碱基切除、修复过程中发挥关键作用。在HRD肿瘤细胞中DNA双链无法修复，PARP抑制剂又阻断单链修复，从而形成“合成致死”效应，导致肿瘤细胞死亡。 PARP抑制剂对PARP的作用机制包括2个方面：(1)在PARP活性位点与烟酰胺腺嘌呤二核苷酸竞争，抑制多聚（ADP-核糖）聚合物形成；(2)结合到PARP1和(或)PARP2的烟酰胺腺嘌呤二核苷酸结合口袋，造成构象异构，稳定DNA-PARP的可逆解离，使PARP保持对DNA的结合，这一过程被称为DNA-PARP复合物的“捕获（trapping）”，从而导致DNA-PARP复合物长期存在，抑制DNA后续修复过程［5］。越来越多的临床研究表明，PARP抑制剂的作用不仅限于BRCA突变或HRD阳性的卵巢癌患者，铂敏感的卵巢癌患者也可从中获益，其机制可能与PARP抑制剂的捕获作用有关。 1.2 药理学特性 不同PARP抑制剂的药理学特性有所不同，已获美国食品药品监督管理局（Food and Drug Administration，FDA）、中国国家药品监督管理局（National Medical Products Administration，NMPA）批准的几种PARP抑制剂在生物利用度、半衰期、代谢酶和组织分布等方面各有优势。 1.2.1 奥拉帕利（olaparib） 包括片剂和胶囊2种剂型（胶囊剂型未在中国申请上市），片剂口服给药后1.5h达到中位血浆峰浓度。其体外蛋白结合率约为82%，表观分布容积（apparent volume of distribution，Vd）为（158±136）L，在体内主要通过CYP3A4/5酶代谢；300mg单次给药后，半衰期为（14.9±8.2）h。 1.2.2 尼拉帕利（niraparib） 胶囊剂型。绝对生物利用度约为73%，口服给药后3h内达血浆峰浓度。其与人血浆蛋白的结合率为83.0%，Vd为（1220±1114）L，主要通过羧酸酯酶代谢，形成无活性代谢产物，随后发生葡糖苷酸化，平均半衰期为36h。 1.2.3 氟唑帕利（fluzoparib） 胶囊剂型。单次口服150mg给药后2.5h达血浆峰浓度，人血浆蛋白结合率为74.3%～81.6%，稳态表观分布容积为（34.6±14.5）L，主要通过CYP3A4酶代谢，150mg氟唑帕利多次给药后平均末端消除半衰期约为（9.14±2.38）h。 1.2.4 帕米帕利（pamiparib） 胶囊剂型。在给药后1～2h达到血浆峰浓度，稳态时观察到在有限的中国患者中40mg的暴露量与60mg接近，人血浆蛋白结合率为95.7%，60mg每日2次给药，帕米帕利的Vd约为37L，主要由CYP2C8和CYP3A酶代谢，血浆中消除半衰期约为13h。本品在临床剂量下不大可能是肠道外排转运蛋白P-糖蛋白（P-glycoprotein，P-gp）和乳腺癌抗性蛋白（breast cancer resistance protein，BCRP）、肝摄取转运蛋白有机阴离子转运多肽（organic anion transporting polypeptide，OATP）1B1/1B3、肾摄取转运蛋白有机阳离子转运蛋白（organic cation transporter，OCT）2和有机阴离子转运蛋白（organic anion transporter，OAT）1、OAT3的抑制剂。 1.2.5 塞纳帕利（senaparib） 胶囊剂型。经口服给药后，吸收迅速，单次或每日1次连续给药后药物的血浆浓度中位达峰时间（Tmax）约为2h。与人血浆蛋白结合率均值为96.13%。主要代谢酶是CYP3A4，未发现人体专属的代谢产物。基于群体药代动力学（PopPK）分析，每次给药100mg，每日1次连续给药后，血浆有效半衰期的几何均值为8.92h。本品在临床剂量下不大可能是肠道外排转运蛋白P-gp和BCRP、OATP 1B1/1B3、OCT3和OAT的抑制剂，本品在临床剂量下不大可能是BCRP、OATPB、OAT、OCT转运体的底物。 1.3 获批情况 目前美国FDA批准4种PARP抑制剂、中国NMPA批准5种PARP抑制剂应用于临床，其适应证见表2。 1.4 应用PARP抑制剂的生物标志物 BRCA基因突变或HRD是目前常用的PARP抑制剂应用生物标志物。 1.4.1 BRCA基因检测 BRCA基因突变是首选的PARP抑制剂敏感生物标志物［21］。BRCA基因突变包括胚系BRCA（germ line BRCA，gBRCA）突变和体细胞BRCA（somatic BRCA，sBRCA）突变，从肿瘤组织检测的BRCA突变用组织细胞BRCA（tissue BRCA，tBRCA）突变描述。国内外多采用二代测序（next-generation sequencing，NGS）检测，突变类型包括点突变、小片段插入/缺失等。BRCA基因检测报告解读（胚系变异）依据国际癌症研究机构（International Agency for Research on Cancer，IARC）分类标准（表3）。 本指南推荐卵巢癌患者在初次病理确诊时即进行BRCA基因检测。 1.4.2 HRD检测 除BRCA1/2基因突变外，其他HRR基因，如RAD51、ATM、PALB2、MRE11等损伤或缺失也会导致HRD，HRD作为PARP抑制剂敏感的生物标志物已应用于临床［22］。HRD检测可以使PARP抑制剂敏感人群从约占25%的BRCA突变人群扩大到约占50%的HRD阳性人群。HRD可通过同源重组相关基因突变检测和基因瘢痕检测两种方式判断。前者是从基因水平利用NGS平台对同源重组相关基因进行检测。该方法存在一定的缺陷：(1)除BRCA基因外，其他基因的检出率均较低；(2)不同的HRR基因通道纳入基因存在差异，缺乏公认的标准；(3)不论是HRR基因通道还是HRD基因瘢痕检测均无法检出同源重组通路基因表观遗传改变（如BRCA1启动子区甲基化），因此存在一定的假阴性比例；(4)不同基因对同源重组通路功能影响不同，缺乏量化指标；(5)经济成本效益也需要考虑并知情告知。目前PARP抑制剂临床试验中的HRD检测方法多采用后者，它不仅可以检测BRCA状态，还可以分析基因不稳定状态类型。 目前国际上HRD检测有2个比较成熟的技术平台：Myriad myChoice CDx（Myriad Genetic Laboratories,Inc.）和FoundationFocusTM CDx BRCA LOH（Foundation Medicine,Inc.）。 FoundationFocusTM CDx BRCA LOH检测包括2个主要因素：肿瘤BRCA突变状态和基因组杂合性缺失（loss of heterozygosity，LOH）。tBRCA突变，无论LOH比率多少均为HRD阳性；tBRCA无突变，高LOH（LOH比率≥16%）的患者也归为HRD阳性；BRCA为野生型且LOH比率＜16%则定义为HRD阴性。 Myriad myChoice CDx检测主要针对基因组不稳定状态的3项指标在肿瘤样本中出现的数量进行综合评分，即LOH、端粒等位基因不平衡（telomeric allelic imbalance，TAI）、大片段迁移（large-scale transition，LST）。若分值≥42分或BRCA1/2突变，则定义为HRD阳性；若分值＜42分，且BRCA为野生型，则定义为HRD阴性。 Myriad myChoice CDx和FoundationFocusTM CDx BRCA LOH缺乏应用于中国人群的大样本前瞻性临床研究的验证，HRD检测的设计应结合我国人群的分子遗传学特征。目前国内HRD检测产品尚未获批，但已有相关研究探索基于中国人群的遗传多态性数据开发HRD算法［23-24］，相关检测平台已应用于一些临床研究，其中基于ADx-GSS算法的HRD试剂盒被纳入中国NMPA创新医疗器械的特别审查程序。 2  卵巢癌的一线维持治疗 卵巢癌一线维持治疗是对新诊断卵巢癌患者完成初始化疗后达到临床完全缓解（CR）或部分缓解（PR）者所给予的后续维持性治疗，旨在推迟复发，改善生存预后。应用化疗药物进行维持治疗的临床疗效难以肯定，目前不再推荐临床应用。应用抗血管生成药物贝伐珠单抗维持治疗前需与初始化疗联合应用，除高复发风险患者外，一般人群的PFS时间延长不够理想，仅3～4个月。近年来，PARP抑制剂作为一线维持治疗药物完成了多项Ⅲ期临床随机对照试验，疗效显著，已成为部分卵巢癌患者一线维持治疗的标准选择。 2.1 奥拉帕利相关研究 2.1.1 SOLO-1研究［10］ 针对BRCA1/2基因突变的晚期上皮性卵巢癌（epithelial ovarian cancer，EOC）患者，在初始治疗有效后应用奥拉帕利对比安慰剂进行Ⅲ期临床随机对照试验。全球数据中位随访时间为41个月，与安慰剂组相比，奥拉帕利组患者复发或死亡风险下降70%，两组患者的3年PFS率分别为60%和27%［风险比（hazard ratio，HR）=0.30，95%CI：0.23～0.41，P＜0.001］，中位复发时间推迟到3年以上。无论手术时机如何、化疗反应状态和残留病灶大小［25］，接受奥拉帕利维持治疗的晚期卵巢癌患者PFS均明显改善。随访5年数据［26］显示，奥拉帕利组和安慰剂组患者的中位PFS时间分别为56.0个月和13.8个月，复发或死亡风险降低67%（HR=0.33，95%CI：0.25～0.43），两组患者5年的PFS率分别为48%和21%；且PFS获益在高风险和低风险亚组中一致。随访7年后，奥拉帕利组和安慰剂组患者的中位OS为未达到(not reached,NR)和75.2个月，复发或死亡风险降低45%（HR=0.55,95%CI：0.40～0.76，P=0.0004），两组患者7年的OS率分别为67%和46.5%［27］。中国队列的疗效（独立盲法评估的HR=0.39，95%CI：0.17～0.86，P=0.0168）和安全性数据与全球数据基本一致［28］。 2.1.2 PAOLA-1研究［14］ 这是一项Ⅲ期临床随机对照试验，针对一线含铂类药物联合贝伐珠单抗治疗有效的晚期EOC患者，在继续应用贝伐珠单抗维持治疗的同时加用或不加用奥拉帕利。中位随访时间22.9个月，在贝伐珠单抗联合奥拉帕利组和贝伐珠单抗联合安慰剂组中，BRCA突变患者的中位PFS时间分别为37.2个月和21.7个月（HR=0.31，95%CI：0.20～0.47）；BRCA野生型/HRD阳性患者中位PFS时间分别为28.1个月和16.6个月（HR=0.43，95%CI：0.28～0.66）；BRCA野生型/HRD阴性/未知患者中位PFS时间分别为16.9个月和16.0个月（HR=0.92，95%CI：0.72～1.17），但差异无统计学意义。随访5年数据显示［29］，在贝伐珠单抗联合奥拉帕利组和贝伐珠单抗联合安慰剂组中，BRCA突变患者的中位PFS时间分别为60.7个月和21.7个月（HR=0.45，95%CI：0.32～0.64）,5年OS率分别为73.2%和53.8%，中位OS时间分别为75.2个月和66.9个月（HR=0.60，95%CI：0.39～0.93）；BRCA野生型/HRD阳性患者中位PFS时间分别为30.0个月和16.6个月（HR=0.47，95%CI：0.32～0.7）,5年OS率分别为54.7%和44.2%，中位OS时间分别为NR和52个月（HR=0.71，95%CI：0.45～1.13）；BRCA野生型/HRD阴性/未知患者的中位PFS时间分别为17.3个月和16.0个月（HR=0.90，95%CI：0.72～1.13），5年OS率分别为25.7%和32.3%，中位OS时间分别为36.8个月和40.4个月（HR=1.19，95%CI：0.88～1.63）。研究表明，在贝伐珠单抗维持治疗的基础上加用奥拉帕利可使BRCA突变和BRCA野生型/HRD阳性患者获益，但对BRCA野生型/HRD阴性（双阴性）患者没有额外获益。无论手术时机或术后残留病灶状况［30］如何，与贝伐珠单抗相比，奥拉帕利联合贝伐珠单抗维持治疗均改善PFS，初始肿瘤细胞减灭术且术后肉眼无残留病灶者获益最显著。在HRD阳性患者中，无论国际妇产科联盟（International Federation of Gynecology and Obstetrics，FIGO）分期、疾病进展风险的高低和年龄大小［31-33］，在贝伐珠单抗基础上联合奥拉帕利患者PFS均明显改善。 2.1.3 一项国内多中心的真实世界研究结果［34］ 对于新诊断BRCA野生型/HRD阳性的卵巢癌患者，奥拉帕利单药维持治疗的中位PFS时间为21个月，1年PFS率为75.2%，表明奥拉帕利可为中国此类人群提供了新的治疗选择。 2.1.4 DUO-O研究［35］ 这是一项针对BRCA野生型的新诊断晚期卵巢癌患者应用度伐利尤单抗+紫杉醇/卡铂+贝伐珠单抗治疗后度伐利尤单抗+贝伐珠单抗+奥拉帕利维持治疗的Ⅲ期随机、安慰剂对照研究。组1为化疗+贝伐珠单抗后应用贝伐珠单抗维持治疗，组2为化疗联合贝伐珠单抗+度伐利尤单抗后应用贝伐珠单抗+度伐利尤单抗维持治疗，组3为化疗+贝伐珠单抗+度伐利尤单抗治疗后应用贝伐珠单抗+度伐利尤单抗+奥拉帕利维持治疗。随访近3年结果表明，在ITT人群中，组3和组1的中位PFS时间分别为25.1个月和19.3个月（HR=0.61，95%CI:0.51~0.73）。在BRCA野生型HRD阳性人群中，中位PFS分别为45.1个月和23.3个月(HR=0.46，95%CI:0.33~0.65），在HRD阴性人群中，中位PFS分别为20.9个月和17.4个月(HR=0.68，95%CI:0.54~0.86）。研究表明，与对照组相比，一线化疗联合贝伐珠单抗+度伐利尤单抗，随后贝伐珠单抗+度伐利尤单抗+奥拉帕利维持治疗可改善PFS。 2.2 尼拉帕利相关研究 2.2.1 PRIMA研究［13］ 是在欧美人群中开展的初始治疗后应用尼拉帕利或安慰剂维持治疗的Ⅲ期随机对照试验，入组具有复发高危因素的晚期EOC，排除FIGO Ⅲ期初次减瘤术后无肉眼残留病灶者。约35.2%患者采用尼拉帕利个体化起始剂量给药。无论是否存在BRCA突变均可纳入研究，随机分组时将HRD状态作为分层因素。研究显示BRCA突变者获益最大，尼拉帕利组和安慰剂组患者中位PFS时间分别为22.1个月和10.9个月（HR=0.40，95%CI：0.27～0.62，P＜0.001）。亚组分析显示，在尼拉帕利组和安慰剂组中，BRCA野生型/HRD阳性患者中位PFS时间分别为19.6个月和8.2个月（HR=0.50，95%CI：0.31～0.83，P=0.006）；BRCA野生型/HRD阴性患者的中位PFS时间分别为8.1个月和5.4个月（HR=0.68，95%CI：0.49～0.94，P=0.020），其获益程度明显小于BRCA突变患者和HRD阳性患者。在PRIMA研究中，不论为何年龄组［36］、手术时机和残留病灶［37］，接受尼拉帕利维持治疗的晚期卵巢癌患者均改善PFS。6年随访数据显示：在HRD阳性患者中，安慰剂组后续接受PARPi的比例为48.4%，尼拉帕利组的5年PFS率是安慰剂组的2倍（35% vs 16%），中位OS分别是71.9个月和69.8个月（HR=0.95）；HRP患者中，安慰剂组后续接受PARPi的比例为18.8%，尼拉帕利和安慰机组中位OS分别是36.6个月和32.2个月（HR=0.93）［38］。研究显示ITT人群OS两组无显著差异。 2.2.2 PRIME研究［15］ 是尼拉帕利在中国新诊断晚期卵巢癌患者中开展的多中心、随机、安慰剂对照Ⅲ期临床研究。与PRIMA研究的不同点是,该研究无论术后残余病灶状态如何均可入组，纳入FIGO Ⅲ期初次减瘤术后无残余病灶卵巢癌，且全人群采用尼拉帕利个体化起始剂量给药。在尼拉帕利组和安慰剂组中，整体人群的中位PFS时间分别为24.8个月和8.3个月（HR=0.45，95%CI：0.34～0.60，P＜0.001）；gBRCA突变患者的中位PFS时间分别为NR和10.8个月（HR=0.40，95%CI：0.23～0.68，P＜0.001）；非gBRCA突变/HRD阳性患者的中位PFS时间分别为24.8个月和11.1个月（HR=0.58，95%CI：0.36～0.93，P=0.022）；HRD阴性患者的中位PFS时间分别为16.6个月和5.5个月（HR=0.41，95%CI：0.22～0.75）。无论患者一线含铂化疗后是否达到CR或PR，与安慰剂相比，尼拉帕利均显著延长PFS时间［39］。 2.2.3 一项前瞻性中国多中心真实世界研究RENI-1结果［40］ 在全人群中，无论BRCA突变或HRD状态如何，尼拉帕利一线维持均有PFS获益；BRCA突变和HRD阳性者获益较显著。 2.2.4 OVARIO研究［41-42］ 是一项评估尼拉帕利联合贝伐珠单抗用于新诊断晚期卵巢癌患者维持治疗的Ⅱ期单臂临床研究，主要研究终点为18个月PFS率。研究显示整体人群18个月、24个月的PFS率分别为62%和53%，HRD阳性人群分别为76%和63%，HRD阴性人群分别为47%和42%，HRD未知人群分别为56%和50%。中位随访时间28.7个月，整体人群中位PFS时间为19.6个月，BRCA突变、BRCA野生型/HRD阳性、HRD阴性、HRD未知人群分别为NR、28.3个月、14.2个月和12.1个月。该研究初步表明尼拉帕利联合贝伐珠单抗应用于一线维持治疗可以获益。 2.3 氟唑帕利相关研究 FZOCUS-1研究［19］是一项随机、双盲、安慰剂对照的Ⅲ期临床研究，旨在评估氟唑帕利单药或联合阿帕替尼用于晚期卵巢癌一线维持治疗的疗效和安全性。研究结果显示，在氟唑帕利单药组和安慰剂组中，整体人群的中位PFS时间分别为NR和11.1个月（HR=0.49，95%CI：0.37～0.67，P＜0.0001）；gBRCA突变患者的中位PFS时间分别为NR和14.9个月（HR=0.40，95%CI：0.22～0.73，P=0.0009）；非gBRCA突变患者的中位PFS时间分别为25.5个月和8.4个月（HR=0.53，95%CI：0.37～0.75，P=0.0001）。研究表明，氟唑帕利单药用于一线维持治疗可使晚期EOC患者全人群有不同程度的显著获益。 2.4  塞纳帕利相关研究  FLAMES研究［20］是一项随机、双盲、安慰剂对照、多中心的Ⅲ期临床研究。结果显示：在塞纳帕利组和安慰剂组中，整体人群的中位PFS时间分别为NR和13.6个月（HR=0.43，95%CI：0.32～0.58，P＜0.001）；BRCA突变患者的中位PFS时间分别为NR和15.6个月（HR=0.43，95%CI：0.24～0.76，P＜0.001）；BRCA野生型患者的中位PFS时间分别为NR和12.9个月（HR=0.43，95%CI：0.30～0.61，P＜0.001）。事后分析显示，BRCA野生型/HRD阳性患者的中位PFS时间分别为NR和12.9个月（HR=0.3，95%CI：0.15～0.6）；BRCA野生型/HRD阴性患者的中位PFS时间分别为27.1个月和19.5个月（HR=0.74，95%CI：0.36～1.54）。研究表明塞纳帕利用于一线维持治疗可使BRCA突变和BRCA野生型/HRD阳性患者PFS显著获益。 基于上述研究证据，推荐相应PARP抑制剂用于一线维持治疗（表4）。 3 复发性卵巢癌的维持治疗 卵巢癌复发分为铂敏感复发和铂耐药复发，前者指化疗结束后6个月及以上的复发，后者指化疗结束后不足6个月的复发。初始治疗后未控制，呈持续性甚至进展性疾病者，也属于铂耐药范畴。铂敏感复发的治疗原则是继续使用以铂类为基础的联合化疗，耐药者则一般不优先推荐使用含铂化疗，常选用非铂类化疗药物治疗。复发患者经治疗缓解后可考虑维持治疗，以推迟复发时间或降低复发风险。长期以来，用于复发性卵巢癌维持治疗的药物不多，贝伐珠单抗维持治疗的疗效持续时间较短。近年来，PARP抑制剂用于铂敏感复发维持治疗的研究取得重大进展，已被视为铂敏感复发维持治疗的标准治疗。 3.1 奥拉帕利相关研究 3.1.1 Study 19研究［8］ 针对铂敏感复发患者，Ⅱ期研究显示，奥拉帕利维持治疗组和安慰剂组患者的中位PFS时间分别为8.4个月和4.8个月（HR=0.35，95%CI：0.25～0.49，P＜0.001）。亚组分析显示BRCA突变患者中位PFS时间分别为11.2个月和4.3个月（HR=0.18，95%CI：0.10～0.31，P＜0.0001）；BRCA野生型患者中位PFS时间分别为7.4个月和5.5个月（HR=0.54，95%CI：0.34～0.85，P=0.0075）。总生存（overall survival，OS）分析显示［43］，奥拉帕利组和安慰剂组患者中位OS时间分别为29.8个月和27.8个月［HR=0.73，95%CI：0.55～0.95，P=0.02138（未达预设的统计学差异阈值）］；探索性限制性分析显示奥拉帕利组和安慰剂组患者的中位OS时间分别为41.6个月和35.3个月。BRCA突变患者中位OS时间分别为34.9个月和30.2个月（HR=0.62，95%CI：0.42～0.93，P=0.02140），BRCA野生型患者中位OS时间分别为24.5个月和26.6个月（HR=0.84，95%CI：0.57～1.25，P=0.39749）。