On February 5, 2018 Astellas Pharma Inc. (TSE: 4503), President and CEO: Yoshihiko Hatanaka, "Astellas," and Pfizer Inc. (NYSE: PFE) reported results from the Phase 3 PROSPER trial in patients with non-metastatic (M0) Castration-Resistant Prostate Cancer (CRPC) (Press release, Astellas Pharma US, FEB 5, 2018, View Source [SID1234523731]). The results show that the use of XTANDI (enzalutamide) plus androgen deprivation therapy (ADT) significantly reduced the risk of developing metastases or death by 71 percent compared to ADT alone. The median for the primary endpoint, metastasis-free survival (MFS), was 36.6 months for men who received XTANDI compared to 14.7 months with ADT alone (n=1401; HR=0.29 [95% CI: 0.24-0.35]; p<0.0001). These data will be presented at the 2018 Genitourinary Cancers Symposium in San Francisco.

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Marketing applications based on the results of the PROSPER study have been submitted to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The FDA and EMA each have a filing review period during which they evaluate whether an application is complete and acceptable for filing. The data are also being submitted to additional regulatory authorities around the world.

"In patients with non-metastatic CRPC, there is a high unmet need to delay development of metastases and the progression to advanced prostate cancer. There are currently no approved systemic therapies for patients with non-metastatic CRPC in the U.S.," said Maha Hussain, M.D., Robert H. Lurie Comprehensive Cancer Center of Northwestern University, who will present the data. "In the PROSPER trial, treatment with enzalutamide plus ADT delayed the development of metastases compared to standard of care ADT alone and, if approved, may provide men with non-metastatic CRPC an important new treatment option."

PROSPER also investigated time to prostate-specific antigen (PSA) progression, time to first use of new antineoplastic therapy and overall survival (OS) as key secondary endpoints. The analysis demonstrated that patients who received XTANDI plus ADT had a 93 percent reduction in relative risk of PSA progression compared to patients who received ADT alone (HR=0.07 [95% CI: 0.05-0.08]; P<0.0001). XTANDI plus ADT delayed the median time to PSA progression by 33.3 months (37.2 months [95% CI: 33.1-NR] versus 3.9 months with ADT alone [95% CI: 3.8-4.0]).

XTANDI plus ADT prolonged the median time to first use of new antineoplastic therapy by 21.9 months versus ADT alone (39.6 months [95% CI: 37.7-NR] vs. 17.7 months [95% CI: 16.2-19.7]), a 79 percent relative risk reduction (HR=0.21 [95% CI: 0.17-0.26]; p<0.0001). At the time of the first interim analysis, median OS had not yet been reached in either treatment arm. However, these interim results demonstrated a trend in favor of XTANDI that was not statistically significant (HR=0.80 [95% CI: 0.58-1.09]; p=0.1519).

Adverse events in the PROSPER trial were generally consistent with those reported in prior enzalutamide clinical trials in patients with metastatic CRPC. Grade 3 or higher adverse events were reported in 31 percent of men treated with XTANDI plus ADT and in 23 percent of men treated with ADT alone. The most common (≥2%) Grade 3 or higher adverse events that were reported more often in XTANDI plus ADT-treated patients included hypertension (5% vs. 2%) and fatigue (3% vs. 1%). Major adverse cardiovascular events were reported in 5 percent of patients who received XTANDI plus ADT and 3 percent with ADT alone. Three seizures (<1%) were reported with XTANDI plus ADT patients and none were reported for those who received ADT alone. The percentage of patients in whom adverse events were the primary reason leading to treatment discontinuation was low in both study arms (9% with XTANDI plus ADT versus 6% with ADT alone).

About PROSPER
The Phase 3 randomized, double-blind, placebo-controlled, multi-national trial enrolled approximately 1,400 patients with non-metastatic castration-resistant prostate cancer (CRPC) at sites in the United States, Canada, Europe, South America and the Asia-Pacific region. PROSPER enrolled patients with prostate cancer that had progressed, based on a rising prostate-specific antigen (PSA) level despite androgen deprivation therapy (ADT), but who had no symptoms and no prior or present evidence of metastatic disease. The trial evaluated enzalutamide at a dose of 160 mg taken orally once daily plus ADT, versus placebo plus ADT.

The primary endpoint of the PROSPER trial, metastasis-free survival (MFS), is a measure of the amount of time that passes until a cancer can be radiographically detected as having metastasized, or until death, within 112 days of treatment discontinuation. Secondary endpoints included time to PSA progression, time to first use of antineoplastic therapy and overall survival.

For more information on the PROSPER trial, go to www.clinicaltrials.gov.

About Castration-Resistant Prostate Cancer
Prostate cancer is the second most common cancer in men worldwide.1 More than 164,000 men in the United States are estimated to be newly diagnosed with prostate cancer in 2018.2 In the European Union, the estimated number of new prostate cancer cases in 2015 was 365,000.3

Castration-resistant prostate cancer (CRPC) refers to the subset of men whose prostate cancer progresses despite castration levels of testosterone.4 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.5 Many men with non-metastatic CRPC and a rapidly rising PSA level go on to develop metastatic CRPC.6

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

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.