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达罗鲁胺片

公司：拜耳医药保健制药公司

批准日期：2019年7月30日

治疗：前列腺癌

 

Nubeqa（darolutamide）达罗鲁胺片,是雄激素受体拮抗剂，用于治疗非转移性去势抵抗性前列腺癌（nmCRPC）。

 

新泽西州WHIPPANY，2019年7月30日/美通社-PR Newswire /  -美国食品和药物管理局（FDA）今天批准了Nubeqa®（darolutamide），一种雄激素受体抑制剂（ARi），用于治疗非转移性去势抵抗患者前列腺癌（nmCRPC）.1 FDA的批准是基于评估Nubeqa加雄激素剥夺疗法（ADT）的III期ARAMIS试验，该试验证明了无转移生存（MFS）的主要疗效终点的显着改善，中位数为40.4个月，安慰剂加ADT为18.4个月（p <0.0001）.1 MFS定义为从随机化到第一次盲证独立中心评价（BICR）-证实远处转移或任何原因导致死亡的时间的时间最后一次可评估扫描后33周，以先发生者为准。Nubeqa根据FDA的优先审查指定获得批准，该指定用于可能显着改善严重疾病治疗的安全性或有效性的药物。

 

“在这个阶段的前列腺癌患者通常没有这种疾病的症状。在这种情况下治疗的首要目标是延迟前列腺癌的传播，并限制治疗的负担副作用，”医学博士马修史密斯说。马萨诸塞州综合医院癌症中心泌尿生殖系恶性肿瘤项目主任博士。 “这项批准标志着前列腺癌界的重要新选择。”

 

在美国，估计2019年将有超过73,000名男性被诊断患有去势抵抗性前列腺癌（CRPC）。这些患者中约有40％患有前列腺癌，这些前列腺癌尚未扩散到身体的其他部位，并且还与前列腺上升有关特异性抗原（PSA）水平，尽管有睾丸激素水平，称为nmCRPC.2,3这很重要，因为大约三分之一的患有nmCRPC的男性在两年内继续发生转移.4 PSA监测对于确定患者并帮助抵消疾病传播前男性的不良待遇.5,6

 

“我们知道，当需要采取行动时，患有nmCRPC的男性仍然处于生命的黄金时期并处于疾病的关键时刻，”执行副总裁兼首席科学官Howard R. Soule博士说。 ，前列腺癌基金会（PCF）。 “26年来，PCF一直致力于旨在改善患者治疗效果的研究，我们欢迎增加新的治疗方案，为男性提供更多选择，与医生一起选择适合自己的治疗方案。”

 

 

“经过Nubeqa的批准，我们现在有了一种新疗法，扩展了MFS，使医生能够更灵活地治疗患有nmCRPC的男性，”拜耳药物事业部执行委员会成员兼肿瘤学战略业务部负责人Robert LaCaze说。在拜耳。 “拜耳很自豪能够在nmCRPC治疗领域取得最新进展.Nubeqa是我们前列腺癌组合的最新成员，反映了拜耳致力于在前列腺癌连续体的不同阶段为男性寻找治疗方法。”

在ARAMIS试验中，由于不良反应，两组均表现出9％的停药率.1接受Nubeqa治疗的患者中最常见的不良反应包括心力衰竭（0.4％）和死亡（0.4％）。1发生不良反应Nubeqa组（安慰剂组≥2％）更常见的是疲劳（16％对11％），四肢疼痛（6％对3％）和皮疹（3％对1％）.1Nubeqa未在女性和女性中进行过研究对胚胎-胎儿毒性有警告和预防措施

总生存期（OS）和疼痛进展时间是额外的次要疗效终点.1最终MFS分析时OS数据尚未成熟.1 MFS结果由疼痛进展时间延迟支持，至少定义为与安慰剂相比，Nubeqa治疗患者的疼痛评分基础与简单疼痛清单-短期形式或阿片类药物的开始相比有2点的恶化.1研究中所有患者的疼痛进展率为28％。

拜耳已经向欧盟（EU），日本和其他卫生部门申请批准Nubeqa。Nubeqa由拜耳和全球运营的芬兰制药公司Orion Corporation联合开发。

 

Nubeqa将提供成人口服片剂.