该研究初步表明奥拉帕利可使铂敏感复发患者获益。 3.1.2  SOLO-2研究［9］ 该研究是针对gBRCA突变的铂敏感复发患者的Ⅲ期临床研究，结果显示，奥拉帕利组和安慰剂组患者中位PFS时间分别为19.1个月和5.5个月（HR=0.30，95%CI：0.22～0.41，P＜0.0001）；独立盲法评估的中位PFS时间分别为30.2个月和5.5个月（HR=0.25，95%CI：0.18～0.35，P＜0.0001）。OS分析显示［44］，奥拉帕利组和安慰剂组患者的中位OS时间分别为51.7个月和38.8个月（HR=0.74，95%CI：0.54～1.00，P=0.054），安慰剂组中38%的患者后续接受PARP抑制剂治疗，校正安慰剂组交叉用药后，奥拉帕利组和安慰剂组患者的中位OS分别为51.7个月和35.4个月（HR=0.56，95%CI：0.35～0.97）。本研究首次证实奥拉帕利维持治疗可以使gBRCA突变患者OS显著获益。 3.1.3  OPINION研究［45］ 该研究是针对非gBRCA突变的铂敏感复发患者的Ⅲb期研究，主要分析显示，奥拉帕利维持治疗整体人群的中位PFS时间为9.2个月。亚组分析显示，sBRCA突变患者中位PFS时间为16.4个月，HRD阳性（包括sBRCA突变）患者中位PFS时间为11.1个月，HRD阳性（除外sBRCA突变）患者中位PFS时间为9.7个月，HRD阴性患者中位PFS时间为7.3个月。该研究补充证实了奥拉帕利对非gBRCA突变铂敏感复发患者维持治疗的有效性。 3.1.4  L-MOCA研究［46］ 该研究是针对亚洲铂敏感复发卵巢癌患者的Ⅲ期单臂研究，其中91.5%为中国患者，研究结果显示奥拉帕利维持治疗整体人群的中位PFS时间为16.1个月，预估的6个月和12个月PFS率分别为76.0%和57.1%。其中，BRCA突变患者中位PFS时间为21.2个月，gBRCA突变患者中位PFS时间为21.4个月，BRCA野生型患者中位PFS时间为11.0个月。亚组分析显示既往接受二线治疗的患者中位PFS时间可达到18.0个月，其中二线BRCA突变患者中位PFS时间可达24.9个月，二线BRCA野生型患者中位PFS时间可达14.1个月，与全人群的亚组分析结果趋势一致。中期OS数据显示［47］中位随访时间40个月，ITT人群中位OS时间达到了54.4个月，42个月的OS率为59.7%；其中BRCA突变亚组的mOS还未达到（51.9个月-NE）；BRCA野生型/HRD阳性亚组和HRP亚组的中位OS时间分别为54.6个月和37.2个月。研究表明，无论BRCA突变状态如何，奥拉帕利维持治疗均可使亚洲铂敏感复发患者显著获益。 美国FDA基于其他PARP抑制剂在非BRCA突变患者铂敏感复发维持治疗后潜在的死亡风险增加的数据，将奥拉帕利适应证也同样限制于BRCA突变人群。但在中国奥拉帕利铂敏感复发人群适应证目前未发生变化。 3.2  尼拉帕利相关研究 3.2.1  NOVA研究［7］ 该研究针对铂敏感复发患者，均采用尼拉帕利300mg/d固定起始剂量，在尼拉帕利组和安慰剂组中，gBRCA突变患者中位PFS时间分别为21.0个月和5.5个月（HR=0.27，95%CI：0.17～0.41，P＜0.001）；gBRCA野生型/HRD阳性患者中位PFS时间分别为12.9个月和3.8个月（HR=0.38，95%CI：0.24～0.59，P＜0.001）；BRCA野生型/HRD阳性患者中位PFS时间分别为9.3个月和3.7个月（HR=0.38，95%CI：0.23～0.63，P＜0.001）；BRCA野生型/HRD阴性患者中位PFS时间分别为6.9个月和3.8个月（HR=0.58，95%CI：0.36～0.92，P=0.02）。研究表明尼拉帕利维持治疗为不同BRCA和HRD状态的铂敏感复发患者带来不同程度的生存获益。在NOVA研究中，不论为何年龄组［48］和化疗反应状态［49］，在gBRCA突变和非gBRCA突变者中，接受尼拉帕利维持治疗的铂敏感复发患者PFS均改善。OS分析显示［50］，在尼拉帕利组和安慰剂组中，gBRCA突变患者的中位OS时间分别为40.9个月和38.1个月（HR=0.85，95%CI：0.61～1.20），安慰剂组中49.2%的患者后续接受PARP抑制剂治疗；非gBRCA突变患者的中位OS时间分别为31.0个月和34.8个月（HR=1.06，95%CI：0.81～1.37）。基于NOVA研究中非gBRCA突变患者队列的OS次要终点的风险比为1.06（95%CI:0.81~1.37），目前美国FDA将尼拉帕利铂敏感复发维持治疗的适应证限制在gBRCA突变人群。 3.2.2  NORA研究［12］ 该研究是对中国铂敏感复发卵巢癌患者开展的采用尼拉帕利个体化起始剂量的Ⅲ期随机对照研究。在整体人群中，尼拉帕利组和安慰剂组患者的中位PFS时间分别为18.3个月和5.4个月（HR=0.32，95%CI：0.23～0.45，P＜0.0001）。亚组分析提示，在尼拉帕利组和安慰剂组中，gBRCA突变患者的中位PFS时间分别为NR和5.5个月（HR=0.22，95%CI：0.12～0.39，P＜0.0001）；非gBRCA突变患者中位PFS时间分别为11.1个月和3.9个月（HR=0.40，95%CI：0.26～0.61，P＜0.0001）。该研究表明采用尼拉帕利个体化起始剂量可为不同BRCA状态的中国铂敏感复发患者带来生存获益。在NORA研究中，不论为何化疗反应状态［51］、前次含铂化疗后6～12个月或≥12个月疾病进展［52］，在gBRCA突变和非gBRCA突变者中，接受尼拉帕利维持治疗的铂敏感复发患者均能改善PFS。另外，无论是否接受二次肿瘤细胞减灭术［53］，尼拉帕利维持治疗均可改善患者PFS。OS最终分析显示［54］，在整体人群中，尼拉帕利组和安慰剂组患者的中位OS时间分别为51.5个月和47.6个月（HR=0.86，95%CI:0.60～1.23），安慰剂组中46.6%的患者后续接受PARP抑制剂治疗;gBRCA突变患者的中位OS时间分别是56.0个月和47.6个月（HR=0.86，95%CI:0.46～1.58），安慰剂组中57.1%的患者后续接受PARP抑制剂治疗；非gBRCA突变患者中位OS时间分别是46.5个月和46.9个月（HR=0.87，95%CI:0.56～1.35），安慰剂组中39.6%的患者后续接受PARP抑制剂治疗。采用符合方案分析（Per-protocol Analysis，PP分析），非gBRCA突变患者的中位OS时间分别是50.6个月和46.9个月（HR=0.84，95%CI:0.54～1.32）。研究提示尼拉帕利个体化起始剂量可为不同BRCA状态的中国铂敏感复发性患者带来OS获益趋势。中国获批的尼拉帕利铂敏感复发人群适应证目前未发生变化。 3.3  氟唑帕利相关研究  FOZCUS-2研究［18］是针对铂敏感复发卵巢癌患者维持治疗的Ⅲ期临床研究。