英文药名：LYNPARZA(olaparib hard capsules) 中文药名：奥拉帕尼硬胶囊 生产厂家：AstraZeneca 药品简介 奥拉帕尼LYNPARZA（olaparib）：第一个LDT协同诊断测试也被批准鉴定适宜的患者的产品已上市 近日，抗癌新药Lynparza（奥拉帕尼，Olaparib）获美国和欧盟批准作为一种单药疗法，用于铂敏感复发性BRCA突变卵巢癌成人患者的维持治疗，该药也成为用于BRCA突变铂敏感复发性卵巢癌的首个PARP抑制剂。 Lynparza（奥拉帕尼 Olaparib）是一种首创口服多聚ADP核糖聚合酶（PARP）抑制剂，利用DNA修复途径的缺陷，优先杀死癌细胞。 批准日期：2014年12月19日[美国批准] 2014年12月19日[欧盟批准]；公司：AstraZeneca LYNPARZA(奥拉帕尼[olaparib])胶囊，为口服使用 初次批准：2014 作用机制 Lynparza是一种聚(ADP-核糖)聚合酶(PARP)酶抑制剂，包括 PARP1，PARP2，和PARP3。 PARP酶是涉及正常细胞动态平衡，例如DNA转录，细胞周期调节，和DNA修复。奥拉帕尼在体外曾被显示抑制选择肿瘤细胞株生长和在人类的小鼠异种移植人癌模型减低肿瘤生长作为单药治疗或基于铂化疗后两方面。注意到用奥拉帕尼治疗后在细胞株中和有BRCA 缺陷的小鼠肿瘤模型增加细胞毒性和抗-肿瘤活性。体外研究已显示奥拉帕尼-诱导细胞毒性可能涉及PARP酶活性的抑制作用和PARP-DNA复合物形成增加，导致细胞动态平衡破坏和细胞死亡。 适应证和用途 Lynparza是一个多聚二磷酸腺苷核糖聚合酶[poly(ADP-ribose)polymerase](PARP)抑制剂适用在有害的或被怀疑有害的生殖系突变的BRCA(当用FDA批准的测试检测)晚期卵巢癌曾被3种或更多化疗既往线治疗患者为单药治疗。 这个适应证是根据客观反应率和反应时间在加速批准下被批准的。继续批准这个适应证可能取决于在验证性试验中确证和临床获益的描述。 剂量和给药方法 ⑴推荐剂量是400mg每天2次。 ⑵ 继续治疗直至疾病进展或不能接受的毒性。 ⑶对不良反应，考虑治疗剂量中断或减低剂量。 剂型和规格 胶囊：50mg 禁忌证 无。 警告和注意事项 ⑴ 骨髓增生异常综合征/急性髓性白血病：暴露于Lynparza患者发生(MDS/AML)，而有些病例是致命性。在基线时监视患者血液学毒性和其后每月。如确证 MDS/AML终止。 ⑵肺炎：暴露于Lynparza患者发生和有些病例致死性。如怀疑肺炎中断治疗。确证时终止。 ⑶胚胎-胎儿毒性：Lynparza可致胎儿危害。忠告有生育力女性对胎儿潜在危害和避免妊娠。 不良反应 ⑴在临床试验中最常见不良反应(≥20%)是贫血，恶心，疲乏(包括乏力)，呕吐，腹泻，味觉障碍，消化不良，头痛，食欲减退，鼻咽炎/咽炎/URI，咳嗽，关节痛/肌肉骨骼痛，肌痛，背痛，皮炎/皮疹和腹痛/不适。 ⑵最常见实验室异常(≥25%)是肌酐增加，红细胞均数体积升高，血红蛋白减低，淋巴细胞减低，绝对中性粒细胞计数减低，和血小板减低。 药物相互作用 ⑴CYP3A抑制剂：避免同时使用强和中度CYP3A抑制剂。如不能避免抑制剂，减低剂量。 ⑵CYP3A诱导剂：避免同时使用强和中度 CYP3A诱导剂。如中度CYP3A 诱导剂不能避免，被认识到减低疗效潜能。 特殊人群中使用 哺乳母亲：终止治疗或终止哺乳。 临床研究 在有害的或被怀疑有害的生殖系突变的BRCA(gBRCAm)晚期癌患者(研究1)单臂研究中研究Lynparza的疗效。总共纳入以前曾用3或更多化疗线治疗的137例有可测量的，gBRCAm相关联卵巢癌患者。所有患者接受Lynparza在剂量400 mg每天2次作为单药治疗直至疾病进展或不能耐受的毒性。研究者按照RECIST v1.1评估总体反应率(ORR)和反应时间(DOR)。 患者的中位年龄为 58岁，多数为高加索人(94%)和93%有ECOG PS 0或1。有害的或被怀疑有害的，在97%(59/61)对血样品可得到的患者生殖线BRCA突变状态被回顾性通过协同诊断BRAC分析CDxTM确证，它是被FDA批准为Lynparza 治疗选择患者。 贮存 贮存在25ºC(77°F)，外出允许至15-30ºC(59-86ºF)[见USP控制室温] Lynparza不应被暴露至温度大于40ºC或104ºF。如怀疑已被暴露于温度大于40ºC或104ºF不要服用。 注：本品已获多个国家上市，采购者请在线咨询：2363244352  3330889895 欧洲盒包装 50mg*448粒/盒（4*112粒） 美国瓶包装 50mg*112粒胶囊瓶 Lynparza 50mg hard capsules 1. Name of the medicinal product Lynparza 50 mg hard capsules 2. Qualitative and quantitative composition Each hard capsule contains 50 mg of olaparib. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Hard capsule. White, opaque, size 0 hard capsule, marked with “OLAPARIB 50 mg” and the AstraZeneca logo in black ink. 4. Clinical particulars 4.1 Therapeutic indications Lynparza is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (germline and/or somatic) high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy. 4.2 Posology and method of administration Treatment with Lynparza should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Patients must have confirmation of a breast cancer susceptibility gene (BRCA) mutation (either germline or tumour) before Lynparza treatment is initiated. BRCA mutation status should be determined by an experienced laboratory using a validated test method (see section 5.1). There are limited data in patients with somatic BRCA-mutated tumours (see section 5.1). Genetic counselling for patients with BRCA mutations should be performed according to local regulations. Posology The recommended dose of Lynparza is 400 mg (eight capsules) taken twice daily, equivalent to a total daily dose of 800 mg. Patients should start treatment with Lynparza no later than 8 weeks after completion of their final dose of the platinum-containing regimen. It is recommended that treatment be continued until progression of the underlying disease. There are no data on retreatment with Lynparza following subsequent relapse (see section 5.1). Missing dose If a patient misses a dose of Lynparza, they should take their next normal dose at its scheduled time. Dose adjustments for adverse reactions Treatment may be interrupted to manage adverse reactions such as nausea, vomiting, diarrhoea, and anaemia and dose reduction can be considered (see section 4.8). The recommended dose reduction is to 200 mg twice daily (equivalent to a total daily dose of 400 mg). If a further final dose reduction is required, then reduction to 100 mg twice daily (equivalent to a total daily dose of 200 mg) could be considered. Dose adjustments for co-administration with CYP3A inhibitors Concomitant use of strong and moderate CYP3A inhibitors is not recommended and alternative agents should be considered. If a strong or moderate CYP3A inhibitor must be co-administered, the recommended olaparib dose reduction is to 150 mg taken twice daily (equivalent to a total daily dose of 300 mg) with a strong CYP3A inhibitor or 200 mg taken twice daily (equivalent to a total daily dose of 400 mg) with a moderate CYP3A inhibitor (see sections 4.4 and 4.5). Elderly No adjustment in starting dose is required for elderly patients. There is limited clinical data in patients aged 75 or over. Renal impairment For patients with moderate renal impairment (creatinine clearance 31 to 50 ml/min) the recommended dose of Lynparza is 300 mg twice daily (equivalent to a total