Phase 3 Study Shows XTANDI® (enzalutamide) plus Leuprolide Significantly Improves Metastasis-Free Survival in Men with Non-Metastatic Prostate Cancer
At the time of the analysis, a positive trend in the key secondary endpoint of overall survival (OS) was also observed, but these data were not yet mature. Patients in the trial will be followed for a subsequent final OS analysis. The study also met a key secondary endpoint with a statistically significant and clinically meaningful improvement in MFS for patients treated with XTANDI monotherapy versus placebo plus leuprolide. Additional key secondary endpoints reached statistical significance, including time to prostate-specific antigen (PSA) progression and time to first use of new antineoplastic therapy. Other secondary endpoints are being analyzed. No new safety signals have been observed to date in the preliminary safety analysis, which is consistent with the established safety profile of XTANDI.
"As the only novel hormone therapy approved for three disease states of prostate cancer in the
"While current treatment options for localized prostate cancer are intended to be curative, some men remain at higher risk for biochemical recurrence following primary treatment, which may result in metastases," said Ahsan Arozullah, M.D., MPH, Senior Vice President and Head of Development Therapeutic Areas, Astellas. "The EMBARK trial is the first study to demonstrate a statistically significant improvement in MFS using the combination of XTANDI plus leuprolide in men with this stage of disease."
Detailed results from EMBARK will be presented at a future medical meeting. These data will also be discussed with regulatory authorities, including the
The Phase 3, randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,068 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC; also known as non-metastatic castration-sensitive prostate cancer or nmCSPC) with high-risk biochemical recurrence (BCR) at sites in
The primary endpoint of the trial was metastasis-free survival (MFS) for enzalutamide plus leuprolide and placebo plus leuprolide. MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death. For more information on the EMBARK (NCT02319837) trial go to www.clinicaltrials.gov.
XTANDI has not been approved for the treatment of patients with nmHSPC with high-risk BCR.
About Non-Metastatic Hormone-Sensitive Prostate Cancer with High-Risk Biochemical Recurrence
Non-metastatic hormone- (or castration-) sensitive prostate cancer (nmHSPC or nmCSPC) means there is no detectable evidence of the cancer spreading to distant parts of the body (metastases) with conventional radiological methods (CT/MRI) and the cancer still responds to medical or surgical treatment to lower testosterone levels.1,2 Of men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy, or both, an estimated 20-40% will experience a biochemical recurrence (BCR) within 10 years.3 About 9 out of 10 men with high-risk BCR will develop metastatic disease, and 1 in 3 will die as a result of the recurrence.3 The EMBARK trial focused on men with high-risk BCR. Per the EMBARK protocol, patients with nmHSPC with high-risk BCR are those initially treated by radical prostatectomy or radiotherapy, or both, with a PSA doubling time ≤ 9 months. High-risk BCR patients with a PSA doubling time of ≤ 9 months have a higher risk of metastases and death.4
About XTANDI® (enzalutamide)
XTANDI (enzalutamide) is an androgen receptor signaling inhibitor. The recommended dosage of XTANDI is 160 mg (capsules or tablets) administered orally once daily with or without food. XTANDI is a standard of care that has received regulatory approvals for use in men with mHSPC, mCRPC, and nmCRPC in
E.U. Important Safety Information
Enzalutamide is indicated in the
1. Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT).
2. High-risk non-metastatic castration-resistant prostate cancer (CRPC).
3. Metastatic CRPC who are asymptomatic or mildly symptomatic after failure of ADT in whom chemotherapy is not yet clinically indicated. It is also indicated in adult men with metastatic CRPC whose disease has progressed on or after docetaxel therapy.
For Important Safety Information for enzalutamide please see the full Summary of Product Characteristics at: https://www.ema.europa.eu/en/documents/overview/xtandi-epar-medicine-overview_en.pdf.
XTANDI (enzalutamide) is indicated in the
Warnings and Precautions
Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and 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. 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) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that 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 seven randomized 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 combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%). Grade 3-4 ischemic events occurred in 1.4% of patients on XTANDI versus 0.7% 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 occurred in patients receiving XTANDI. 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. In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo.
Embryo-Fetal Toxicity The 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.
Adverse Reactions (ARs) In the data from the four randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.
In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse events (AEs) were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade
In PROSPER, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AE as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.
Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia.
Hypertension: In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of XTANDI patients and 5% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.
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 coadministration 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.
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The information contained in this release is as of
This release contains forward-looking information about XTANDI® (enzalutamide) and potential new indication being evaluated for the treatment of men with non-metastatic hormone-sensitive prostate cancer with high-risk biochemical recurrence (BCR), including their potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, uncertainties regarding the commercial success of XTANDI; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from the clinical studies; whether and when drug applications for any of the potential new indications for XTANDI or any potential indications for XTANDI may be filed in any jurisdictions; whether and when regulatory authorities in any jurisdictions may approve any such applications, which will depend on a myriad of factors, including making a determination as to whether the product's benefits outweigh its known risks and determination of the product's efficacy and, if approved, whether XTANDI for any such potential new indications will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety, and/or other matters that could affect the availability or commercial potential of XTANDI, including for the potential new indications; dependence on the efforts and funding by
A further description of risks and uncertainties can be found in
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1 Cancer.net. Prostate Cancer: Types of Treatment (12-2022). https://www.cancer.net/cancer-types/prostate-cancer/types-treatment. Accessed
3 Ward JF, Moul JW. Rising prostate-specific antigen after primary prostate cancer therapy. Nat Clin Pract Urol. 2005 Apr;2(4):174-82. doi: 10.1038/ncpuro0145. PMID: 16474760.
4 Paller, Channing J et al. "Management of patients with biochemical recurrence after local therapy for prostate cancer." Hematology/oncology clinics of
5 Data on file.
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