On December 20, 2018 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Pfizer Inc. (NYSE: PFE) reported that the Phase 3 ARCHES trial evaluating XTANDI (enzalutamide) plus androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC) met its primary endpoint, significantly improving radiographic progression-free survival (rPFS) versus ADT alone (Press release, Pfizer, DEC 20, 2018, View Source [SID1234532182]). The preliminary safety analysis of the ARCHES trial appears consistent with the safety profile of XTANDI in previous clinical trials in castration-resistant prostate cancer (CRPC). Detailed results will be submitted for presentation at an upcoming medical congress.

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"While XTANDI is currently approved for both metastatic and non-metastatic CRPC, there still remains a need for more treatment options for men with metastatic hormone-sensitive prostate cancer," said Mace Rothenberg, M.D., Chief Development Officer, Oncology, Pfizer Global Product Development. "With these top-line results, we believe XTANDI has the potential to help men whose disease has progressed outside the prostate gland, but still responds to treatment to lower testosterone."

"The results from ARCHES demonstrate a statistically significant improvement in a key marker of disease progression – radiographic progression-free survival," said Steven Benner, M.D., senior vice president and global therapeutic area head, Oncology Development, Astellas. "Based on the top-line results of ARCHES, we look forward to discussing the data with relevant health authorities to potentially support expanding the indication for XTANDI."

XTANDI is currently approved in the U.S. and Japan for the treatment of CRPC and in the EU for the treatment of metastatic and high-risk non-metastatic CRPC. Since its initial approval in 2012, XTANDI has been prescribed to more than 330,000 men worldwide.1

About ARCHES

The Phase 3, randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,150 patients with metastatic hormone-sensitive prostate cancer (mHSPC) at sites in the United States, Canada, Europe, South America and the Asia-Pacific region. Patients in the ARCHES trial were randomized to receive XTANDI 160 mg daily or placebo and continued on a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or had a history of bilateral orchiectomy. The ARCHES trial included patients with both low- and high- volume disease and both newly diagnosed patients with mHSPC and patients who had prior definitive therapy and subsequently developed metastatic disease. The trial also included some patients who had received recent treatment with docetaxel for mHSPC, but whose disease had not progressed. The primary endpoint of the trial was radiographic progression-free survival (rPFS), defined as the time from randomization to the first objective evidence of radiographic disease progression as assessed by central review, or death, whichever occurs first. For more information on the ARCHES (NCT02677896) trial go to www.clinicaltrials.gov.

About Metastatic Hormone-Sensitive Prostate Cancer

In men with prostate cancer, the disease is considered metastatic once the cancer has spread outside of the prostate gland to other parts of the body, such as the bones, lymph nodes, bladder and rectum.2 Men are considered hormone (or castration) sensitive if their disease still responds to medical or surgical treatment to lower testosterone levels.3 Approximately 38,000 men in the U.S. develop metastatic HSPC every year.4,5

About XTANDI (enzalutamide) capsules

XTANDI (enzalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with castration-resistant prostate cancer.

As part of Pfizer and Astellas’ ongoing commitment to the clinical development of enzalutamide, XTANDI is also being evaluated in the EMBARK trial, in men with high-risk non-metastatic HSPC. Details about EMBARK (NCT02319837) are available on www.clinicaltrials.gov.

Important Safety Information for XTANDI in CRPC

Warnings and Precautions

Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. Patients in the study had one or more of the following pre-disposing factors: use of medications that may lower the seizure threshold; history of traumatic brain or head injury, cerebrovascular accident or transient ischemic attack, Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. 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.

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease In the placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.7% vs 1.2%). Grade 3-4 ischemic events occurred in 1.2% of patients on XTANDI versus 0.5% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures In the placebo-controlled clinical studies, falls occurred in 10% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 8% of patients treated with XTANDI and in 3% of patients treated with placebo. 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.

Embryo-Fetal Toxicity Safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI. XTANDI should not be handled by females who are or may become pregnant.

Adverse Reactions

The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI patients from the randomized placebo-controlled trials were asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache and weight decreased. In the bicalutamide-controlled study, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In the placebo-controlled study of metastatic CRPC (mCRPC) 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 mCRPC 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 placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher adverse reactions were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an adverse event as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. In the bicalutamide-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

Lab Abnormalities: In the two placebo-controlled trials in patients with mCRPC, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). In the placebo-controlled trial in patients with nmCRPC, Grade 1-4 neutropenia occurred in 8% of patients receiving XTANDI (0.5% Grade 3-4) and in 5% of patients receiving placebo (0.2% Grade 3-4).

Hypertension: In the two placebo-controlled trials in patients with mCRPC, hypertension was reported in 11% of XTANDI patients and 4% of placebo patients. Hypertension led to study discontinuation in

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.