Nubeqa患者的价值计划

拜耳致力于确保在美国接受Nubeqa治疗的患者可以获得药物并获得他们可能需要的支持。作为这一承诺的一部分，拜耳推出了一项创新的患者支持计划DUDE（Darolutamide用户药物体验）访问服务™，该计划为符合条件的患者提供为期两个月的免费试用计划，同时为商业保险患者提供0美元的共付费用。出线。

 

临床试验结果

FDA批准Nubeqa®（darolutamide）是基于ARAMIS试验，一项随机，双盲，安慰剂对照，多中心III期研究，评估口服Nubeqa对接受nmCRPC的患者的安全性和有效性伴随促性腺激素释放激素（GnRH）类似物或双侧睾丸切除术。在临床研究中，1,509名患者以2：1的比例随机分组，每日口服两次600毫克的Nubeqa或安慰剂加ADT。研究中允许有癫痫病史的患者进行研究

 

该试验的主要疗效终点是MFS，定义为从随机化到最后一次可评估扫描后33周内因任何原因引起的BICR证实的远处转移或死亡的首次证据的时间，以先发生者为准.1 Nubeqa plus ADT显示MFS有统计学意义上的显着改善，中位MFS为40.4个月，安慰剂加ADT为18.4个月[HR = 0.41,95％CI（0.34,0.50），p <0.0001] .1 OS和疼痛进展时间为在最终MFS分析时，OS数据尚未成熟.1 MFS结果得到疼痛进展时间延迟的支持，定义为疼痛评分基线至少2个点恶化。与安慰剂相比，Nubeqa治疗患者的疼痛清单-阿片类药物的简短形式或开始.1研究中所有患者中有28％报告疼痛进展。

 

 

Nubeqa手臂发生不良反应（安慰剂组≥2％）是疲劳（16％对11％），四肢疼痛（6％对3％）和皮疹（3％对1％）.1观察到的唯一反应接受Nubeqa治疗的患者中≥10％的不良反应是疲劳.1此外，Nubeqa治疗2％或更多患者的临床显着不良反应包括缺血性心脏病（4.0％对安慰剂组为3.4％）和心力衰竭（2.1％）安慰剂组为0.9％.1研究双组中9％的患者因不良反应而停药.1接受Nubeqa治疗的患者中最常见的不良反应包括心力衰竭（0.4％）和死亡（0.4％）.1 Nubeqa治疗患者中13％因不良反应引起的剂量中断.1需要剂量间隔的最常见不良反应接受Nubeqa治疗的患者包括高血压（0.6％），腹泻（0.5％）和肺炎（0.5％）。1 Nubeqa治疗患者中6％因不良反应导致剂量减少.1最常见的不良反应Nubeqa治疗患者需要减少剂量，包括疲劳（0.7％），高血压（0.3％）和恶心（0.3％）.1

 

关于Nubeqa®（darolutamide）

Nubeqa®（darolutamide）是一种雄激素受体抑制剂（ARi），具有独特的化学结构，可竞争性抑制雄激素结合，AR核转位和AR介导的转录.1 Nubeqa被批准用于治疗非转移性去势抵抗患者前列腺癌（nmCRPC）.1正在进行转移性激素敏感性前列腺癌（ARASENS）的III期研究。

 

拜耳已经在欧盟（EU），日本和其他国家提交了darolutamide的申请。

 

关于前列腺癌

前列腺癌是全球男性中第二大常见的恶性肿瘤和第五大癌症原因.7 2018年，估计有120万男性被诊断患有前列腺癌，全球约有358,000人死于此疾病.7前列腺癌是由异常引起的前列腺内的细胞增殖，这是男性生殖系统的一部分.8它主要影响50岁以上的男性，并且风险随着年龄的增长而增加.9治疗选择范围从手术到放射治疗再到使用激素受体拮抗剂治疗，即，阻止睾酮形成或阻止其在目标位置发挥作用的物质.10但是，几乎在所有情况下，癌症最终都会对传统的激素治疗产生抗药性.11

去势抵抗性前列腺癌（CRPC）是该疾病的一种晚期形式，即使体内睾酮的量减少到非常低的水平，癌症仍在继续发展。去势抵抗患者的治疗选择领域正在迅速发展，但直到两年前，还没有FDA批准的治疗方案选择CRPC患者，这些患者的前列腺癌尚未扩散到身体的其他部位且前列腺上升-特定抗原（PSA）水平，尽管是阉割睾酮水平，称为非转移性去势抵抗性前列腺癌，或nmCRPC.6,12约三分之一的nmCRPC患者在两年内继续发生转移.4对于进行性nmCRPC，较短的PSA倍增时间与缩短的首次转移和死亡时间相关