daily dose of 600 mg) (see section 5.2). Lynparza can be administered in patients with mild renal impairment (creatinine clearance 51 to 80 ml/min) with no dose adjustment. Lynparza is not recommended for use in patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤ 30 ml/min) since there are no data in such patients. Lynparza may only be used in patients with severe renal impairment if the benefit outweighs the potential risk, and the patient should be carefully monitored for renal function and adverse events. Hepatic impairment Lynparza can be administered to patients with mild hepatic impairment (Child-Pugh classification A) with no dose adjustment (see section 5.2). Lynparza is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been studied in these patients. Non-Caucasian patients There are limited clinical data available in non-Caucasian patients. However, no dose adjustment is required on the basis of ethnicity (see section 5.2). Patients with performance status 2 to 4 There are very limited clinical data available in patients with performance status 2 to 4. Paediatric population The safety and efficacy of Lynparza in children and adolescents has not been established. No data are available. Method of administration Lynparza is for oral use. Due to the effect of food on olaparib absorption, patients should take Lynparza at least one hour after food, and refrain from eating preferably for up to 2 hours afterwards. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Breast-feeding during treatment and 1 month after the last dose (see section 4.6). 4.4 Special warnings and precautions for use Haematological toxicity Haematological toxicity has been reported in patients treated with olaparib, including clinical diagnoses and/or laboratory findings of generally mild or moderate (CTCAE grade 1 or 2) anaemia, neutropaenia, thrombocytopaenia and lymphopaenia. Patients should not start treatment with Lynparza until they have recovered from haematological toxicity caused by previous anticancer therapy (haemoglobin, platelet, and neutrophil levels should be within normal range or CTCAE grade 1). Baseline testing, followed by monthly monitoring, of complete blood counts is recommended for the first 12 months of treatment and periodically after this time to monitor for clinically significant changes in any parameter during treatment. If a patient develops severe haematological toxicity or blood transfusion dependence, treatment with Lynparza should be interrupted and appropriate haematological testing should be initiated. If the blood parameters remain clinically abnormal after 4 weeks of Lynparza dose interruption, bone marrow analysis and/or blood cytogenetic analysis are recommended. Myelodysplastic syndrome/Acute Myeloid Leukaemia Myelodysplastic syndrome/Acute Myeloid Leukaemia (MDS/AML) have been reported in a small number of patients who received Lynparza alone or in combination with other anti-cancer drugs; the majority of cases have been fatal. The duration of therapy with olaparib in patients who developed MDS/AML varied from < 6 months to > 2 years. The cases were typical of secondary MDS/cancer therapy-related AML. All patients had potential contributing factors for the development of MDS/AML; the majority of cases were in gBRCA mutation carriers and some of the patients had a history of previous cancer or of bone marrow dysplasia. All had received previous platinum- containing chemotherapy regimens and many had also received other DNA damaging agents and radiotherapy. If MDS and/or AML are confirmed while on treatment with Lynparza, it is recommended that the patient be treated appropriately. If additional anticancer therapy is recommended, Lynparza should be discontinued and not given in combination with other anticancer therapy. Pneumonitis Pneumonitis has been reported in a small number of patients receiving olaparib, and some reports have been fatal. The reports of pneumonitis had no consistent clinical pattern and were confounded by a number of pre-disposing factors (cancer and/or metastases in lungs, underlying pulmonary disease, smoking history, and/or previous chemotherapy and radiotherapy). If patients present with new or worsening respiratory symptoms such as dyspnoea, cough and fever, or a radiological abnormality occurs, Lynparza treatment should be interrupted and prompt investigation initiated. If pneumonitis is confirmed, Lynparza treatment should be discontinued and the patient treated appropriately. Embryofoetal toxicity Based on its mechanism of action (PARP inhibition), olaparib could cause foetal harm when administered to a pregnant woman. Nonclinical studies in rats have shown that olaparib causes adverse effects on embryofoetal survival and induces major foetal malformations at exposures below those expected at the recommended human dose of 400 mg twice daily. Pregnancy/contraception Lynparza should not be used during pregnancy and in women of childbearing potential not