更新结果显示，氟唑帕利组和安慰剂组患者的中位PFS时间分别为15.7个月和5.5个月（HR=0.31，95%CI：0.22～0.44，P＜0.0001），亚组分析显示，在氟唑帕利和安慰剂组中，gBRCA突变人群的中位PFS时间分别为18.4个月和5.2个月（HR=0.18，95%CI：0.10～0.31，P＜0.0001），非gBRCA突变人群的中位PFS时间分别为13.6个月和5.5个月（HR=0.57，95%CI：0.38～0.86）。该研究表明氟唑帕利可为不同BRCA状态的中国铂敏感复发患者维持治疗带来PFS获益。 3.4  PARP抑制剂维持治疗后的再次维持治疗  OReO研究［55］是针对既往接受过多线治疗和一次PARP抑制剂维持治疗且末次含铂化疗达到CR/PR的复发性卵巢癌患者，再次应用奥拉帕利维持治疗的Ⅲb期随机对照研究。结果显示，奥拉帕利再次维持治疗对比安慰剂组，BRCA突变患者中位PFS时间分别为4.3个月和2.8个月（HR=0.57，95%CI：0.37～0.87，P=0.022）；非BRCA突变患者中位PFS时间分别为5.3个月和2.8个月（HR=0.43，95%CI：0.26～0.71，P=0.0023），其中BRCA野生型/HRD阳性患者中位PFS时间分别为5.3个月和2.8个月（HR=0.52，95%CI：0.26～1.10）；BRCA野生型/HRD阴性患者中位PFS时间分别为5.4个月和2.8个月（HR=0.49，95%CI：0.21～1.23）。研究表明奥拉帕利再次维持治疗对不同BRCA和HRD状态的患者可有一定程度的PFS获益。值得注意的是，与BRCA突变组相比，非BRCA突变组再次奥拉帕利维持治疗的PFS获益略大，分析发现非BRCA突变组中PARP抑制剂先后使用不同种类的比例高于BRCA突变组。 基于以上临床研究证据，本指南推荐相应PARP抑制剂用于铂敏感复发卵巢癌的维持治疗（表5）。对铂敏感复发的BRCA突变患者，既往应用PARP抑制剂维持治疗未进展者，推荐可以再次应用PARP抑制剂维持治疗（2A类推荐）。 4  复发性卵巢癌的后线治疗 对既往接受大于二线化疗的复发性卵巢癌患者的治疗为后线治疗。后线治疗患者的一般状况较差，对药物反应不敏感，可供临床选择的有效药物比较缺乏，而PARP抑制剂相对于细胞毒性化疗药物毒性较小，用于后线治疗具有一定优势。多种PARP抑制剂相继获得美国FDA或中国NMPA批准用于多次复发的卵巢癌的后线治疗，为此类患者提供了“去化疗”的治疗选择。 4.1 铂敏感复发卵巢癌的治疗 对铂敏感复发卵巢癌患者应该首选含铂化疗方案，但对于难以耐受含铂化疗、对铂类药物过敏、不再同意接受化疗者，有必要探索其他替代治疗方案。 4.1.1 奥拉帕利相关研究 4.1.1.1 SOLO-3研究［56-57］ 该研究是应用奥拉帕利单药治疗既往接受了二线及以上化疗的gBRCA突变铂敏感复发卵巢癌患者的Ⅲ期随机对照研究，结果显示，与由医生自主决定的不含铂类的化疗方案相比，奥拉帕利单药治疗显著提高了患者的客观缓解率（objective response rate，ORR）［72.2% vs 51.4%，比值比（odds ratio，OR）=2.53，95%CI：1.40～4.58，P=0.002］，奥拉帕利组和化疗组的独立盲法评估的中位PFS时间分别为13.4个月和9.2个月（HR=0.62，95%CI：0.43～0.91，P=0.013）。最终生存分析显示，奥拉帕利组和化疗组患者的中位OS时间分别为34.9个月和32.9个月，两组比较差异无统计学意义（HR=1.07，95%CI：0.76～1.49，P=0.714），可能与25%的化疗组患者提前退出研究影响评估OS相关。但SOLO-3研究中≥3线化疗亚组分析提示，奥拉帕利组和化疗组的OS分别为29.9个月和39.4个月（HR=1.33,95%CI:0.84~2.18）。 4.1.1.2 CLIO研究［58］ 在BRCA野生型铂敏感复发的EOC患者中，与标准治疗（卡铂联合多柔比星脂质体/吉西他滨）相比，奥拉帕利单药治疗的ORR、疾病控制率、中位PFS时间、中位OS时间比较差异均无统计学意义。 4.1.1.3 LIGHT研究［59-60］ 是基于BRCA突变和HRD状态评估铂敏感复发EOC患者接受奥拉帕利治疗的研究。结果显示，gBRCA突变、sBRCA突变、BRCA野生型/HRD阳性、BRCA野生型/HRD阴性患者的ORR分别为69%、64%、29%、10%；中位PFS时间分别为11.0个月、10.8个月、7.2个月、5.4个月；18个月的OS率分别为88.0%、86.4%、78.6%、59.6%。 4.1.2 尼拉帕利相关研究 4.1.2.1 QUADRA研究［11］ 在尼拉帕利单药治疗既往接受过三线及以上治疗的铂敏感复发卵巢癌患者中，BRCA突变患者的ORR为39%，HRD阳性患者的ORR为26%。 4.1.2.2 AVANOVA2研究［61-62］ 该研究是一项比较尼拉帕利联合贝伐珠单抗或尼拉帕利单药治疗不限既往治疗线数的铂敏感复发EOC患者的Ⅱ期随机对照研究。结果显示，中位随访时间16.9个月，在尼拉帕利联合贝伐珠单抗治疗组和尼拉帕利单药治疗组中，患者的中位PFS时间分别为11.9个月和5.5个月（HR=0.35，95%CI：0.21～0.57，P＜0.0001），ORR分别为60%和27%（OR=4.23，P=0.001）。其中，BRCA突变患者中位PFS时间分别为14.4个月和9.0个月（HR=0.49，95%CI：0.21～1.15）；BRCA野生型/HRD阳性患者中位PFS时间分别为11.9个月和4.1个月（HR=0.19，95%CI：0.06～0.59）；BRCA野生型/HRD阴性患者中位PFS时间分别为11.3个月和4.2个月（HR=0.40，95%CI：0.19～0.85）。生存分析显示，尼拉帕利联合贝伐珠单抗治疗组和尼拉帕利单药治疗组患者的中位OS时间分别为29.4个月和27.8个月（HR=0.75，95%CI：0.44～1.28，P=0.30）。 4.1.3 氟唑帕利相关研究FZOCUS-3研究［16］ 应用氟唑帕利治疗既往2～4线含铂化疗的gBRCA突变铂敏感复发EOC患者，结果显示：独立评审委员会（Independent Review Committee，IRC）和研究者评估的ORR分别为69.9%和70.8%；中位PFS时间分别为12.0个月和10.3个月。中位OS时间尚未达到，12个月和18个月OS率分别为93.7%和89.2%。 4.1.4  帕米帕利相关研究  在BGB-290-102研究［17］中，应用帕米帕利治疗既往二线及以上含铂化疗的gBRCA突变的铂敏感复发EOC患者，结果显示：IRC和研究者评估的ORR分别为64.6%和62.2%；IRC评估的中位PFS时间为15.2个月。中位OS时间尚未达到，6个月和12个月OS率分别为93.2%和83.5%。 4.1.5 塞纳帕利相关研究  SABRINA研究探索塞纳帕利治疗既往二线及以上含铂化疗的BRCA突变的铂敏感复发EOC患者，结果显示：IRC和研究者评估的ORR分别为66.3%和58.7%；IRC评估的中位PFS为11.1个月;中位OS时间尚未达到［63］。 