奥拉帕尼硬胶囊，Lynparza, 50mg hard capsules(olaparib)，获FDA批准第一个LDT协同诊断测试也被批准鉴定适宜的患者
LYNPARZA（olaparib）胶囊剂为供口服使用
美国最初批准：2014年  公司：AstraZeneca
适应症和用法
Lynparza是聚（ADP-核糖）聚合酶（PARP）抑制剂的患者有害的或怀疑的有害的种系的BRCA突变（由FDA批准的试验检测）晚期卵巢癌表示作为单一疗法谁已经用三个或更多个先前行化疗。
基于客观缓解率和反应持续时间在加速审批的指示批准。继续批准该适应症可能是在验证和临床获益描述验证性试验队伍。
【用法用量】
•推荐的剂量是每天服用两次400毫克。
•继续治疗直至疾病进展或不可接受的毒性。
•对于不良反应，考虑治疗或减少剂量的剂量中断。
剂型和规格
胶囊：50毫克
禁忌
无
警告和注意事项
•骨髓增生异常综合征/急性髓系白血病（MDS/ AML）患者发生接触Lynparza，有些情况下是致命的。监测患者的血液学毒性在基线和此后每月。如果MDS/AML确认停止。
•肺炎：患者发生接触Lynparza，有些情况下是致命的。中断治疗，如果肺炎之嫌。如果肺炎确认停止。
•胚胎胎儿毒性：Lynparza可引起胎儿危害。奉劝女性的潜在风险繁殖潜力的一个胎儿，避免怀孕。
不良反应
•最常见的不良反应（≥20％）的临床试验是贫血，恶心，乏力（包括乏力），呕吐，腹泻，味觉障碍，消化不良，头痛，食欲下降，鼻咽炎/咽炎/ URI，咳嗽，关节痛/肌肉骨骼痛，肌痛，背部疼痛，皮炎/皮疹和腹痛/不适。
•最常见的实验室检查异常（≥25％）为提高肌酐，平均红细胞体积升高，降低血红蛋白，降低淋巴细胞，减少中性粒细胞绝对计数，并减少血小板。
药物相互作用
•CYP3A抑制剂：避免同时使用强和中度CYP3A酶抑制剂。如果不能避免的抑制剂，减少剂量。
•CYP3A诱导剂：避免同时使用强和中度CYP3A诱导剂。如果不能避免适度CYP3A诱导剂，应了解对于降低功效的潜力。
特殊人群中使用
•哺乳母亲：停止治疗或停止哺乳。

LYNPARZA™ APPROVED BY THE US FOOD AND DRUG ADMINISTRATION FOR THE TREATMENT OF ADVANCED OVARIAN CANCER IN PATIENTS WITH GERMLINE BRCA-MUTATIONS
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Treatment of gBRCA-mutated advanced ovarian cancer
Lynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
The indication is approved under accelerated approval based on objective response rate and duration of response [seeClinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious germline BRCA-mutations [seeIndications and Usage (1)andClinical Studies (14)]. Information on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics.
2.2 Recommended Dosing
The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.
If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time.
Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [seeHow Supplied/Storage and Handling (16.2)].
2.3 Dose Adjustments for Adverse Reactions
To manage adverse reactions, consider dose interruption of treatment or dose reduction.
The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.
If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.
2.4 Dose Modifications for Use with CYP3A Inhibitors
Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [seeDrug Interactions (7.2)].
3 DOSAGE FORMS AND STRENGTHS
Lynparza (olaparib) is supplied as a white, opaque, hard capsule (50 mg), marked in black ink with “OLAPARIB 50 mg” on the cap and the AstraZeneca logo on the body.
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
5.1 Myelodysplastic syndrome/Acute Myeloid LeukemiaMyelodysplastic syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.
Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (≤CTCAE Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Lynparza.
5.2 Pneumonitis
Pneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza.
5.3 Embryo-Fetal Toxicity
Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus [seeUse in Specific Populations (8.1)].
Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Lynparza [seeUse in Specific Populations (8.6)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere in the labeling:
• Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1) ]
• Pneumonitis [see Warnings and Precautions (5.2) ]
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy.
In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [seeClinical Studies (14)], adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. Table 1 presents the frequency of adverse reactions reported in ≥20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received 3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to Lynparza in these patients was 158 days.
Table 1 Adverse Reactions Reported in ≥20% of Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza

3 or more lines of prior chemotherapy
Adverse Reaction	Grades 1-4 N=223 %	Grades 3-4 N=223 %
Blood and Lymphatic disorders
Anemia	34	18
Gastrointestinal disorders
Abdominal pain/discomfort	43	8
Decreased appetite	22	1
Nausea	64	3
Vomiting	43	4
Diarrhea	31	1
Dyspepsia	25	0
General disorders
Fatigue/asthenia	66	8
Infections and infestations
Nasopharyngitis/URI	26	0
Musculoskeletal and Connective Tissue disorders
Arthralgia/musculoskeletal pain	21	0
Myalgia	22	0

 Table 2 presents the frequency of abnormal laboratory findings in the 223 patients with gBRCA-mutated advanced ovarian cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily.
Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer Receiving Lynparza 

Laboratory Parameter1	3 or more lines of prior chemotherapy
	Grades 1-4 N=223 %	Grades 3-4 N=223 %
Decrease in hemoglobin (anemia)	90	15
Decrease in absolute neutrophil count (neutropenia)	25	7
Decrease in platelets (thrombocytopenia)	30	3
Decrease in lymphocytes (lymphopenia)	56	17
Mean corpuscular volume elevation	57	-
Increase in creatinine	30	2

The following adverse reactions and laboratory abnormalities have been identified in ≥10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash. The following adverse reactions and laboratory abnormalities have been identified in ≥1 to <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.
Table 3 presents adverse reactions reported in ≥20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCA-mutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA mutation compared to 4.4 months for patients with gBRCA mutation on placebo.
Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of those receiving placebo; dose reductions in 15% of Lynparza and 5% of placebo patients; and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction.
Table 3 Adverse Reactions Reported in ≥20% of Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial 

Adverse Reactions	Lynparza N=53		Placebo N=43
	Grades 1-4 %	Grades 3-4 %	Grades 1-4 %	Grades 3-4 %
Blood and Lymphatic disorders
Anemia	25	4	7	2
Gastrointestinal disorders
Abdominal pain/discomfort	47	0	58	2
Decreased appetite	25	0	14	0
Nausea	75	2	37	0
Vomiting	32	4	9	0
Diarrhea	28	4	21	2
Dyspepsia	25	0	14	0
Dysgeusia	21	0	9	0
General disorders
Fatigue (including asthenia, lethargy)	68	6	53	2
Infections and infestations
Nasopharyngitis/Pharyngitis/URI	43	0	16	0
Musculoskeletal and Connective tissue disorders
Arthralgia/Musculoskeletal pain	32	4	21	0
Myalgia	25	2	12	0
Back pain	25	6	21	0
Nervous system disorder
Headache	25	0	19	2
Respiratory, Thoracic, Mediastinal disorders
Cough	21	0	14	0
Skin and Subcutaneous Tissue
Dermatitis/Rash	25	0	14	0

Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial

Laboratory parameter1	Lynparza N=53		Placebo N=43
	Grades 1-4 %	Grades 3-4 %	Grades 1-4 %	Grades 3-4 %
Decrease in hemoglobin	85	8	58	2
Decrease in absolute neutrophil count	32	8	23	0
Decrease in platelets	26	6	19	0
Mean corpuscular volume elevation	85	-	44	-
Increase in creatinine	26	0	5	0

Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.
7 DRUG INTERACTIONS
Olaparib is primarily metabolized by CYP3A.
7.1 Anticancer Agents
Clinical studies of Lynparza in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.
7.2 Drugs that may Increase Olaparib Plasma Concentrations
In patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold.
Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ritinovir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [seeDosage and Administration (2.4)].
Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
7.3 Drugs that may Decrease Olaparib Plasma Concentrations
In patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%.
Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [seeClinical Pharmacology (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category D [seeWarnings and Precautions (5.3)]
Risk summary Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the pregnancy.
Animal Data
In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before mating through to day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day (with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).
In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center; fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery. Some findings noted above in the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.
8.3 Nursing Mothers
It is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from olaparib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and efficacy of Lynparza has not been established in pediatric patients.
8.5 Geriatric Use
In clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged ≥65years. The safety profile was similar irrespective of age with the exception of AEs of CTCAE ≥3 which were reported more frequently in patients aged ≥65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System Organ Class accounted for this observed difference.
8.6 Females of Reproductive Potential
Lynparza can cause fetal harm when administered to a pregnant woman [seeUse in Specific Populations (8.1)]. Advise female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being considered, use highly effective contraception during treatment with Lynparza and for at least one month following the last dose of Lynparza. Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Lynparza.
8.7 Hepatic Impairment
The effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin >1.5 X ULN and AST/ALT ≥2.5 X ULN (≥5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials. There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN) [seeClinical Pharmacology (12.3)].
8.8 Renal Impairment
Based on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or patients on dialysis [seeClinical Pharmacology (12.3)].
10 OVERDOSAGE
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.
11 DESCRIPTION
Olaparib is an inhibitor of the mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme.
The chemical name is 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-one and it has the following chemical structure:

The empirical molecular formula for Lynparza is C24H23FN4O3 and the relative molecular mass is 434.46.
Olaparib is a crystalline solid, is non-chiral and shows pH-independent low solubility of approximately 0.1 mg/mL across the physiological pH range.
Lynparza is available in 50 mg capsules for oral administration. Each capsule contains olaparib as the active ingredient and the following inactive ingredients:
• Capsule content: lauroyl polyoxylglycerides
• Capsule shell: hypromellose, titanium dioxide, gellan gum, potassium acetate
• Capsule printing ink: shellac, ferrosoferric oxide
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Lynparza is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3. PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy. Increased cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis and cell death.
12.3 Pharmacokinetics
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 (accumulation ratio of 1.4 – 1.5 for twice daily dosing), with steady state exposures achieved within 3 to 4 days.
Limited data suggest that the systemic exposure (AUC) of olaparib increases less than proportionally with dose over the dose range of 100 to 400 mg, but the PK data were variable across trials.
Co-administration with a high fat meal slowed the rate (Tmax delayed by 2 hours) of absorption, but did not significantly alter the extent of olaparib absorption (mean AUC increased by approximately 20%).
Distribution
Olaparib had a mean (± standard deviation) apparent volume of distribution at steady state of 167 ± 196 L after a single 400 mg dose of olaparib. The in vitro protein binding of olaparib at plasma concentrations achieved following dosing at 400 mg twice daily is approximately 82%.
Metabolism
In vitro, CYP3A4 was shown to be the enzyme primarily responsible for the metabolism of olaparib.
Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted for the majority of the circulating radioactivity in plasma (70%). It was extensively metabolized with unchanged drug accounting for 15% and 6% of radioactivity in urine and feces, respectively. The majority of the metabolism is attributable to oxidation reactions with a number of the components produced undergoing subsequent glucuronide or sulfate conjugation.
Excretion
A mean (± standard deviation) terminal plasma half-life of 11.9 ± 4.8 hours and apparent plasma clearance of 8.6 ± 7.1L/h were observed after a single 400 mg dose of olaparib.
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 feces. The majority of the material was excreted as metabolites.
Based on preliminary data from a dedicated renal impairment trial, the mean AUC and Cmax of olaparib increased by 1.5- and 1.2-fold, respectively, when olaparib was dosed in patients with mild renal impairment (CLcr = 50-80 mL/min; N=14) compared to those with normal renal function (CLcr >80 mL/min; N=8). There are no data in patients with CLcr <50 mL/min or in patients on dialysis.
Drug Interactions
In vitro, olaparib was an inhibitor of CYP3A4 and an inducer of CYP2B6 at higher concentrations than are clinically achieved. Olaparib produced little/no inhibition of other CYP isozymes. In vitro studies have shown that olaparib is a substrate of CYP3A4.
Based on the data from a drug-interaction trial (N=57), the AUC and Cmax of olaparib increased by 2.7-and 1.4-fold, respectively, when olaparib was administered in combination with itraconazole, a strong CYP3A inhibitor. Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that a moderate CYP3A inhibitor (fluconazole) may increase the AUC and Cmax of olaparib by 2-and 1.1-fold, respectively.
Based on the data from a drug-interaction trial (N=22), the AUC and Cmax of olaparib decreased by 87% and 71%, respectively, when olaparib was administered in combination with rifampicin, a strong CYP3A inducer. Simulations using PBPK models suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC and Cmax of olaparib by 50 - 60% and 20 - 30%, respectively.
In vitro studies have shown that olaparib is a substrate of P-gp and an inhibitor of BCRP, OATP1B1, OCT1, OCT2, OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been conducted with olaparib.
Olaparib was clastogenic in an in vitro chromosomal aberration assay in mammalian CHO cells and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of olaparib and indicates potential for genotoxicity in humans. Olaparib was not mutagenic in a bacterial reverse mutation (Ames) test.
In a fertility study, female rats received oral olaparib at doses of 0.05, 0.5, and 15 mg/kg/day for at least 14 days before mating through the first week of pregnancy. There were no adverse effects on mating and fertility rates at doses up to 15 mg/kg/day (maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).
In a male fertility study, olaparib had no effect on mating and fertility in rats at oral doses up to 40 mg/kg/day following at least 70 days of olaparib treatment (with systemic exposures of approximately 7% of the human exposure (AUC0-24h) at the recommended dose).
Close
14 CLINICAL STUDIES
The efficacy of Lynparza was investigated in a single-arm study in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers (Study 1). A total of 137 patients with measurable, gBRCAm-associated ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. All patients received Lynparza at a dose of 400 mg twice daily as monotherapy until disease progression or intolerable toxicity. Objective response rate (ORR) and duration of response (DOR) were assessed by the investigator according to RECIST v1.1.
The median age of the patients was 58 years, the majority were Caucasian (94%) and 93% had an ECOG PS of 0 or 1. Deleterious or suspected deleterious, germline BRCA mutation status was verified retrospectively in 97% (59/61) of the patients for whom blood samples were available by the companion diagnostic BRACAnalysis CDx™, which is FDA approved for selection of patients for Lynparza treatment.
Efficacy results from Study 1 are summarized in Table 5.
Table 5 Overall Response and Duration of Response in Patients with gBRCA-mutated Advanced Ovarian Cancer Who Received 3 or More Prior Lines of Chemotherapy in Study 1 N=137 Objective Response Rate (95% CI)34% (26, 42)Complete Response 2%Partial Response 32%Median DOR in months (95% CI)7.9 (5.6, 9.6)
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
Lynparza 50 mg is a white, opaque, hard capsule, marked in black ink with: “OLAPARIB 50 mg” on the cap and AstraZeneca logo on the body; available in:
Bottles of 112 capsules NDC 0310-0657-58
16.2 Storage Store at 25ºC (77ºF), excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room Temperature]
Lynparza should not be exposed to temperatures greater than 40ºC or 104ºF. Do not take Lynparza if it is suspected of having been exposed to temperatures greater than 40ºC or 104ºF.