using reliable contraception during therapy and for 1 month after receiving the last dose of Lynparza (see section 4.6). Interactions Olaparib co-administration with strong or moderate CYP3A inhibitors is not recommended (see section 4.5). If a strong or moderate CYP3A inhibitor must be co-administered, the dose of olaparib should be reduced (see sections 4.2 and 4.5). Olaparib co-administration with strong or moderate CYP3A inducers is not recommended (see section 4.5). In the event that a patient already receiving olaparib requires treatment with a strong or moderate CYP3A inducer, the prescriber should be aware that the efficacy of olaparib may be substantially reduced (see section 4.5). In the event that a patient already receiving olaparib requires treatment with a P-gp inhibitor, careful monitoring of olaparib associated adverse events and management of those events via the dose reduction strategy is recommended (see section 4.2). 4.5 Interaction with other medicinal products and other forms of interaction Pharmacodynamic interactions Clinical studies of olaparib in combination with other anticancer medicinal products, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity. The recommended Lynparza monotherapy dose is not suitable for combination with other anticancer medicinal products. Combination of olaparib with vaccines or immunosuppressant agents has not been studied. Therefore, caution should be taken if these drugs are co-administered with olaparib and patients should be closely monitored. Pharmacokinetic interactions Effect of other drugs on olaparib CYP3A4/5 are the isozymes predominantly responsible for the metabolic clearance of olaparib. A clinical study to evaluate the impact of rifampicin, a known CYP3A inducer has shown that co-administration with olaparib decreased olaparib mean Cmax by 71% (Treatment ratio: 0.29; 90% CI: 0.24-0.33) and mean AUC by 87% (Treatment ratio: 0.13; 90% CI: 0.11-0.16). Therefore, known strong inducers of this isozyme (e.g. phenytoin, rifampicin, rifapentine, carbamazepine, nevirapine, phenobarbital and St John's Wort) are not recommended with olaparib, as it is possible that the efficacy of olaparib could be substantially reduced. The magnitude of the effect of moderate to strong inducers (e.g. efavirenz, rifabutin) on olaparib exposure is not established, therefore the co-administration of olaparib with these drugs is also not recommended (see section 4.4). A clinical study to evaluate the impact of itraconazole, a known CYP3A inhibitor has shown that co-administration with olaparib increased mean olaparib mean Cmax 1.42-fold (90% CI: 1.33-1.52) and mean AUC 2.70-fold (90% CI: 2.44-2.97). Therefore, known strong (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, boceprevir, telaprevir) or moderate (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of this isozyme are not recommended with olaparib (see section 4.4). If the strong or moderate CYP3A inhibitors must be co-administered, the dose of olaparib should be reduced. The recommended olaparib dose reduction is to 150 mg taken twice daily (equivalent to a total daily dose of 300 mg) with a strong CYP3A inhibitor or 200 mg taken twice daily (equivalent to a total daily dose of 400 mg) with a moderate CYP3A inhibitor (see sections 4.2 and 4.4). It is also not recommended to consume grapefruit juice while on olaparib therapy. In vitro olaparib is a substrate for the efflux transporter P-gp and therefore P-gp inhibitors may increase exposure to olaparib (see section 4.4). Effect of olaparib on other drugs Olaparib inhibits CYP3A4 in vitro and is predicted to be a mild CYP3A inhibitor in vivo. Therefore, caution should be exercised when sensitive CYP3A substrates or substrates with a narrow therapeutic margin (e.g. simvastatin, cisapride, cyclosporine, ergot alkaloids, fentanyl, pimozide, sirolimus, tacrolimus and quetiapine) are combined with olaparib. Appropriate clinical monitoring is recommended for patients receiving CYP3A substrates with a narrow therapeutic margin concomitantly with olaparib. Induction of CYP1A2, 2B6 and 3A4 has been shown in vitro with CYP2B6 being most likely to be induced to a clinically relevant extent. The potential for olaparib to induce CYP2C9, CYP2C19 and P-gp can also not be excluded. Therefore, olaparib upon co-administration may reduce the exposure to substrates of these metabolic enzymes and transport protein. The efficacy of hormonal contraceptives may be reduced if co-administered with olaparib (see also sections 4.4 and 4.6). In vitro, olaparib inhibits the efflux transporter P-gp (IC50 = 76μM), therefore it cannot be excluded that olaparib may cause clinically relevant drug interactions with substrates of P-gp (e.g. simvastatin, pravastatin, dabigatran, digoxin and colchicine). Appropriate clinical monitoring is recommended for patients receiving this type of medication concomitantly. In vitro, olaparib has been shown to be an inhibitor of OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. It cannot be excluded that olaparib may increase the exposure to substrates of OATP1B1 (e.g. bosentan, glibenclamide, repaglinide, statins and valsartan), OCT1 (e.g. metformin), OCT2 (e.g. serum creatinine), OAT3 (e.g. furosemide and methotrexate), MATE1 (e.g. metformin) and MATE2K (e.g. metformin). In particular, caution should be exercised if olaparib is administered in combination with any statin. 