4.2 铂耐药复发卵巢癌的治疗 铂耐药复发卵巢癌患者对含铂化疗方案一般不再敏感，原则上推荐非铂化疗，但临床反应率十分有限，多在20%左右。一旦铂耐药复发，患者往往难以治愈，在姑息治疗的同时必须兼顾生活质量，比化疗药物毒性较低的PARP抑制剂对于BRCA突变患者是一种“去化疗”的治疗选择。 4.2.1 奥拉帕利相关研究 4.2.1.1 Study 42研究［6］ 对既往接受三线及以上含铂化疗方案的BRCA突变铂耐药复发卵巢癌患者给予奥拉帕利治疗，ORR达31.1%。奥拉帕利是第一个在复发性卵巢癌治疗中表现出临床疗效的PARP抑制剂［64］。 4.2.1.2 CLIO研究［58］ 针对铂耐药复发卵巢癌患者，奥拉帕利单药治疗组患者的ORR高于化疗组（18% vs 6%），但尚未有统计学意义；亚组分析提示BRCA突变型患者较野生型患者获益显著。 4.2.2 尼拉帕利相关研究 4.2.2.1 QUADRA研究［11］ 尼拉帕利单药治疗铂耐药复发卵巢癌，BRCA突变患者、HRD阳性患者和HRD阴性/未知患者的ORR分别为27%、10%和3%，这提示尼拉帕利对BRCA突变铂耐药复发卵巢癌有一定疗效。 4.2.2.2 TOPACIO研究［65］ 尼拉帕利联合帕博利珠单抗治疗铂耐药复发/难治性卵巢癌患者的ORR为18%，疾病控制率为65%，治疗效果不受BRCA状态的影响。 4.2.2.3 ANNIE研究［66］ 尼拉帕利联合安罗替尼治疗铂耐药复发性卵巢癌疗效可评估者的ORR为50.0%，中位PFS时间为9.2个月，OS最终分析中位时间为18.2个月［67］。该研究初步表明此种联合治疗可作为耐药复发卵巢癌的一种新选择。 4.2.3  帕米帕利相关研究  在BGB-290-102研究［17］中，应用帕米帕利治疗既往二线及以上含铂化疗的gBRCA突变的铂耐药复发EOC，结果显示：IRC和研究者评估的ORR分别为31.6%和26.3%；IRC评估的中位PFS时间为6.2个月。中位OS时间为13.6个月，6个月和12个月OS率分别为73.4%和50.5%。据此，帕米帕利在国内首先获批铂耐药复发卵巢癌后线治疗适应证。 基于SOLO-3研究中奥拉帕利组OS无获益，美国FDA已经撤回奥拉帕利后线治疗适应证。尼拉帕利后线治疗的QUADRA研究为单臂设计，无法提供对照比较的OS数据，其后线治疗适应证亦被美国FDA撤回。中国NMPA未批准过奥拉帕利、尼拉帕利后线治疗适应证，目前国内有PARP抑制剂（氟唑帕利、帕米帕利）获批用于复发性卵巢癌的治疗。 基于上述研究证据，推荐相应PARP抑制剂用于复发性卵巢癌的后线治疗（表6）。 5 PARP抑制剂在新辅助治疗中的探索研究 NANT研究［68］是尼拉帕利单药新辅助治疗HRD阳性的晚期卵巢癌的Ⅱ期单臂、多中心研究。入组67例，48例完成新辅助治疗和评估，ORR为62.5%，DCR为87.5%；在BRCA突变患者亚组(n=22)中，ORR和DCR分别为77.3%和100.0%。40例完成IDS，80.0%实现R0切除，在BRCA突变患者亚组(n=21)中，R0切除率为85.7%。 NOW研究［69］旨在确定奥拉帕利单药在胚系BRCA1/2、RAD51C/D、PALB2突变的卵巢癌新辅助治疗中的可行性。入组15例，13例可评估，PR率53.8%，12个月PFS率 0.81，14例行IDS，85.7%实现R0切除。 NEO研究［70］是奥拉帕利新辅助治疗铂敏感复发性高级别浆液性卵巢癌的Ⅱ期、随机、多中心临床研究。术前短疗程奥拉帕利治疗后共41例行再次肿瘤细胞减灭术后，随机分为奥拉帕利治疗组和化疗后奥拉帕利维持治疗组，研究提示病灶完全切除的患者中，单独使用奥拉帕利与化疗后序贯奥拉帕利同样有效，而且毒性更小。 一项研究［71］探索奥拉帕利联合帕博利珠单抗新辅助治疗HRD阳性新诊断晚期卵巢癌，共入组20例，ORR为70%，BRCA突变者为84.6%。 一项帕米帕利联合索凡替尼用于新辅助新诊断晚期卵巢癌的Ⅱ期研究［72］显示其ORR为100%，均为PR；R0率为90%（18/20），余R1。R0者中，11例BRCA突变，6例BRCA野生型/HRD阳性，1例HRD阴性。18例R0者中，1例BRCA突变者为病理完全缓解。 以上均为小样本的非随机对照研究，初步提示有可能取代新辅助化疗，但这种治疗模式的探索需要证实其OS的实际获益。目前证据尚不足以推荐PARP抑制剂单药或联合治疗用于新诊断、铂敏感复发卵巢癌患者的新辅助治疗。PARP抑制剂用于一线、二线维持治疗和后线治疗的药物用法见表7。 6  PARP抑制剂使用的安全性管理 6.1 PARP抑制剂的常见不良反应及其处理  在PARP抑制剂用药过程中，大部分患者会出现不同程度的不良反应，特点如下：(1)不良反应以轻度或中度为主，即不良事件通用术语标准（common terminology criteria for adverse events，CTCAE）毒性分级1～2级更为常见，患者耐受性高于化疗（细胞毒性药物）。(2)大部分不良反应出现在服药前期（前3个月），随着用药时间逐渐延长，患者耐受，不良反应的程度逐渐减弱。(3)PARP抑制剂的不良反应呈现剂量相关性，大部分不良反应通过减量、对症治疗等方法可控制。(4)血液学、胃肠道不良反应及疲劳最常见。大部分3～4级不良反应为血液学不良反应，且是调整药物剂量、中断和停止用药的最主要原因，0.9%～27.6%的患者因不良反应而终止用药，大部分患者可长期用药维持治疗［9,11-12］。(5)不同PARP抑制剂的药物结构、药代动力学以及代谢途径不完全一致，需要患者关注不同药物毒性特点，更好地进行预防监测和处理。(6)奥拉帕利联合贝伐珠单抗维持治疗毒性与两种药物单独使用毒性并未出现明显的叠加效应，毒性可耐受。奥拉帕利或尼拉帕利联合贝伐珠单抗常见的不良反应为疲劳、恶心、贫血、血小板减少和高血压。3级以上不良反应发生率为48.5%～77.1%，主要为贫血、血小板减少和高血压。需要注意尼拉帕利、PARP抑制剂联合贝伐珠单抗使用相关高血压的监测和管理。临床医生需要重视PARP抑制剂使用过程中的毒性管理，通过告知使患者对毒性有适当预知，合理地监测和处理，提高患者依从性，并减少用药中断造成的血药浓度波动，提高患者生存质量和疗效。 6.1.1  血液学不良反应 使用PARP抑制剂的患者需要定期检查血常规，尤其是刚开始用药时。奥拉帕利在治疗的最初 12 个月内，推荐在基线以及随后的每月进行一次全血细胞计数检测。尼拉帕利建议在开始用药的第1个月内每周检测一次全血细胞计数，在接下来11个月的治疗中每月监测一次。氟唑帕利建议在治疗的最初3个月内，推荐在基线进行全血细胞计数检测以及随后每2周监测一次。帕米帕利建议在治疗的最初3个月内，每周监测一次。塞纳帕利建议在治疗的最初3个月内，推荐在基线进行全血细胞计数检测以及随后每2周监测一次。随后，定期监测治疗期间出现的具有临床意义的参数变化。根据这些变化可能需要暂停用药或减量和(或)进一步治疗。 