 

重要安全信息

胚胎-胎儿毒性：NUBEQA的安全性和有效性尚未确定。NUBEQA可导致胎儿伤害和怀孕。建议男性与具有生殖潜力的女性伴侣在使用NUBEQA治疗期间使用有效避孕药，并在最后一次给药后使用1周。

 

 

 

不良反应

接受NUBEQA的患者中有25％发生严重不良反应，接受安慰剂的患者中有20％发生严重不良反应。接受NUBEQA治疗的患者中有1％的严重不良反应是尿潴留，肺炎和血尿。总体而言，3.9％接受NUBEQA治疗的患者和3.2％接受安慰剂治疗的患者死于不良反应，包括死亡（0.4％），心力衰竭（0.3％），心脏骤停（0.2％），一般身体健康恶化（0.2％）和NUBEQA的肺栓塞（0.2％）。

 

NUBEQA组中发生的不良反应（安慰剂组≥2％）是疲劳（16％对11％），四肢疼痛（6％对3％）和皮疹（3％对1％）。

 

NUBEQA治疗组中≥2％的临床显着不良反应包括缺血性心脏病（安慰剂组为4.0％vs。3.4％）和心力衰竭组（安慰剂组为2.1％vs。0.9％）。

 

药物相互作用

其他药物对NUBEQA的影响-伴随使用NUBEQA联合P-gp和强或中度CYP3A4诱导剂可降低多拉米胺暴露，这可能会降低NUBEQA活性。避免同时使用NUBEQA与联合P-gp和强或中等CYP3A4诱导剂。

 

同时使用NUBEQA联合P-gp和强CYP3A4抑制剂会增加darolutamide暴露，这可能会增加NUBEQA不良反应的风险。更频繁地监测患者的NUBEQA不良反应，并根据需要修改NUBEQA剂量。

 

NUBEQA对其他药物的影响-  NUBEQA是乳腺癌耐药蛋白（BCRP）转运蛋白的抑制剂。同时使用NUBEQA会增加BCRP底物的暴露（AUC）和最大浓度，这可能会增加BCRP底物相关毒性的风险。避免在可能的情况下同时使用BCRP底物。如果一起使用，更频繁地监测患者的不良反应，并考虑BCRP底物药物的剂量减少。当与NUBEQA同时使用时，请参阅BCRP基材的批准产品标签。

1 INDICATIONS AND USAGE

NUBEQA is indicated for the treatment of patients with non-metastatic castration resistant prostate cancer (nmCRPC).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dose of NUBEQA is 600 mg (two 300 mg film-coated tablets) taken orally, twice daily, equivalent to a

total daily dose of 1200 mg. Swallow tablets whole with food[see Clinical Pharmacology (12.3)].

Patients receiving NUBEQA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or

should have had a bilateral orchiectomy.

Advise patients to take any missed dose as soon as they remember prior to the next scheduled dose, and not to take two

doses together to make up for a missed dose.

2.2 Dosage Modification

If a patient experiences a greater than or equal to Grade 3 toxicity or an intolerable adverse reaction, withhold dosing or

reduce to 300 mg twice daily until symptoms improve. Then the treatment may be resumed at a dose of 600 mg twice

daily.

Dose reduction below 300 mg twice daily is not recommended.

2.3 Recommended Dosage in Patients with Severe Renal Impairment

For patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m2 ) not receiving hemodialysis, the recommended

dose of NUBEQA is 300 mg twice daily[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.4 Recommended Dosage in Patients with Moderate Hepatic Impairment

For patients with moderate hepatic impairment (Child-Pugh Class B), the recommended dose of NUBEQA is 300 mg

twice daily[see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Tablets (300 mg): white to off-white oval film-coated tablets marked with “300” on one side and “Bayer” on the other.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Embryo-Fetal Toxicity

The safety and efficacy of NUBEQA have not been established in females. Based on its mechanism of action, NUBEQA

can cause fetal harm and loss of pregnancy when administered to a pregnant female[see Clinical Pharmacology (12.1)].

Advise males with female partners of reproductive potential to use effective contraception during treatment and for 1

week after the last dose of NUBEQA[see Use in Specific Populations (8.1,8.3)].

6 ADVERSE REACTIONS

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.

