An anonymous director reports

XTANDI (ENZALUTAMIDE) PLUS LEUPROLIDE REDUCED THE RISK OF METASTASIS BY 58% IN NON-METASTATIC HORMONE-SENSITIVE PROSTATE CANCER VERSUS PLACEBO PLUS LEUPROLIDE

Astellas Pharma Inc. and Pfizer Inc. have released data showing Xtandi (enzalutamide) plus leuprolide significantly reduced the risk of metastasis or death by 58 per cent versus placebo plus leuprolide (hazard ratio: 0.42, 95-per-cent confidence interval, 0.30 to 0.61, P less than 0.0001), as assessed by the primary end point of metastasis-free survival (MFS), in men 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). These data from the phase 3 Embark trial, which evaluated patients across three study arms (Xtandi plus leuprolide [n equals 355], placebo plus leuprolide [n equals 358] or Xtandi monotherapy [n equals 355]), were presented as a plenary session during the 2023 American Urological Association annual meeting (Saturday, April 29, at 9:45 a.m. CT).

The overall safety profile was consistent with the known safety profile of each of the medicines. The most common adverse events in those treated with Xtandi plus leuprolide were fatigue, hot flush and arthralgia, and in those treated with Xtandi monotherapy, were fatigue, gynecomastia and arthralgia.

"There are patients with localized prostate cancer who undergo prostatectomy or radiation therapy in an attempt to cure their disease, but, unfortunately, some patients will develop BCR," said Neal Shore, MD, FACS, U.S. chief medical officer of urology and surgical oncology, GenesisCare, director, Carolina Urologic Research Center, and primary investigator for the Embark study. "Importantly, some patients with BCR are at very high risk for developing metastatic disease, which can lead to a cascade of therapeutic interventions. The clinical goal of BCR therapy is to delay cancer progression and avoid metastatic disease. The MFS results from the Embark study demonstrate that this intervention with Xtandi plus leuprolide was statistically significant for patients with high-risk BCR."

"The Embark study is a phase 3 trial exploring the potential of enzalutamide in patients with non-metastatic hormone-sensitive prostate cancer with high-risk BCR," said Stephen J. Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle and the Warschaw Robertson Law Families chair in prostate cancer at Cedars-Sinai Cancer and co-principal investigator of the clinical trial. "If approved, we hope to bring a new option to men earlier in the course of their disease."

Consistent with the study's primary end point, statistically significant and clinically meaningful improvements were also observed in the trial's key secondary end points in both the Xtandi combination and monotherapy arms. Specifically, the Xtandi monotherapy arm demonstrated that treatment with Xtandi reduced the risk of metastasis or death by 37 per cent versus leuprolide plus placebo (HR: 0.63, 95-per-cent CI, 0.46 to 0.87, P equals 0.0049), meeting its MFS end point. Treatment with Xtandi plus leuprolide and Xtandi monotherapy reduced the risk of PSA progression by 93 per cent (HR: 0.07, 95-per-cent CI, 0.03-0.14, P less than 0.0001) and 67 per cent (HR: 0.33, 95-per-cent CI, 0.23 to 0.49, P less than 0.0001), respectively, versus placebo plus leuprolide. The progression risk in starting a new antineoplastic therapy was reduced by 64 per cent in those treated with Xtandi plus leuprolide (HR: 0.36, 95-per-cent CI, 0.26 to 0.49, P less than 0.0001) and 46 per cent in those treated with Xtandi monotherapy (HR: 0.54, 95-per-cent CI, 0.41 to 0.71, P less than 0.0001) versus placebo plus leuprolide.

A positive trend in the key secondary end point of overall survival (OS) was also observed in the Xtandi combination arm at the time of the analysis, but these data were not yet mature. Patients in the trial will be followed for a subsequent final OS analysis.

Detailed results from the trial will be submitted for peer-reviewed publication. Additionally, the Embark data will be discussed with regulatory authorities, including the U.S. Food and Drug Administration (FDA), to support a potential regulatory submission for Xtandi in this indication in 2023.