6.1.1.1 贫血 贫血是使用PARP抑制剂最常见的血液学不良反应，总体发生率为21.0%～89.4%，3～4级不良反应发生率为5.0%～41.6%。一般处理原则：(1)血红蛋白水平降至80～100g/L者，可在监测血常规的情况下继续使用PARP抑制剂，对缺铁、叶酸缺乏患者可补充铁剂和叶酸补充剂，促红细胞生成素需谨慎使用。(2)血红蛋白水平＜80g/L者，暂停使用PARP抑制剂，对于出现贫血症状的患者必要时采用红细胞输注治疗，待血红蛋白水平恢复至≥90g/L后，下调一个剂量水平恢复PARP抑制剂使用（常用PARP抑制剂的减量方法见表8，氟唑帕利待血红蛋白恢复至≥80g/L后恢复用药，塞纳帕利待血红蛋白恢复至≥100g/L后恢复用药），恢复用药后每周监测血红蛋白水平至平稳。(3)如果停药28d内血红蛋白仍未能恢复至可用药水平，或减量至最低剂量仍再次发生血红蛋白降至80g/L以下，应停止用药。使用帕米帕利的患者首次发生血红蛋白水平低于90g/L时，需要暂停用药，治疗直至血红蛋白水平恢复至≥90g/L，下调一个剂量水平给药。再次发生，适当的支持性治疗或暂停用药后治疗直至血红蛋白水平恢复至≥90g/L后继续40mg每日2次剂量水平用药或暂停用药后降至20mg每日2次剂量水平恢复用药；若贫血危及生命，需紧急治疗：暂停给药并遵医嘱治疗直至血红蛋白水平恢复至≥90g/L，下调一个剂量水平以20mg每日2次给药；在20mg每日2次剂量水平再次出现贫血危及生命，且贫血不是由于其他干扰事件（如胃肠道出血）引起，应停用帕米帕利。 6.1.1.2 血小板减少  血小板减少的发生率为14%～70%，3～4级血小板减少的发生率为1%～34%。处理方法：(1)血小板计数降至（50～100）×109/L患者，可在监测血常规的情况下继续使用PARP抑制剂。(2)血小板计数＜50×109/L者，暂停使用PARP抑制剂，待血小板计数恢复至75×109/L以上（氟唑帕利待血小板计数恢复至50×109/L以上），下调一个剂量水平并恢复PARP抑制剂使用。(3)治疗可使用血小板生成素、白介素-11、血小板生成素受体激动剂等药物。血小板计数低于20×109/L，有出血倾向患者予输注血小板。(4)如果停药28d内血小板计数仍未能恢复至可用药水平，或减至用药最低剂量仍再次发生血小板减少，停止用药。 使用尼拉帕利患者：对体重＜77kg或血小板计数＜150×109/L的患者，建议尼拉帕利的初始剂量为200mg/d，监测血小板计数如低于100×109/L者，则暂停使用PARP抑制剂，待血小板计数恢复至100×109/L以上，根据血小板计数的最低值决定恢复使用PARP抑制剂的剂量：如血小板计数最低值为（75～100）×109/L，可原剂量恢复PARP抑制剂使用；如血小板计数最低＜75×109/L，或2次以上发生血小板计数＜100×109/L，减量恢复PARP抑制剂使用，每周监测血小板计数至平稳。 使用塞纳帕利患者：血小板计数＜75×109/L者，暂停使用，待血小板计数恢复至75×109/L以上恢复用药或降低一个剂量水平。 6.1.1.3 中性粒细胞减少 中性粒细胞减少是第3种常见的血液学不良反应，总发生率5.0%～61.1%，其中4.0%～33.6%为3～4级不良反应。处理方法：(1)中性粒细胞计数降至（1.0～2.0）×109/L，在监测血常规的情况下可继续使用PARP抑制剂。(2)中性粒细胞计数＜1.0×109/L，暂停使用PARP抑制剂，必要时使用粒细胞刺激因子等药物治疗。待中性粒细胞计数恢复至1.5×109/L以上，下调剂量恢复用药。使用氟唑帕利者待中性粒细胞计数恢复至1.0×109/L以上，首次发生中性粒细胞缺乏且不伴发热可考虑原剂量恢复用药，2次以上发生中性粒细胞缺乏或伴发热，或伴血小板降低至75×109/L以下患者需下调一个剂量水平恢复使用，恢复用药后每周监测中性粒细胞计数至平稳。(3)中性粒细胞减少治疗可考虑使用短效重组人粒细胞集落刺激因子，如果停药28d内中性粒细胞计数仍未恢复至可用药水平，或减至用药最低剂量仍再次发生中性粒细胞计数降低至1.0×109/L以下，应停止用药。 6.1.2 非血液学不良反应 6.1.2.1 胃肠道不良反应  恶心是最常见的胃肠道不良反应，发生率为48.0%～73.6%。其他常见胃肠道不良反应包括便秘、呕吐和腹泻，1～2级不良反应多见。预防和管理：(1)告知患者发生恶心等胃肠道症状的可能性较大，给患者合理的预期；(2)对症治疗，可以参照细胞毒药物化疗引起胃肠道不良反应的管理，可使用胃肠动力药、5-羟色胺受体拮抗剂等止吐药物，必要时在睡前30～60min服用止吐药物，注意服用奥拉帕利、氟唑帕利等时应避免使用阿瑞匹坦等神经激肽-1（neurokinin-1，NK-1）抑制剂（CYP3A4中度抑制剂），PARP抑制剂在睡前服用有助于减少恶心的发生；(3)暂停PARP抑制剂用药及减量：CTCAE 2级以上不良反应经治疗后未能缓解，或出现3级以上不良反应，需暂停PARP抑制剂用药，直至不良反应降至1级或缓解，恢复PARP抑制剂用药时要考虑减量（特别是第2次暂停用药后）。PARP抑制剂剂量已减至最低、不良反应症状仍持续的患者要停止用药。 6.1.2.2  疲劳  疲劳是常见的不良反应，29.2%～66.0%使用PARP抑制剂的患者有疲劳症状，大部分为1～2级症状，疲劳的持续时间可能超过最初的3个月，3级以上的疲劳症状发生率小于10%。预防和管理：(1)给患者合理的预期，告知可能发生的疲劳症状；(2)对症治疗，必要的镇痛、抗抑郁治疗；(3)非药物干预，认知行为疗法和营养咨询；(4)如果疲劳仍然持续，出现CTCAE 2级以上不良反应，且处理后无法缓解，或出现3级以上不良反应，应暂停用药。待症状改善后原剂量或减量（特别是第2次暂停用药后）继续用药。对于剂量已减至最低、疲劳症状仍难以控制的患者要考虑停止用药。 6.1.2.3  高血压  PARP抑制剂尤其是联合贝伐珠单抗使用过程中，部分患者会出现高血压。奥拉帕利、尼拉帕利联合贝伐珠单抗在卵巢癌一线维持治疗中，46%~50%患者出现不同程度高血压，其中17%~27%为3~4级，治疗过程中需要注意高血压监测和治疗。 尼拉帕利在卵巢癌二线维持治疗中，19.3%、8.2%的患者分别出现任意级别、3~ 4级高血压，大部分患者可以用降压药控制，不到1%患者因高血压停药；在中国人群，该数据分别为11.1%和1.1%。使用尼拉帕利时对高血压监测和管理：(1)使用尼拉帕利前既往高血压得到较好控制；(2)用药期间应监测血压和心率，前两个月内至少每周监测一次，然后第一年内每月一次，此后定期监测；(3)必要时采用降压药物控制血压；(4)调整尼拉帕利用量：出现3级及以上高血压应暂停用药，28d内可控制患者，下调一个剂量水平并恢复用药；对于剂量已减至最低仍出现3级及以上高血压，超过28d无法控制患者，停止用药。 6.1.2.4  其他不良反应  几种PARP抑制剂均有头痛（5.3%～30.0%）和失眠（5.6%～31.4%）的报道，多为1～2级不良反应。较少出现的不良反应包括呼吸困难、鼻咽炎、咳嗽、心动过速和心悸；以及偶有患者出现血清肌酐水平升高和肝功转氨酶升高。