Type of information: Positive opinion for the granting of a Market Authorisation in the EU
Product name: Xtandi®
Therapeutic area: Cancer - Oncology
- androgen receptor inhibitor. Xtandi® (enzalutamide) is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. It has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to Xtandi®. Xtandi® decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model.
Company: Medivation (USA - CA), now Pfizer (USA - NY) Astellas (Japan)
- patients with metastatic castration-resistant prostate cancer who have previously received docetaxel
- adult men with high-risk non-metastatic castration-resistant prostate cancer
- On 20 September 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive
opinion recommending a change to the terms of the marketing authorisation for Xtandi®. The CHMP adopted a new indication for the treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer.
The full indications for Xtandi® will be as follows:
• the treatment of adult men with high-risk non-metastatic castration-resistant prostate cancer (CRPC)
• the treatment of adult men with metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated
• the treatment of adult men with metastatic CRPC whose disease has progressed on or after docetaxel therapy.
- • On June 24, 2013, Astellas Pharma and Medivation announced that following the regulatory review process by the European Medicines Agency (EMA) and a positive opinion from the Committee for Medicinal Products for Human Use on April 25, 2013, the European Commission (EC) has granted the marketing authorization for Xtandi™ (enzalutamide) capsules for the treatment of adult men with metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel therapy. The European Commission approval triggers a $15 million milestone payment to Medivation under its collaboration with Astellas, which is reflected in Astellas' current fiscal year (from 1st April 2013 to 31st March 2014) financial forecast.
- • On June 3, 2013, Astellas Pharma and Medivation announced that after a priority review, Health Canada has approved XTANDI® (enzalutamide) capsules for the treatment of patients with metastatic castration-resistant prostate cancer in the setting of medical or surgical castration who have received docetaxel therapy.
- • On May 24, 2013, Astellas Pharma and Medivation announced that Astellas has submitted an application for marketing approval of enzalutamide to the Ministry of Health, Labour and Welfare in Japan for the treatment of prostate cancer. This filing application is based mainly on results obtained from the global Phase 3 trial (the AFFIRM trial)* and a Phase 1-2 trial conducted in Japan.
- • On 25 April 2013, the Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion, recommending the granting of a marketing authorisation for Xtandi®, 40 mg, soft capsule, intended for for the treatment of adult men with metastatic castration-resistant prostate cancer whose disease has progressed on or after docetaxel therapy. The benefits with Xtandi® are its ability to improve the survival of patients and to delay the progression of disease. The most common side effects are hot flush and headache. A pharmacovigilance plan for Xtandi® will be implemented as part of the marketing authorisation.
- • On September 13, 2012, Medivation and Astellas Pharma announced the availability of Xtandi® (enzalutamide) capsules for patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. Xtandi® was approved by the FDA on August 31, 2012. Xtandi® is being distributed through a network of specialty pharmacies and specialty distributors. Astellas and Medivation also announced the launch of a comprehensive patient access support program for Xtandi® capsules to ensure patients who are prescribed Xtandi® can access the drug in a timely manner. The new program, Xtandi® Access Services(SM), will provide access and reimbursement support to physicians and patients and assist eligible patients without insurance. Examples of support available through this program include help with benefit verification and prior authorization, patient referral to independent non-profit organizations that can assist with out-of-pocket expenses, and prescription forwarding to specialty pharmacies in the network.
- • On August 31, 2012, Medivation and Astellas Pharma have announced that the FDA has granted approval to Xtandi® (enzalutamide) capsules for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. The FDA accepted the Xtandi® New Drug Application (NDA) on July 23, 2012, and granted the filing Priority Review Designation with a Prescription Drug User Fee Act (PDUFA) action date of November 22, 2012. Medivation and Astellas expect to make Xtandi® available to patients in the United States in mid-September 2012. Separately, a Marketing Authorization Application for Xtandi® has been accepted for review by the European Medicines Agency (EMA).
- The recommended dose of Xtandi® is 160 mg (four 40 mg capsules) administered orally once daily. In the phase 3 clinical trial, 48% of Xtandi® patients and 46% of patients in the placebo arm were treated with glucocorticoids.
As a post-marketing requirement, Medivation and Astellas have agreed with the FDA to conduct an open-label safety study of Xtandi®(160 mg/day) in patients who are at high risk for seizure. Medivation and Astellas have agreed to provide the data from this study in 2019.
The efficacy and safety of Xtandi® were assessed in a randomized, placebo-controlled, multicenter phase 3 clinical trial. A total of 1,199 patients with mCRPC who had previously received docetaxel were randomized 2:1 to receive either Xtandi® orally at a dose of 160 mg once daily (N = 800) or placebo (N = 399). Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. The primary endpoint of the trial was overall survival. Xtandi®-treated patients had a statistically-significant improvement in median overall survival compared to the placebo group: 18.4 months in the Xtandi® group versus 13.6 months in the placebo group (P < 0.0001). Xtandi® provided a 37% reduction in risk of death compared to placebo (hazard ratio = 0.631). Seizure occurred in 0.9% of patients on Xtandi® and 0% of the placebo-treated patients. The most common adverse reactions (? 5%) are asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse reactions were reported among 47% of Xtandi®-treated patients and 53% of placebo-treated patients
- • On July 24, 2012, Medivation and Astellas Pharma announced that the FDA has accepted for filing the New Drug Application (NDA) for enzalutamide (formerly MDV3100) for the potential treatment of men with castration-resistant prostate cancer previously treated with docetaxel-based chemotherapy and granted Priority Review Designation. The FDA's acceptance of the NDA triggers a $10 million milestone payment to Medivation under its Collaboration Agreement with Astellas.
- •On June 26, 2012, Medivation and Astellas Pharma announced that Astellas has submitted a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for enzalutamide (formerly MDV3100) for the treatment of men with metastatic castration-resistant prostate cancer who have been previously treated with docetaxel-based chemotherapy.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2012-08-31
UE authorization: 2013-06-21
Favourable opinion UE: 2013-04-25/2018-09-20
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: