批准日期：2018年2月22日 公司：Johnson & Johnson
Apalutamide是一种雄激素受体(AR)抑制剂直接地结合至AR的配体-结合结构域。Apalutamide 抑制AR核转位，抑制DNA结合，和妨碍AR -介导的转录。一个主要代谢物，N-desmethyl apalutamide，是一个效力较弱AR抑制剂，和表现出apalutamide活性的三分之一在一项体外转录受体分析。 Apalutamide给药致减低的肿瘤细胞增殖和增加凋亡导致减低肿瘤容积在前列腺小鼠移植物模型。
ERLEADA(apalutamide) 60mg膜包衣片为略微黄至灰绿色椭圆形片在一侧凹陷有“AR 60”。 ERLEADA 60mg片是可得到在120片瓶。每瓶含硅胶干燥剂。
NDC 号59676 600
贮存在20°C至25°C(68°F至77°F); 外出允许至15°C至30°C(59°F至86°F) [见USP控制室温].
ERLEADA™ (apalutamide), a Next-Generation Androgen Receptor Inhibitor, Granted U.S. FDA Approval for the Treatment of Patients with Non-Metastatic Castration-Resistant Prostate Cancer
ERLEADA™ is the first FDA-approved therapy to treat patients with non-metastatic castration-resistant prostate cancer
Approval is based on Phase 3 SPARTAN clinical trial data which showed ERLEADA™ decreased the risk of distant metastasis or death by 72 percent and improved median metastasis-free survival by more than two years
The major efficacy outcome was supported by statistically significant improvements for secondary endpoints, including time to metastasis, progression-free survival, and time to symptomatic progression
U.S. Food and Drug Administration (FDA) has approved ERLEADA™ (apalutamide), a next-generation androgen receptor inhibitor,for the treatment of patients with non-metastatic castration-resistant prostate cancer (NM-CRPC). ERLEADA™ is the first FDA-approved treatment for these patients. Today’s approval follows an FDA Priority Review designation based upon data from the Phase 3 SPARTAN study, which demonstrated a 72 percent reduction in risk of distant metastasis or death, and an increase in median metastasis-free survival (MFS) by more than two years (difference of 24.31 months) in patients with NM-CRPC.
“The need to delay metastasis is critical to the treatment of prostate cancer. Nearly 90 percent of patients with castration-resistant prostate cancer will eventually develop bone metastases, at which point the prognosis sharply worsens,” said Mathai Mammen, M.D., Ph.D., Global Head, Janssen Research & Development, LLC. “We are excited about what this approval means for patients living with prostate cancer, and that physicians now have an important and much-needed treatment option that has been shown to delay the progression of castration-resistant prostate cancer.”
ERLEADA™ received FDA approval based on the Phase 3 data from the SPARTAN clinical trial, which assessed the efficacy and safety of ERLEADA™ versus placebo in patients with NM-CRPC who had a rapidly rising PSA while receiving continuous androgen deprivation therapy.
SPARTAN, a Phase, randomized, double-blind, placebo-controlled, multi-center study, enrolled,207 patients with non-metastatic castration-resistant prostate ancer.
Patients were randomized 2:1 to receive either ERLEADA™ orally at a dose of 240 mg once daily (n=806), or placebo once daily (n=401).4 All patients in the SPARTAN trial received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy.
ERLEADA™ decreased the risk of distant metastasis or death by 72 percent compared to placebo (HR = 0.28; 95% CI, 0.23-0.35; P<0.0001).4 The median MFS was 40.51 months for ERLEADA™ compared to 16.20 months for placebo, prolonging MFS by more than two years (difference of 24.31 months).4 MFS benefit was consistently seen across patient subgroups including prostate specific antigen doubling time (PSADT) (≤6 months or >6 months), use of a prior bone-sparing agent (yes or no), and locoregional disease (N0 or N1).
The major efficacy outcome was supported by statistically significant improvements for the following secondary endpoints: time to metastasis (TTM), progression-free survival (PFS) and time to symptomatic progression.4 The median TTM was 40.51 months for ERLEADA™ compared to 16.59 months for placebo (HR=0.27; 95% CI, 0.22-0.34; P<0.0001) and the median PFS was 40.51 months compared to 14.72 months for placebo (HR=0.29; 95% CI, 0.24-0.36; P<0.0001).4 Overall survival data were not mature at the time of final MFS analysis (24% of the required number of events).