4.6 Fertility, pregnancy and lactation Women of childbearing potential/contraception in females Women of childbearing potential should not become pregnant while on Lynparza and not be pregnant at the beginning of treatment. A pregnancy test should be performed on all pre-menopausal women prior to treatment. Women of childbearing potential must use effective contraception during therapy and for 1 month after receiving the last dose of Lynparza. Since it cannot be excluded that olaparib may reduce exposure to substrates of CYP3A through enzyme induction, the efficacy of hormonal contraceptives may be reduced if co-administered with olaparib. Therefore, an additional non-hormonal contraceptive method and regular pregnancy tests should be considered during treatment (see section 4.5). Pregnancy Studies in animals have shown reproductive toxicity including serious teratogenic effects and effects on embryofoetal survival in the rat at maternal systemic exposures lower than those in humans at therapeutic doses (see section 5.3). There are no data from the use of olaparib in pregnant women, however, based on the mode of action of olaparib, Lynparza should not be used during pregnancy and in women of childbearing potential not using reliable contraception during therapy and for 1 month after receiving the last dose of Lynparza. (See previous paragraph: “Women of childbearing potential/contraception in females” for further information about birth control and pregnancy testing). Breast-feeding There are no animal studies on the excretion of olaparib in breast milk. It is unknown whether olaparib/or its metabolites are excreted in human milk. Lynparza is contraindicated during breast-feeding and for 1 month after receiving the last dose, given the pharmacologic property of the product (see section 4.3). Fertility There are no clinical data on fertility. In animal studies, no effect on conception was observed but there are adverse effects on embryofoetal survival (see section 5.3). 4.7 Effects on ability to drive and use machines During treatment with Lynparza, asthenia, fatigue, and dizziness have been reported and those patients who experience these symptoms should observe caution when driving or using machines. 4.8 Undesirable effects Summary of the safety profile Olaparib monotherapy has been associated with adverse reactions generally of mild or moderate severity (CTCAE 1 or 2) and generally not requiring treatment discontinuation. The most frequently observed adverse reactions across clinical trials in patients receiving olaparib monotherapy (≥ 10%) were nausea, vomiting, diarrhoea, dyspepsia, fatigue, headache, dysgeusia, decreased appetite, dizziness, anaemia, neutropaenia, lymphopaenia, mean corpuscular volume elevation, and increase in creatinine. Tabulated list of adverse reactions The following adverse reactions have been identified in clinical studies with patients receiving Lynparza monotherapy. Their frequency is presented using CIOMS III frequency classification and then listed by MedDRA System Organ Class (SOC) and at the preferred term level. Frequencies of occurrence of undesirable effects are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000). This section includes only data derived from completed studies where patient exposure is known. Table 1 Tabulated list of adverse reactions Adverse Reactions MedDRA System Organ Class Frequency of All CTCAE grades Frequency of CTCAE grade 3 and above Immune system disorders Common Rasha Uncommon Hypersensitivitya, Dermatitisa Metabolism and nutrition disorders Very common Decreased appetite Uncommon Decreased appetite Nervous system disorders Very common Headache, Dizziness, Dysgeusia, Uncommon Dizziness, Headache Gastrointestinal disorders Very common Nausea, Vomiting, Diarrhoea, Dyspepsia Common Upper abdominal pain, Stomatitis Common Nausea, Vomiting, Diarrhoea Uncommon Upper abdominal pain, Stomatitis General disorders and administration site conditions Very common Fatigue (including asthenia) Common Fatigue (including asthenia) Investigations Very common Anaemia (decrease in haemoglobin)b, c, Neutropaenia (decrease in absolute neutrophil count) b, c, Lymphopaenia (decrease in lymphocytes) b, c, Increase in blood creatinine b, e, Mean corpuscular volume elevation b,d Common Thrombocytopaenia (decrease in platelets) b, c Very common Anaemia (decrease in haemoglobin)b, c, Lymphopaenia (decrease in lymphocytes) b, c Common Neutropaenia (decrease in absolute neutrophil count) b, c, Thrombocytopaenia (decrease in