olaparib或成为用于BRCA突变铂敏感复发性卵巢癌的首个PARP抑制
欧洲药品管理局（EMA）人用医药产品委员会（CHMP）支持加速批准olaparib，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。
Olaparib是一种创新的口服多聚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，阿斯利康正在调查olaparib用于BRCA突变卵巢癌的治疗。
今年6月底，阿斯利康（AZN）“死而复生”的抗癌药Lynparza（olaparib）被FDA专家委员会否决。近日，该药在欧盟却收获了好消息。欧洲药品管理局（EMA）人用医药产品委员会（CHMP）支持加速批准olaparib，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。EMA通常都会采纳CHMP的意见，这也意味着olaparib将在3个月内获批，该药也将成为用于BRCA突变铂敏感复发性卵巢癌的首个PARP抑制剂。
CHMP的积极意见，是基于一项II期临床（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，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，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。对于olaparib而言，阿斯利康正在开展多个III期临床，评价该药用于卵巢癌、胃癌、乳腺癌的治疗。
关于Lynparza（olaparib）：
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%。
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产地国家：美国
原产地英文商品名:
Lynparza hard capsules 50mg/cap 112caps/box
原产地英文药品名:
olaparib
中文参考商品译名:
Lynparza 50毫克/胶囊 112胶囊/盒
中文参考药品译名:
奥拉帕尼
生产厂家中文参考译名:
阿斯利康
生产厂家英文名:
AstraZeneca