Warnings and Precautions include seizure, falls and fractures. In the SPARTAN trial, the most common adverse reactions (≥10%) were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.
About Non-Metastatic Castration-Resistant Prostate Cancer
Non-metastatic castration-resistant prostate cancer (NM-CRPC) refers to a disease state when the cancer no longer responds to medical or surgical treatments that lower testosterone, but has not yet been discovered in other parts of the body using a total body bone scan or CT scan.Features include: lack of detectable metastatic disease;5 rapidly rising prostate-specific antigen while on androgen deprivation therapy (ADT) and serum testosterone level below 50 ng/dL.Ninety percent of patients with CRPC will eventually develop bone metastases, which can lead to pain, fractures and spinal cord compression. The relative 5-year survival rate for patients with distant stage prostate cancer is 30 percent.It is critical to delay the onset of metastasis in patients with NM-CRPC.
ERLEADA™ (apalutamide) is an androgen receptor (AR) inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer.
ERLEADA™ is an AR inhibitor that binds directly to the ligand-binding domain of the AR. ERLEADA™ inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription.4 A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of ERLEADA™ in an in vitro transcriptional reporter assay.4 ERLEADA™ administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer.
Full prescribing information will be available soon at www.ERLEADA.com.
Important Safety Information4
Pregnancy-ERLEADA™ can cause fetal harm and potential loss of pregnancy.
WARNINGS AND PRECAUTIONS
Falls and Fractures - In the SPARTAN study, falls and fractures occurred in 16% and 12% of patients treated with ERLEADA™ compared to 9% and 7% treated with placebo respectively. Falls were not associated with loss of consciousness or seizure. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone targeted agents.
Seizure-In a randomized study (SPARTAN), two patients (0.2%) treated with ERLEADA™ experienced a seizure. Permanently discontinue ERLEADA™ in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA™. Advise patients of the risk of developing a seizure while receiving ERLEADA™ and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.
Adverse Reactions-The most common adverse reactions (≥10%) were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.
Hematology: anemia ERLEADA™ 70% (Grade 3-4 0.4%) placebo 64% (Grade 3-4 0.5%) leukopenia ERLEADA™ 47% (Grade 3-4 0.3%) for, placebo 29% (Grades 3-4 0%), lymphopenia ERLEADA™ 41% (Grade 3-4 2%), placebo 21% (Grade 3-4 2%);
Chemistry – hypercholesterolemia ERLEADA™ 76%(Grade3-4 0.1%), placebo 46% (Grade 3-4 0%); hypertriglycemia ERLEADA™ 70%(Grade 3-4 2%) Placebo 59% (0.8%); hypertriglyceridemia ERLEADA™ 67%(Grade 3-4 2%) placebo 49%(Grade 3-4 0.8%); Hyperkalemia ERLEADA™ 32%(Grade 3-4 2%) Placebo 22%(Grade 3-4 0.5%)
Rash - Rash was most commonly described as macular or maculo-papular. Adverse reactions were 24% with ERLEADA™ versus 6% with placebo. Grade 3 rashes (defined as covering > 30% body surface area [BSA]) were reported with ERLEADA™ treatment (5%) versus placebo (0.3%).
The onset of rash occurred at a median of 82 days. Rash resolved in 81% of patients within a median of 60 days (range: 2 to 709 days) from onset of rash. Four (4%) of patients treated with ERLEADA™ received systemic corticosteroids. Rash recurred in approximately half of patients who were re-challenged with ERLEADA™.
Hypothyroidism - Hypothyroidism was reported for 8% of patients treated with ERLEADA™ and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA™ and 7% of patients treated with placebo. The median onset was Day 113. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose-adjusted.
Effect of Other Drugs on ERLEADA - Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary however, reduce the ERLEADA™ dose based on tolerability [see Dosage and Administration].
Effect of ERLEADA™ on Other Drugs – ERLEADA™ is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA™ with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA™ with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA™ and evaluate for loss of activity.
P-gp, BCRP or OATP1B1 substrates - Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA™ with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with ERLEADA™ and evaluate for loss of activity if medication is continued.