On March 19, 2018 Pfizer Inc. (NYSE: PFE) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Yoshihiko Hatanaka, "Astellas") reported that a supplemental New Drug Application (sNDA) for XTANDI (enzalutamide) has been accepted for filing and granted Priority Review designation by the U.S. Food and Drug Administration (FDA) (Press release, Astellas Pharma US, MAR 19, 2018, View Source [SID1234525408]). If approved, the sNDA would expand the indication of XTANDI to include men with non-metastatic Castration-Resistant Prostate Cancer (CRPC), based on data from the Phase 3 PROSPER trial. XTANDI is currently indicated for the treatment of patients with metastatic CRPC.

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The FDA grants Priority Review designation to applications for drugs that, if approved, may offer significant improvements in the safety and effectiveness of the treatment of serious conditions when compared to standard applications. Under Priority Review, the FDA aims to take action on an application within six months of receipt, as compared to ten months under standard review. The Prescription Drug User Fee Act (PDUFA) goal date assigned by the FDA is July 2018. In addition, the European Medicines Agency (EMA) has validated the Type II Variation submitted for XTANDI seeking to expand the current indication to the same patient population and started the review process on March 5.
"Once cancer spreads and metastasizes, men with castration-resistant prostate cancer face a daunting prognosis and challenging odds," said Steven Benner, M.D., senior vice president and global therapeutic area head, Oncology Development, Astellas. "We’re pleased to see the FDA’s Priority Review designation as we work to potentially bring XTANDI to men living with non-metastatic CRPC."
"Treatment options have been limited for men with non-metastatic CRPC, in whom the only evidence of progressive disease is a rapidly rising PSA," said Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development. "XTANDI is already established as a standard of care for men with metastatic CRPC. This milestone marks an important step toward our ability to bring XTANDI to CRPC patients in an earlier setting."
The PROSPER trial evaluated XTANDI plus androgen deprivation therapy (ADT) versus ADT alone in 1,401 patients with non-metastatic CRPC. The study met its primary endpoint, demonstrating that the use of XTANDI plus ADT significantly reduced the risk of developing metastasis or death compared to ADT alone. Adverse events in the PROSPER trial were higher in the enzalutamide plus ADT arm compared to ADT alone (87% vs. 77%), and were generally consistent with those reported in prior enzalutamide clinical trials in patients with metastatic CRPC. Results from the PROSPER trial were presented at the 2018 Genitourinary Cancers Symposium (ASCO GU) in February.1 For more information on the PROSPER trial, go to www.clinicaltrials.gov.

The FDA approved XTANDI in 2012 for the treatment of patients with metastatic CRPC who had previously received docetaxel. In 2014, the FDA approved XTANDI to treat patients with metastatic CRPC.

About Prostate Cancer
Prostate cancer is the second most common cancer in men worldwide.2 More than 164,000 men in the United States are estimated to be newly diagnosed with prostate cancer in 2018.3 In the European Union, the estimated number of new prostate cancer cases in 2015 was 365,000.4
Castration-resistant prostate cancer (CRPC) refers to the subset of men whose prostate cancer progresses despite castration levels of testosterone.5 Non-metastatic CRPC means there is no clinically detectable evidence of the cancer spreading to other parts of the body (metastases), and there is a rising prostate-specific antigen (PSA) level.6 Many men with non-metastatic CRPC and a rapidly rising PSA level go on to develop metastatic CRPC.7

About XTANDI (enzalutamide) capsules
XTANDI (enzalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with metastatic castration-resistant prostate cancer.
Important Safety Information for XTANDI
Contraindications
XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.

Warnings and Precautions
Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors, seizures were reported in 2.2% of patients. See section 5.1 of the Prescribing Information for the list of predisposing factors. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Permanently discontinue XTANDI in patients who develop a seizure during treatment.
Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions
The most common adverse reactions (≥10%) that occurred more commonly (≥2% over placebo) in the XTANDI patients from the two placebo-controlled clinical trials were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo. In the bicalutamide-controlled study of chemotherapy-naïve patients, the most common adverse reactions (≥10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss.
In the placebo-controlled study of patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In the placebo-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the bicalutamide-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.
Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Infections: In the study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death.
Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.
Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in <1% of patients in each arm.
Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.
Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see Full Prescribing Information for additional safety information.
About the Enzalutamide Development Program
Pfizer and Astellas are collaborating on a comprehensive development program that includes studies of enzalutamide across the full spectrum of advanced prostate cancer. Ongoing studies of enzalutamide in prostate cancer include the ARCHES trial in metastatic hormone-sensitive prostate cancer and the EMBARK trial in non-metastatic hormone-sensitive prostate cancer