ARAMIS, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had

non-metastatic castration-resistant prostate cancer (nmCRPC). In this study, patients received either NUBEQA at a dose

of 600 mg, or a placebo, twice a day. All patients in the ARAMIS study received a concomitant gonadotropin-releasing

hormone (GnRH) analog or had a bilateral orchiectomy. The median duration of exposure was 14.8 months (range: 0 to

44.3 months) in patients who received NUBEQA.

Reference ID: 4469847 Overall, serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving

placebo. Serious adverse reactions in ≥ 1 % of patients who received NUBEQA included urinary retention, pneumonia

and hematuria. Overall 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo died from adverse

reactions, which included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration

(0.2%), and pulmonary embolism (0.2%) for NUBEQA.

Permanent discontinuation due to adverse reactions occurred in 9% of patients receiving NUBEQA or placebo. The most

frequent adverse reactions requiring permanent discontinuation in patients who received NUBEQA included cardiac

failure (0.4%), and death (0.4%).

Dosage interruptions due to adverse reactions occurred in 13% of patients treated with NUBEQA. The most frequent

adverse reactions requiring dosage interruption in patients who received NUBEQA included hypertension (0.6%),

diarrhea (0.5%), and pneumonia (0.5%).

Dosage reductions due to adverse reactions occurred in 6% of patients treated with NUBEQA. The most frequent adverse

reactions requiring dosage reduction in patients treated with NUBEQA included fatigue (0.7%), hypertension (0.3%), and

nausea (0.3%).

Table 1 shows adverse reactions in ARAMIS reported in the NUBEQA arm with a ≥2% absolute increase in frequency

compared to placebo. Table 2 shows laboratory test abnormalities related to NUBEQA treatment and reported more

frequently in NUBEQA-treated patients compared to placebo-treated patients in the ARAMIS study.

 

7 DRUG INTERACTIONS

7.1 Effect of Other Drugs on NUBEQA

Combined P-gp and Strong or Moderate CYP3A4 Inducer

Concomitant use of NUBEQA with a combined P-gp and strong or moderate CYP3A4 inducer decreases darolutamide

exposure which may decrease NUBEQA activity[see Clinical Pharmacology (12.3)]. Avoid concomitant use of

NUBEQA with combined P-gp and strong or moderate CYP3A4 inducers.

Reference ID: 4469847Combined P-gp and Strong CYP3A4 Inhibitors

Concomitant use of NUBEQA with a combined P-gp and strong CYP3A4 inhibitor increases darolutamide exposure[see

Clinical Pharmacology (12.3)]which may increase the risk of NUBEQA adverse reactions.Monitor patients more

frequently for NUBEQA adverse reactions and modify NUBEQA dosage as needed[see Dosage and Administration

(2.2)].

7.2 Effects of NUBEQA on Other Drugs

Breast Cancer Resistance Protein (BCRP) Substrates

NUBEQA is an inhibitor of BCRP transporter. Concomitant use of NUBEQA increases the AUC and Cmax of BCRP

substrates[see Clinical Pharmacology (12.3)],which may increase the risk of BCRP substrate-related toxicities.

Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more

frequently for adverse reactions, and consider dose reduction of the BCRP substrate drug. Consult the approved product

labeling of the BCRP substrate when used concomitantly with NUBEQA.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The safety and efficacy of NUBEQA have not been established in females. Based on its mechanism of action, NUBEQA

can cause fetal harm and loss of pregnancy[see Clinical Pharmacology (12.1)].Animal embryo-fetal developmental

toxicology studies were not conducted with darolutamide. There are no human data on the use of NUBEQA in pregnant

females.

8.2 Lactation

Risk Summary

The safety and efficacy of NUBEQA have not been established in females. There are no data on the presence of

darolutamide or its metabolites in human milk, the effect on the breastfed child, or the effect on milk production.

8.3 Females and Males of Reproductive Potential

Contraception

Males

Based on the mechanism of action, advise male patients with female partners of reproductive potential to use effective

contraception during treatment and for 1 week after the last dose of NUBEQA[see Use in Specific Populations (8.1)].

Infertility

Males

Based on animal studies, NUBEQA may impair fertility in males of reproductive potential[see Nonclinical Toxicology

(13.1)].

8.4 Pediatric Use

Safety and effectiveness of NUBEQA in pediatric patients have not been established.