platelets) b, c Uncommon Increase in blood creatinine b, e a Rash includes PTs of rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash pruritic, exfoliative rash and generalised erythema. Hypersensitivity includes PTs of hypersensitivity and drug hypersensitivity. Dermatitis includes PTs of dermatitis, dermatitis allergic and dermatitis exfoliative. b Represents the incidence of laboratory findings, not of reported adverse events. c Decreases were CTCAE grade 2 or greater for haemoglobin, absolute neutrophils, platelets and lymphocytes. d Elevation in mean corpuscular volume from baseline to above the ULN (upper limit of normal). Levels appeared to return to normal after treatment discontinuation and did not appear to have any clinical consequences. e Data from a double blind placebo controlled study showed a median increase (in percentage change from baseline) up to 23% remaining consistent over time and returning to baseline after treatment discontinuation, with no apparent clinical sequelae. 90% of patients were CTCAE grade 0 at baseline, and 10% were CTCAE grade 1 at baseline. Description of selected adverse reactions Gastrointestinal toxicities are frequently reported with olaparib therapy and are generally low grade (CTCAE grade 1 or 2) and intermittent and can be managed by dose interruption, dose reduction and/or concomitant medicinal products (e.g. antiemetic therapy). Antiemetic prophylaxis is not required. Anaemia and other haematological toxicities are generally low grade (CTCAE grade 1 or 2) however, there are reports of CTCAE grade 3 and higher events. Baseline testing, followed by monthly monitoring of complete blood counts is recommended for the first 12 months of treatment and periodically after this time to monitor for clinically significant changes in any parameter during treatment which may require dose interruption or reduction and/or further treatment. Paediatric population No studies have been conducted in paediatric patients. Other special populations Limited safety data are available in elderly (age ≥ 75 years) and non-Caucasian patients. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: UK Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Ireland HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie e-mail: medsafety@hpra.ie Malta ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal 4.9 Overdose There is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other antineoplastic agents, ATC code: L01XX46 Mechanism of action and pharmacodynamic effects Lynparza is a potent inhibitor of human poly (ADP-ribose) polymerase enzymes (PARP-1, PARP-2, and PARP-3), and has been shown to inhibit the growth of selected tumour cell lines in vitro and tumour growth in vivo either as a standalone treatment or in combination with established chemotherapies. PARP are required for the efficient repair of DNA single strand breaks and an important aspect of PARP-induced repair requires that after chromatin modification, PARP auto-modifies itself and dissociates from the DNA to facilitate access for base excision repair (BER) enzymes. When Lynparza is bound to the active site of DNA-associated PARP it prevents the dissociation of PARP and traps it on the DNA, thus blocking repair. In replicating cells this leads to DNA double strand breaks (DSBs) when replication forks meet the PARP-DNA adduct. In normal cells, homologous recombination repair (HRR), which requires functional BRCA1 and 2 genes, is effective at repairing these DNA double-strand breaks. In the absence of functional BRCA1 or 2, DNA DSBs cannot be repaired via HRR. Instead, alternative and error-prone pathways are activated, such as the non-homologous end joining (NHEJ) pathway, leading to increased genomic instability. After a number of rounds of replication genomic instability can reach insupportable levels and result in cancer cell death, as cancer cells have a high DNA damage load relative to normal cells. In BRCA-deficient in vivo models, olaparib given after platinum treatment resulted in a delay in tumour progression and an increase in overall survival compared to platinum treatment alone. Detection of BRCA mutation Patients are eligible for Lynparza treatment if they have a confirmed deleterious or suspected deleterious BRCA mutation (i.e., a mutation that disrupts normal gene function) in either the germline or the tumour (detected using an appropriately validated test). Clinical efficacy The safety and efficacy of olaparib as a maintenance therapy in the treatment of platinum-sensitive relapsed (PSR) high grade serous ovarian, including fallopian tube or primary peritoneal cancer patients, following treatment with two or more platinum containing regimens, was studied in a Phase II randomised, double blind, placebo controlled trial (study 19). The study compared the efficacy of olaparib maintenance treatment taken until progression with no maintenance treatment in 265 (136 olaparib and 129 placebo) PSR serous ovarian