On October 21, 2016 Astellas Pharma Inc. (TSE: 4503) and Pfizer Inc. (NYSE: PFE (link is external)) reported that the U.S. Food and Drug Administration (FDA) approved a supplemental New Drug Application (sNDA) to update the U.S. product labeling for XTANDI (enzalutamide) capsules to include new clinical data versus bicalutamide from the TERRAIN study (Press release, Pfizer, OCT 21, 2016, View Source [SID1234515947]). The data demonstrate improvement in radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (CRPC) who were treated with enzalutamide compared to patients who were treated with bicalutamide.

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The TERRAIN study evaluated men with metastatic CRPC and the results from this study were published in the Lancet Oncology. The updated label includes data that enzalutamide reduces the risk of radiographic progression or death by 40% compared with bicalutamide, showing a median rPFS of 19.5 months for the enzalutamide group versus a median of 13.4 months for the bicalutamide group (hazard ratio = 0.60 [0.43, 0.83]; 95% confidence interval) based on an analysis recommended by the FDA. The safety profile of enzalutamide was consistent with results of earlier enzalutamide trials.

"The addition of data from the TERRAIN trial continues to build the body of evidence that demonstrates the clinical impact XTANDI can have for patients living with metastatic CRPC," said Steven Benner, M.D., senior vice president, therapeutic area head for oncology development, Astellas. "Advances in scientific knowledge as seen through clinical trials like TERRAIN would not be possible without the participation of hundreds of patients, family members and clinical investigators, and we thank them for their valuable contributions."

According to the American Cancer Society, each year approximately 181,000 new cases of prostate cancer will be diagnosed and an estimated 26,000 men will die of the disease in 2016.1 Up to 40 percent of men diagnosed with prostate cancer who undergo therapy develop metastatic, or advanced, prostate cancer.2 In the U.S., the five-year relative survival rate for prostate cancer patients with metastatic disease is 28 percent, compared with 100 percent for prostate cancer patients with non-metastatic disease.3

"We are pleased with the FDA’s decision to update the XTANDI label with these data from the first and largest comparative trial that demonstrated safety and efficacy of enzalutamide compared to bicalutamide," said Mohammad Hirmand, M.D., interim chief medical officer at Medivation, Inc., which is now part of Pfizer. "We believe these data will help physicians better understand the differences between enzalutamide and bicalutamide for their patients living with metastatic CRPC."

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion onApril 1, 2016 recommending approval of a type II variation to include data from the TERRAIN trials in the European label for XTANDI.

About the TERRAIN trial

The Phase II TERRAIN trial enrolled 375 chemotherapy-naïve patients with metastatic CRPC in North America and Europe. Radiographic progression-free survival was defined as the time from randomization to the first objective evidence of radiographic progression as assessed by Independent Central Review or death, whichever occurred first. The trial was designed to evaluate patients who were randomized 1:1 to receive enzalutamide at a dose of 160 mg taken orally once daily versus bicalutamide at a dose of 50 mg taken once daily.

Grade 3-4 adverse reactions were reported in 38.8% of enzalutamide-treated patients and 37.6% of bicalutamide-treated patients. Individual Grade 3 or higher adverse events largely occurred at a similar rate (<1% difference) between the enzalutamide vs. bicalutamide treatment groups, with the exception of hypertension (7.1% vs. 4.4%), diarrhea (0% vs. 1.1%) and back pain (2.7% vs. 1.6%). Two seizures were reported in the enzalutamide group and one in the bicalutamide group. The most common Grade 1-4 adverse reactions (incidence ≥10%) occurring during treatment and more common in the enzalutamide-treated versus bicalutamide-treated patients included asthenic conditions, back pain, musculoskeletal pain, hot flush, hypertension, diarrhea, upper respiratory tract infection, and weight loss.

About XTANDI (enzalutamide) capsules

XTANDI (enzalutamide) capsules is an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway within the tumor cell. In preclinical studies, enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors, and inhibit androgen receptor nuclear translocation and interaction with DNA. The clinical significance of this mechanism of action (MOA) is unknown.

XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

Important Safety Information

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 placebo-controlled studies, 8 of 1671 (0.5%) patients treated with XTANDI and 1 of 1243 (0.1%) patients treated with placebo experienced a seizure. In patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. In a placebo-controlled study in chemotherapy-naïve patients, 1 of 871 (0.1%) treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. In bicalutamide-controlled studies conducted in chemotherapy-naïve patients, 3 of 380 (0.8%) patients treated with XTANDI and 1 of 387 (0.3%) patients treated with bicalutamide experienced a seizure. 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 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 a 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 placebo-controlled 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 all 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 (link is external) at View Source (link is external) for additional safety information.

You are encouraged to report negative side effects of prescription drugs to the FDA.

Visit www.fda.gov/medwatch (link is external) or call 1‐800‐FDA‐1088.