8.5 Geriatric Use

Of the 954 patients who received NUBEQA in ARAMIS, 88% of patients were 65 years and over, and 49% were 75 years

and over. No overall differences in safety or efficacy were observed between these patients and younger patients.

8.6 Renal Impairment

Patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m2 ) who are not receiving hemodialysis have a higher

exposure to NUBEQA and reduction of the dose is recommended[see Dosage and Administration (2.3) and Clinical

Pharmacology (12.3)].No dose reduction is needed for patients with mild or moderate renal impairment (eGFR 30-89

mL/min/1.73 m2).The effect of end stage renal disease (eGFR ≤15 mL/min/1.73 m2 ) on darolutamide pharmacokinetics is

unknown.

Reference ID: 4469847 8.7 Hepatic Impairment

Patients with moderate hepatic impairment (Child-Pugh Class B) have a higher exposure to NUBEQA and reduction of

the dose is recommended[see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].No dose reduction is

needed for patients with mild hepatic impairment. The effect of severe hepatic impairment (Child-Pugh C) on

darolutamide pharmacokinetics is unknown.

10 OVERDOSAGE

There is no known specific antidote for darolutamide overdose. The highest dose of NUBEQA studied clinically was 900

mg twice daily, equivalent to a total daily dose of 1800 mg. No dose limiting toxicities were observed with this dose.

Considering the saturable absorption and the absence of evidence for acute toxicity, an intake of a higher than

recommended dose of darolutamide is not expected to lead to systemic toxicity in patients with intact hepatic and renal

function[see Clinical Pharmacology (12.3)].

In the event of intake of a higher than recommended dose in patients with severe renal impairment or moderate hepatic

impairment, if there is suspicion of toxicity, interrupt NUBEQA treatment and undertake general supportive measures

until clinical toxicity has been diminished or resolved. If there is no suspicion of toxicity, NUBEQA treatment can be

continued with the next dose as scheduled.

11 DESCRIPTION

NUBEQA is an androgen receptor inhibitor. The chemical name is N-{(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1

yl]propan-2-yl}-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide.

The molecular weight is 398.85 and the molecular formula is C19H19Cl N6O2. The structural formula is:

 

Darolutamide is an optically active with a specific rotation value [α]20 D= 72.2 o *mL/(dm*g), white to greyish- or

yellowish white crystalline powder, that is soluble in tetrahydrofuran, but practically insoluble in aqueous medium.

Darolutamide has a pKa of 11.75.

NUBEQA (darolutamide) is supplied as film-coated tablets containing 300 mg of darolutamide for oral use. The inactive

ingredients of the tablet are: calcium hydrogen phosphate, croscarmellose sodium, lactose monohydrate, magnesium

stearate, povidone K 30, hypromellose 15 cP, macrogol 3350, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Darolutamide is an androgen receptor (AR) inhibitor. Darolutamide competitively inhibits androgen binding, AR nuclear

translocation, and AR-mediated transcription. A major metabolite, keto-darolutamide, exhibited similarin vitroactivity to

darolutamide. In addition, darolutamide functioned as a progesterone receptor (PR) antagonistin vitro(approximately 1%

activity compared to AR). Darolutamide decreased prostate cancer cell proliferationin vitroand tumor volume in mouse

xenograft models of prostate cancer.

12.2 Pharmacodynamics

Darolutamide exposure at 600 mg twice daily results in PSA mean reduction of more than 90% from baseline.

Cardiac Electrophysiology

The effect of darolutamide (600 mg twice daily) on the QTc interval was evaluated in a subgroup of 500 patients in the

ARAMIS study. No large mean increase in QTc (i.e., > 20 ms) was detected.

Reference ID: 4469847 12.3 Pharmacokinetics

Following administration of 600 mg twice daily, darolutamide mean (%CV) steady-state peak plasma concentration (Cmax)

is 4.79 mg/L (30.9%) and area under the plasma concentration-time curve from time 0 to 12 hours (AUC12h) is 52.82

h•µg/mL (33.9%). Steady-state is reached 2–5 days after repeated dosing with food, with an approximate 2-fold

accumulation.

The exposure (Cmax and AUC12) of the darolutamide and the active metabolite keto-darolutamide increase in a nearly

dose-proportional manner in the dose range of 100 to 700 mg (0.17 to 1.17 times the approved recommended dosage). No

further increase in darolutamide exposure was observed at 900 mg twice daily (1.5 times the approved recommended

dosage).