cancer patients who were in response (CR [complete response] or PR [partial response]) confirmed as per RECIST and/or as per CA-125 criteria as defined by Gynecologic Cancer InterGroup (GCIG) (at least a 50% reduction in CA-125 levels from the last pre-treatment sample, confirmed 28 days later) following completion of two or more previous platinum containing chemotherapy. The primary endpoint was PFS (progression-free survival) based on investigator assessment using RECIST 1.0. Secondary efficacy endpoints included OS (overall survival), DCR (disease control rate) defined as confirmed CR/PR + SD (stable disease), HRQoL (health related quality of life), and disease related symptoms. Exploratory analyses of time to first subsequent therapy or death (TFST) and time to second subsequent therapy or death (TSST- an approximation of PFS2) were also performed. Only PSR patients with partially platinum-sensitive disease (platinum-free interval of 6 to 12 months) and patients with platinum-sensitive disease (platinum-free interval of > 12 months) who were in response following completion of last platinum based chemotherapy were enrolled. Patients could not have received prior olaparib or other PARP inhibitor treatment. Patients could have received prior bevacizumab, except in the regimen immediately prior to randomisation. Retreatment with olaparib was not permitted following progression on olaparib. Patients were randomised into the study a median of 40 days after completing their final platinum chemotherapy. They received an average of 3 previous chemotherapy regimens (range 2-11) and 2.6 previous platinum-containing chemotherapies (range 2-8). Patients in the olaparib group continued to receive treatment longer than those in the placebo group. A total of 54 (39.7%) patients received treatment for > 12 months in the olaparib group compared with 14 (10.9%) patients in the placebo group. The study met its primary objective of statistically significantly improved PFS for olaparib maintenance monotherapy compared with placebo in the overall population (HR 0.35; 95% CI 0.25-0.49; p<0.00001), moreover, pre-planned subgroup analysis by BRCA-mutation status identified patients with BRCA-mutated ovarian cancer (n=136, 51.3%) as the subgroup that derived the greatest clinical benefit from olaparib maintenance monotherapy. In BRCA-mutated patients (n=136) there was a statistically significant improvement in PFS, TFST, and TSST. The median PFS improvement was 6.9 months over placebo for olaparib treated patients (HR 0.18; 95% CI 0.10-0.31; p<0.00001; median 11.2 months versus 4.3 months). The investigator assessment of PFS was consistent with a blinded independent central radiological review of PFS. The time from randomisation to start of first subsequent therapy or death (TFST) was 9.4 months longer for olaparib treated patients (HR 0.33; 95% CI 0.22–0.50; p<0.00001; median 15.6 months versus 6.2 months). The time from randomisation to start of second subsequent therapy or death (TSST) was 8.6 months longer for olaparib treated patients (HR 0.44; 95% CI 0.29-0.67; p=0.00013; median 23.8 months versus 15.2 months. There was no statistically significant difference in OS (HR 0.73; 95% CI 0.45-1.17; p=0.19; median 34.9 months versus 31.9 months). Within the BRCA-mutated population the disease control rate at 24 weeks was 57% and 24% for patients in the olaparib and placebo groups, respectively. No statistically significant differences were observed between olaparib and placebo in patient reported symptoms or HRQoL as measured by improvement and worsening rates in the FACT/NCCN Ovarian Symptom Index (FOSI), Trial Outcome Index (TOI) and Functional Analysis of Cancer Therapy–Ovarian total score (FACT-O total). The key efficacy findings from Study 19 for BRCA-mutated patients are presented in Table 2 and Figures 1 and 2. Table 2: Summary of key efficacy findings for patients with BRCA-mutated PSR ovarian cancer in Study 19 PFS N (events/patients) (%) Median PFS (months) HRa 95% CI p-value Olaparib 400 mg bd 26/74 (35%) 11.2 0.18 0.10-0.31 <0.00001 Placebo 46/62 (74%) 4.3 TSST- an approximation of PFS2 N Median TSST (months) HRa 95% CI p-value Olaparib 400 mg bd 42/74 (57%) 23.8 0.44 0.29-0.67 0.00013 Placebo 49/62 (79%) 15.2 Interim OS (52% maturity) N Median OS (months) HRa 95% CI p-value Olaparib 400 mg bd 37/74 (50%) 34.9 0.73 0.45-1.17 0.19 Placebo b 34/62 (55%) 31.9 a HR= Hazard Ratio. A value <1 favours olaparib. The analysis was performed using a Cox proportional hazards model with factors for treatment, time to disease progression on prior penultimate platinum therapy, objective response to prior last platinum therapy and Jewish descent. b Approximately a quarter of placebo treated patients in the BRCA-mutated subgroup (14/62; 22.6%) received a subsequent PARP inhibitor. N Number of events/number of randomised patients; OS Overall survival; PFS Progression-free survival; CI Confidence interval; TSST Time from randomisation