其他报道的不良反应包括关节痛和背痛。对于非血液学毒性处理原则如下：1～2级不良反应，可在对症治疗、监护情况下继续使用PARP抑制剂；对3级及以上不良反应，需要暂停用药，处理待不良反应降至1级以下再恢复用药，并考虑减量，如已减至最低剂量，症状仍持续超过28d考虑终止用药。 6.1.3  继发恶性肿瘤  在使用PARP抑制剂相关临床研究中少数患者可发生继发性恶性肿瘤（骨髓增生异常综合征或急性髓系白血病），发生率为0～8%（安慰剂组发生率为0～4%），通常发生于长期治疗后，是严重的不良事件。需要指出，所有发生骨髓增生异常综合征或急性髓系白血病患者除PARP抑制剂外，之前均接受过铂类等DNA损伤药物治疗，部分患者还存在骨髓发育不良或其他原发性恶性肿瘤病史，难以完全归结于PARP抑制剂的使用。如果患者在使用PARP抑制剂时出现难以改善的全血细胞减少、双系细胞减少、血小板减少，排除如营养缺乏或病毒感染等原因者，应转诊血液科进行骨髓穿刺检查，一旦诊断为骨髓增生异常综合征或急性髓系白血病，必须立即停用PARP抑制剂。 6.2  PARP抑制剂与其他药物的相互作用 几种PARP抑制剂的代谢途径不同，尼拉帕利主要通过羧酸酯酶代谢，奥拉帕利、氟唑帕利、帕米帕利和塞纳帕利主要通过细胞色素P450酶途径代谢，其中奥拉帕利、氟唑帕利和塞纳帕利通过CYP3A酶代谢，帕米帕利主要通过CYP2C8和CYP3A酶代谢。因此，在服用奥拉帕利、氟唑帕利和塞纳帕利时，不推荐合并使用强效CYP3A抑制剂（如伊曲康唑、克拉霉素、酮康唑、伏立康唑等）。对于中效CYP3A抑制剂（如阿瑞匹坦、环丙沙星、克唑替尼、氟康唑、伊马替尼等），服用奥拉帕利和氟唑帕利时，不推荐合并使用；服用塞纳帕利需慎用中效CYP3A抑制剂。如果必须合并使用，PARP抑制剂需要减量。此外，强效CYP3A诱导剂（如苯妥英、利福平、卡马西平等）可能导致奥拉帕利等药物血药浓度降低，也应避免与奥拉帕利等PARP抑制剂同时使用。在奥拉帕利、氟唑帕利和塞纳帕利治疗期间，应告知患者避免食用含有CYP3A抑制剂的食物，如西柚、西柚汁、酸橙和酸橙汁。帕米帕利与CYP3A抑制剂合用无需调整剂量，而与CYP2C8抑制剂或诱导剂合用尚无数据，应该慎用。尼拉帕利主要通过羧酸脂酶代谢，该酶不是主要的药物代谢酶，与其他药物的交互作用较少，但亦缺乏相关数据。 7 结 语 PARP抑制剂是在HRD基础上通过“合成致死”效应发挥抗肿瘤作用的靶向药物，它的问世改变了卵巢癌的治疗模式，使维持治疗成为卵巢癌全程管理的重要组成部分，具有里程碑式的意义。大量高级别随机对照研究表明，新诊断晚期高级别浆液性和子宫内膜样卵巢癌初始化疗后达到CR或PR的患者应用PARP抑制剂一线维持治疗可使患者获益，特别是对于BRCA基因突变或(和)HRD阳性的患者疗效显著，PFS显著获益，甚至OS获益。铂敏感复发卵巢癌患者达到CR或PR后应用PARP抑制剂维持治疗可使患者获益，但仍应主要用于BRCA突变患者。PARP抑制剂不常规推荐用于复发性卵巢癌的后线治疗，作为“去化疗”的治疗药物仅慎重推荐用于经选择的部分BRCA突变或(和)HRD阳性患者。在PARP抑制剂新辅助治疗方面，目前仅限于研究探索阶段，尚不常规推荐临床应用。PARP抑制剂总体上药物毒性反应低于细胞毒性化疗药物，但仍需对其血液学和非血液学毒性进行严格管理，除了及时处理贫血、血小板减少、疲劳等常见不良反应外，对少见的骨髓增生异常综合征和急性髓系白血病亦应引起高度重视。临床上应严格掌握PARP抑制剂用药适应证，推荐用药前常规检测BRCA基因突变，有条件者进行HRD检测，以精准指导临床用药、评估预后。临床医生应了解PARP抑制剂药代动力学特点、配伍禁忌、毒副反应、耐药产生等问题，关注用药依从性，加强卵巢癌长期治疗管理。 指南执笔人： 孔北华,刘继红,崔   恒,吴小华,黄    鹤,王新宇, 鹿    欣,李   宁,姜   洁,张    瑜,高庆蕾,汪   辉, 姜    桦,宋   坤,殷爱军,温   灏,张国楠,梁志清, 王建六,向   阳,马    丁 指南专家组成员（以姓氏笔画为序）： 马    丁 华中科技大学同济医学院附属同济医院 王丹波 辽宁省肿瘤医院 王世宣 华中科技大学同济医学院附属同济医院 王建六 北京大学人民医院 王新宇 浙江大学医学院附属第一医院 王   薇 上海市第一妇婴保健院 孔北华 山东大学齐鲁医院 吕卫国 浙江大学医学院附属妇产科医院 尹如铁 四川大学华西第二医院 曲芃芃 天津市中心妇产科医院 向   阳 中国医学科学院北京协和医院 刘开江 上海交通大学医学院附属仁济医院 刘继红 中山大学肿瘤防治中心 李   宁 中国医学科学院肿瘤医院 李小平 北京大学人民医院 李秀琴 中国医科大学盛京医院 杨兴升 山东大学齐鲁医院 杨佳欣 中国医学科学院北京协和医院 吴小华 复旦大学附属肿瘤医院 吴琪俊 中国医科大学附属盛京医院临床流行病学教研室 吴令英 中国医学科学院肿瘤医院 汪   辉 浙江大学医学院附属妇产科医院 宋   坤 山东大学齐鲁医院 张国楠 四川省肿瘤医院 张   瑜 中南大学湘雅医院 陈   刚 华中科技大学同济医学院附属同济医院 郑   虹 北京大学肿瘤医院 孟元光 中国人民解放军总医院 赵   霞 四川大学华西第二医院 哈春芳 宁夏医科大学总医院 姜   洁 山东大学齐鲁医院 姜   桦 复旦大学附属妇产科医院 徐丛剑 复旦大学附属妇产科医院 殷爱军 山东大学齐鲁医院 高庆蕾 华中科技大学同济医学院附属同济医院 高雨农 北京大学肿瘤医院 郭瑞霞 郑州大学第一附属医院 黄   鹤 中山大学肿瘤防治中心 崔   恒 北京大学人民医院 康   山 河北医科大学第四医院 鹿   欣 复旦大学附属妇产科医院 梁志清 陆军军医大学第一附属医院 程文俊 江苏省人民医院 温   灏 复旦大学附属肿瘤医院 臧荣余 复旦大学附属中山医院 参考文献 ［1］Chambon P,Weill JD,Mandel P.Nicotinamide mononucleotide activation of a new DNA-dependent polyadenylic acid synthesizing nuclear enzyme［J］.Biochem Biophys Res Commun,1963,11(1):39-43 ［2］Durkacz BW,Omidiji O,Gray DA,et al.(ADP-ribose)n participates in DNA excision repair［J］.Nature,1980,283(5747):593-596 ［3］Bryant HE,Schultz N,Thomas HD,et al.Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase［J］.Nature,2005,434(7035):913-917 ［4］Farmer H,Mccabe N,Lord CJ,et 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