Absorption

Darolutamide Cmax is reached approximately 4 hours after administration of a single 600 mg oral dose.

The absolute bioavailability is approximately 30% following oral administration of a NUBEQA tablet containing 300 mg

darolutamide under fasted conditions.

Food Effect

Bioavailability of darolutamide increased by 2.0 to 2.5-fold when administered with food. A similar increase of exposure

was observed for the active metabolite keto-darolutamide.

Distribution

The apparent volume of distribution of darolutamide after intravenous administration is 119 L.

Protein binding is 92% for darolutamide and 99.8% for the active metabolite, keto-darolutamide. Serum albumin is the

main binding protein for darolutamide and keto-darolutamide.

Elimination

The effective half-life of darolutamide and keto-darolutamide is approximately 20 hours in patients. The clearance (%CV)

of darolutamide following intravenous administration is 116 mL/min (39.7%).

Metabolism

Darolutamide is primarily metabolized by CYP3A4, as well as by UGT1A9 and UGT1A1. Keto-darolutamide total

exposure in plasma is 1.7-fold higher compared to darolutamide.

Excretion

After a single radiolabeled dose as an oral solution, a total of 63.4% of darolutamide-related material is excreted in the

urine (approximately 7% unchanged) and 32.4% (approximately 30% unchanged) in the feces. More than 95% of the dose

was recovered within 7 days after administration.

Specific Populations

In nmCRPC patients, no clinically significant differences in the pharmacokinetics of darolutamide were observed based

on age (48-95 years), race (White, Japanese, non-Japanese Asian, Black or African American), mild to moderate renal

impairment (eGFR 30–89 mL/min/1.73m2 ), or mild hepatic impairment.

In non-cancer subjects with severe renal impairment (eGFR 15–29 mL/min/1.73 m2 ) not receiving dialysis or with

moderate hepatic impairment (Child-Pugh Class B), NUBEQA exposure increased by about 2.5- and 1.9-fold,

respectively, compared to healthy subjects.

The effect of end-stage renal disease (eGFR <15 mL/min/1.73 m2 ) or severe hepatic impairment (Child-Pugh C) on

darolutamide pharmacokinetics has not been studied.

Drug Interaction Studies

Clinical Studies

Combined P-gp and Strong CYP3A4 Inducers

Concomitant use of rifampicin (a combined P-gp and strong CYP3A4 inducer) decreased mean darolutamide AUC0-72 by

72% and Cmaxby 52%.The decrease of darolutamide exposure by moderate CYP3A4 inducers is expected to be in the

range of 36% – 58 %.

Reference ID: 4469847Combined P-gp and Strong CYP3A4 Inhibitors

Itraconazole (a strong combined CYP3A4 and P-gp inhibitor) increased mean darolutamide AUC0-72 by 1.7- and Cmax by

1.4-fold.

CYP3A4 substrates

Concomitant use of darolutamide decreased the mean AUC and Cmax of midazolam (CYP3A4 substrate) by 29% and 32%,

respectively. No clinically significant differences in the pharmacokinetics of midazolam were observed when used

concomitantly with darolutamide.

BCRP Substrates

Concomitant use of darolutamide increased the mean AUC and Cmax of rosuvastatin (BCRP substrate) by approximately

5-fold.

P-gp Substrates

No clinically significant differences in the pharmacokinetics of dabigatran (P-gp substrate) were observed when used

concomitantly with darolutamide.

In Vitro Studies

In vitro, darolutamide inhibits OATP1B1 and OATP1B3. Darolutamide did not inhibit the major CYP enzymes

(CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) or transporters (MRP2, BSEP, OATs, OCTs, MATEs,

OATP2B1, and NTCP) at clinically relevant concentrations.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies to evaluate the carcinogenic potential of darolutamide have not been conducted.

Darolutamide was clastogenic in anin vitrochromosome aberration assay in human peripheral blood lymphocytes.

Darolutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in thein

vivocombined bone marrow micronucleus assay and the Comet assay in the liver and duodenum of the rat.

Fertility studies in animals have not been conducted with darolutamide. In repeat-dose toxicity studies in male rats (up to

26 weeks) and dogs (up to 39 weeks), tubular dilatation of testes, hypospermia, and atrophy of seminal vesicles, testes,

prostate gland and epididymides were observed at doses ≥ 100 mg/kg/day in rats (0.6 times the human exposure based on

AUC) and ≥ 50 mg/kg/day in dogs (approximately 1 times the human exposure based on AUC).