to start of second subsequent therapy or death. Figure 1 Study 19: Kaplan-Meier plot of PFS in BRCA-mutated patients (53% maturity-investigator assessment) months 0 3 6 9 12 15 n-olaparib 74 59 34 15 5 0 n-placebo 62 35 13 2 0 0 olaparib 400 mg bd twice daily, placebo, x-axis=time from randomisation in months, y-axis=PFS (progression-free survival), n-olaparib= number of patients at risk-olaparib, n-placebo=number of patients at risk-placebo Figure 2 Study 19: Kaplan-Meier plot of OS in BRCA-mutated patients (52% maturity) months 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 n-olaparib 74 71 69 67 65 62 56 53 50 48 39 36 26 12 7 0 0 0 n-placebo 62 62 58 52 50 46 39 36 33 29 29 27 21 10 4 0 0 0 olaparib 400 mg bd twice daily, placebo, x-axis=time from randomisation in months, y-axis=OS (overall survival), n-olaparib= number of patients at risk-olaparib, n-placebo=number of patients at risk-placebo In Study 19, 18 patients were identified with a somatic tumour BRCA mutation (a mutation in the tumour but wildtype in the germline). The limited data for these somatic tumour BRCA (sBRCA) mutated patients show that fewer patients on olaparib reported progression events or death events compared with placebo (Table 3). Table 3 Summary of progression-free survival and overall survival: sBRCA mutated population in Study 19 N events/patients (%) PFS Olaparib 400 mg bd 3/8 (38%) Placebo 6/10 (60%) OS Olaparib 400 mg bd 4/8 (50%) Placebo 6/10 (60%) Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Lynparza in all subsets of the paediatric population, in ovarian carcinoma (excluding rhabdomyosarcoma and germ cell tumours) (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetics of olaparib at the 400 mg twice daily capsule dose are characterised by an apparent plasma clearance of ~8.6 L/h, an apparent volume of distribution of ~167 L and a terminal half-life of 11.9 hours. Absorption Following oral administration of olaparib via the capsule formulation, absorption is rapid with peak plasma concentrations typically achieved between 1 to 3 hours after dosing. On multiple dosing there is no marked accumulation, with steady state exposures achieved within ~3 to 4 days. Co-administration with food slowed the rate (tmax delayed by 2 hours) and marginally increased the extent of absorption of olaparib (AUC increased by approximately 20%). Therefore, it is recommended that patients take Lynparza at least one hour after food, and refrain from eating preferably for up to 2 hours afterwards (see section 4.2). Distribution The in vitro protein binding of olaparib at plasma concentrations achieved following dosing at 400 mg twice daily is ~82%. Olaparib is moderately bound to HSA (Humans Serum Albumin) in a non-saturablemanner (approximately 55%) and weakly (approximately 35%) bound to AAG (Acid Alpha-1 Glycoprotein). Biotransformation In vitro, CYP3A4 was shown to be the enzyme primarily responsible for the metabolism of olaparib (see section 4.5). Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted for the majority of the circulating radioactivity in plasma (70%) and was the major component found in both urine and faeces (15% and 6% of the dose respectively). The metabolism of olaparib is extensive. The majority of the metabolism was attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation. Up to 20, 37 and 20 metabolites were detected in plasma, urine and faeces respectively, the majority of them representing < 1% of the dosed material. A ring-opened hydroxycyclopropyl moiety, and two mono-oxygenated metabolites (each~10%) were the major circulating components, with one of the mono-oxygenated metabolites also being the major metabolite in the excreta (6% and 5% of the urinary and faecal radioactivity respectively). In vitro, olaparib produced little/no inhibition of CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1 and is not expected to be a clinically significant time dependent inhibitor of any of these P450 enzymes. In vitro data also show that olaparib is not a substrate for OATP1B1, OATP1B3, OCT1, BCRP or MRP2 and not an inhibitor of OATP1B3, OAT1 or MRP2. Elimination Following a single dose of 14C-olaparib, ~86% of the dosed radioactivity was recovered within a 7-day collection period, ~44% via the urine and ~42% via the faeces. Majority of the material was excreted as metabolites. Special populations Renal impairment In patients with mild renal impairment (creatinine clearance 51 to 80 ml/min), AUC increased by 24% and Cmax by 15% compared with patients with normal renal function. No Lynparza dose adjustment is required for patients with mild renal impairment. In patients with moderate renal impairment (creatinine clearance 31 to 50 ml/min), AUC increased by 44% and Cmax by 26% compared with patients with normal renal function. Lynparza dose adjustment is recommended for patients with moderate renal impairment (see section 4.2). There are no data in patients with severe impairment (creatinine clearance < 30 ml/min). Hepatic impairment In patients with mild hepatic impairment (Child-Pugh classification A), AUC increased by 15% and Cmax by 13% compared with patients with normal hepatic function. No Lynparza dose adjustment is required for patients with mild hepatic impairment (see section 4.2). There are no data in patients with moderate or severe hepatic impairment. Elderly There are limited data in patients aged 75 and over. A population analysis of the available data has found no relationship between olaparib plasma concentrations and patient age. Weight There are no data in obese (BMI > 30 kg/m2) or underweight (BMI < 18 kg/m2) patients. A population analysis of the available data has found no evidence that patient weight affects olaparib plasma concentrations. Race There are insufficient data to evaluate the potential effect of race on olaparib pharmacokinetics as clinical experience is predominantly in Caucasians (94% of patients included in the population analysis were Caucasian). In the limited data available, there was no evidence of a marked ethnic difference in the PK of olaparib between Japanese and Caucasian patients. Paediatric population No studies have been conducted to investigate the pharmacokinetics of olaparib in paediatric patients. 5.3 Preclinical safety data Genotoxicity Olaparib showed no mutagenic potential, but was clastogenic in mammalian cells in vitro. When dosed orally to rats, olaparib induced micronuclei in bone marrow. This clastogenicity is consistent with the known pharmacology of olaparib and indicates potential for genotoxicity in man. Repeat-dose toxicity In repeat-dose toxicity studies of up to 6 months duration in rats and dogs, daily oral doses of olaparib were well-tolerated. The major primary target organ for toxicity in both species was the bone marrow, with associated changes in peripheral haematology parameters. These findings occurred at exposures below those seen clinically and were largely reversible within 4 weeks of cessation of dosing. Studies using human bone marrow cells also showed that direct exposure to olaparib can result in toxicity to bone marrow cells in ex vivo assays. Reproductive toxicology In a female fertility study where rats were dosed until implantation, although extended oestrus was observed in some animals, mating performance and pregnancy rate was not affected. However, there was a slight reduction in embryofoetal survival. In rat embryofoetal development studies, and at dose levels that did not induce significant maternal toxicity, olaparib caused reduced embryofoetal survival, reduced foetal weight and foetal developmental abnormalities, including major eye malformations (e.g. anophthalmia, microphthalmia), vertebral/rib malformation, and visceral and skeletal abnormalities. Carcinogenicity Carcinogenicity studies have not been conducted with olaparib. 6. Pharmaceutical particulars 6.1 List of excipients Capsule content Lauroyl macrogol-32 glycerides Capsule shell Hypromellose Titanium dioxide (E171) Gellan gum (E418) Potassium acetate Printing ink Shellac Iron oxide black (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 18 months. 6.4 Special precautions for storage Do not store above 30°C. 6.5 Nature and contents of container HDPE plastic bottle with a child-resistant closure containing 112 hard capsules. Pack of 448 capsules (4 bottles of 112 capsules). 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder AstraZeneca AB SE-151 85 Södertälje Sweden 8. Marketing authorisation number(s) EU/1/14/959/001 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 16th December 2014 10. Date of revision of the text 20th July 2017 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu 阿斯利康卵巢癌药物奥拉帕尼胶囊，Lynparza, 50mg hard capsules (olaparib)获欧盟批准 近日，欧盟委员会(EC)已批准Lynparza作为一种单药疗法，用于铂敏感复发性BRCA突变卵巢癌成人患者的维持治疗，该药也成为用于BRCA突变铂敏感复发性卵巢癌的首个PARP抑制剂。 Lynparza(奥拉帕尼Olaparib)是一种首创口服多聚ADP核糖聚合酶(PARP)抑制剂，利用DNA修复途径的缺陷，优先杀死癌细胞。目前，阿斯利康正开展多个III期研究，调查奥拉帕尼Olaparib用于BRCA突变卵巢癌、胃癌、乳腺癌的治疗。 Lynparza的获批，是基于一项II期临床研究(Study 191)的数据。该研究在携带BRCA突变卵巢癌患者中开展，数据表明，与安慰剂相比，奥拉帕尼Olaparib显著延长了无进展生存期(PFS)(11.2个月 vs 4.3个月，p<0.00001)。然而，这一数据在今年6月却遭到FDA专家委员会的百般挑剔，FDA专家认为，奥拉帕尼Olaparib并没有改善总生存期(OS)，研究中也发生了几个令人担忧的不良事件，同时对PFS数据的可靠性表示怀疑，因此拒绝加速审批奥拉帕尼Olaparib，同时要求阿斯利康必须完成正在开展的III期研究，FDA将于2015年1月作出审查决定。 阿斯利康对奥拉帕尼Olaparib寄予厚望，认为该药的年销售额将突破20亿美元。不过，阿斯利康对抗癌免疫疗法PD-L1抑制剂MEDI4736和另一种抗癌药AZD9291的期望更高，并预测2者的年销售峰值分别为65亿美元和30亿美元，后者目前正处于I期临床。然而，这些产品要想实现预期目标，将取决于在一系列癌症中的临床成功。 关于Lynparza(奥拉帕尼 Olaparib) 奥拉帕尼Olaparib是一种创新的、潜在首创口服多聚ADP核糖聚合酶(PARP)抑制剂，在临床前模型中已被证明，能够利用DNA修复途径的缺陷，优先杀死癌细胞。这种作用模式，赋予奥拉帕尼Olaparib治疗具有DNA修复缺陷的广泛肿瘤类型的潜力。PARP与广泛的肿瘤类型相关，尤其是乳腺癌和卵巢癌。 关于BRCA基因： BRCA1和BRCA2基因属于肿瘤抑制因子编码基因，这些基因的突变，与遗传性乳腺癌和卵巢癌相关。若一个女性继承了BRCA1或BRCA2突变，患乳腺癌和/或卵巢癌的风险将大大增加。在癌细胞扩增至卵巢以外之前，仅有15%的卵巢癌被发现。尽管当前治疗和诊断已经取得了很大进步，但癌细胞已扩散至卵巢外的患者，5年生存率低于50%。 关于PARP抑制剂： 正处于临床开发阶段的其它PARP抑制剂还有Tesaro从默沙东购入的Niraparib(尼拉帕尼)，阿斯利康的Olaparib(奥拉帕尼)，BioMarin的BMN 673(乳腺癌3期试验)，Clovis Oncology的Rucaparib(2011年从辉瑞购入，卵巢癌2期试验)和Eisai的E7016(黑色素瘤2期试验)。