14 CLINICAL STUDIES

ARAMIS (NCT02200614) was a multicenter, double-blind, placebo-controlled clinical trial in 1509 patients with non

metastatic castration resistant prostate cancer with a prostate-specific antigen doubling time (PSADT) of ≤ 10 months.

Randomization was stratified by PSADT and use of bone-targeted therapy at study entry. Patients with pelvic lymph

nodes less than 2 cm in short axis below the aortic bifurcation were allowed to enter the study. Patients with a history of

seizures were not excluded. Absence or presence of metastasis was assessed by blinded independent central review

(BICR). PSA results were not blinded and were not used for treatment discontinuation.

Patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n=955) or matching placebo

(n=554). Treatment continued until radiographic disease progression as assessed by CT, MRI, 99mTc bone scan by BICR,

unacceptable toxicity or withdrawal. All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently

or had a bilateral orchiectomy.

The following patient demographics and disease characteristics were balanced between treatment arms. The median age

was 74 years (range 48–95) and 9% of patients were 85 years of age or older. The racial distribution was 79% White, 13%

Asian, and 3% Black. A majority of patients (73%) had a Gleason score of 7 or higher at diagnosis. The median PSADT

was 4.5 months. Forty-two percent of patients in both treatment arms had prior surgery or radiotherapy to the prostate.

Eleven percent of patients had enlarged pelvic lymph nodes less than 2 cm at study entry. Six percent of patients were

retrospectively identified by BICR as having metastases at baseline. Seventy-three percent of patients received prior

treatment with an anti-androgen (bicalutamide or flutamide). All patients had an Eastern Cooperative Oncology Group

Performance Status (ECOG PS) score of 0 or 1 at study entry. There were 12 patients enrolled on the NUBEQA arm with

Reference ID: 4469847 a history of seizure. At baseline, 47% of patients reported no pain on the Brief Pain Inventory-Short Form (a 7-day diary

average of the daily worst pain item).

The major efficacy endpoint was metastasis free survival (MFS), defined as the time from randomization to the time of

first evidence of BICR-confirmed distant metastasis or death from any cause within 33 weeks after the last evaluable scan,

whichever occurred first. Distant metastasis was defined as new bone or soft tissue lesions or enlarged lymph nodes above

the aortic bifurcation. Overall survival (OS) and time to pain progression were additional efficacy endpoints.

The efficacy results for MFS from ARAMIS are summarized in Table 3 and Figure 1. Treatment with NUBEQA resulted

in a statistically significant improvement in MFS compared to placebo. MFS results were consistent across patient

subgroups for PSADT (≤ 6 months or > 6 months) or prior use of bone-targeting agents (yes or no). OS data were not

mature at the time of final MFS analysis (57% of the required number of events). Locoregional-only progression occurred

in 6% of patients overall.

 

 

The MFS result was supported by a delay in time to pain progression, defined as at least a 2-point worsening from

baseline of the pain score on Brief Pain Inventory-Short Form or initiation of opioids, in patients treated with NUBEQA

as compared to placebo. Pain progression was reported in 28% of all patients on study.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

NUBEQA (darolutamide) 300 mg film-coated tablets are white to off-white, oval shaped tablets, marked with “300” on

one side, and “BAYER” on the other side. NUBEQA 300 mg tablets are available in bottles of 120 tablets.

NDC 50419-395-01

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled

Room Temperature].

Keep the bottle tightly closed after first opening.

17 PATIENT COUNSELING INFORMATION

Dosage and Administration

Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain

this treatment during the course of treatment with NUBEQA.

Instruct patients to take their dose of two tablets (twice daily). NUBEQA should be taken with food. Each tablet should be

swallowed whole.

Inform patients that in the event of a missed daily dose of NUBEQA, to take any missed dose, as soon as they remember

prior to the next scheduled dose, and not to take two doses together to make up for a missed dose[see Dosage and

Administration (2.1)].

Reference ID: 4469847 Embryo-Fetal Toxicity

Inform patients that NUBEQA can be harmful to a developing fetus and can cause loss of pregnancy[see Use in Specific

Populations (8.1)].

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for

1 week after the last dose of NUBEQA[see Warnings and Precautions (5.1) and Use in Specific Populations (8.1,8.3)].

Infertility