About Embark

The Astellas- and Pfizer-led phase 3, randomized, double-blind, placebo-controlled, multinational 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 United States, Canada, Europe, South America and the Asia Pacific region. Patients who were considered to experience high-risk BCR had a prostate-specific antigen-doubling time (PSA-DT) equal or less than nine months; serum testosterone equal or greater than 150 ng/dL (5.2 nmol/L); and screening PSA by the central laboratory equal or greater than one ng/mL if they had a radical prostatectomy (with or without radiotherapy) as primary treatment for prostate cancer, or at least two ng/mL above the nadir if they had radiotherapy only as primary treatment for prostate cancer. Patients in the Embark trial were randomized to receive enzalutamide 160 milligrams daily plus leuprolide (n equals 355), enzalutamide 160 mg as a monotherapy (n equals 355) or placebo plus leuprolide (n equals 358). Leuprolide 22.5 mg was administered every 12 weeks.

The primary end point of the trial was metastasis-free survival (MFS) for enzalutamide plus leuprolide versus 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.

Xtandi, either in combination with leuprolide or as a monotherapy, has not been approved by any regulatory agency for the treatment of patients with nmHSPC with high-risk BCR.

About non-metastatic hormone-sensitive prostate cancer with high-risk biochemical recurrence

In non-metastatic hormone (or castration)-sensitive prostate cancer (nmHSPC or nmCSPC), no evidence of the cancer spreading to distant parts of the body (metastases) is detectable with conventional radiological methods (CT/MRI), and the cancer still responds to medical or surgical treatment designed to lower testosterone levels (1, 2). Of men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy or both, an estimated 20 to 40 per cent will experience a biochemical recurrence (BCR) within 10 years (3). About nine out of 10 men with high-risk BCR will develop metastatic disease, and one in three will die as a result of the recurrence (4). The Embark trial focused on men with high-risk BCR. Per the Embark protocol, patients with nmHSPC and high-risk BCR are those initially treated by radical prostatectomy, radiotherapy or both, with a prostate-specific antigen-doubling time (PSA-DT) equal or less than nine months. High-risk BCR patients with a PSA-DT of equals or less than nine months have a higher risk of metastases and death (5).

About Xtandi (enzalutamide)

Xtandi (enzalutamide) is an androgen receptor signalling inhibitor. Xtandi has received regulatory approvals in one or more countries around the world for use in men with metastatic hormone-sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC) and non-metastatic castration-resistant prostate cancer (nmCRPC). Xtandi is currently approved for one or more of these indications in more than 100 countries, including in the United States, European Union and Japan. One million patients have been treated with Xtandi globally (6).

U.S. important safety information

Xtandi (enzalutamide) is indicated in the U.S. for the treatment of patients with castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (mCSPC).

Warnings and precautions

Seizure occurred in 0.5 per cent of patients receiving Xtandi in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2 per cent 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, 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 be 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 per cent), tongue (0.1 per cent) or lip (0.1 per cent), have been observed with Xtandi in seven randomized clinical trials. Pharyngeal edema has been reported in postmarketing 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 with patients on the placebo arm (2.9 per cent versus 1.3 per cent). Grade 3 and 4 ischemic events occurred in 1.4 per cent of patients on Xtandi versus 0.7 per cent on placebo. Ischemic events led to death in 0.4 per cent of patients on Xtandi compared with 0.1 per cent 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 and 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 per cent of patients treated with Xtandi compared with 4 per cent of patients treated with placebo. Fractures occurred in 10 per cent of patients treated with Xtandi and in 4 per cent 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 three months after the last dose of Xtandi.

Adverse reactions (ARs): In the data from the four randomized placebo-controlled trials, the most common ARs (equal or greater than 10 per cent) that occurred more frequently (equal or greater than 2 per cent 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 (equal or greater than 10 per cent) 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 per cent of Xtandi-treated patients. Discontinuations due to adverse events (AEs) were reported for 16 per cent of Xtandi-treated patients. In Prevail, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3 and 4 ARs were reported in 44 per cent of Xtandi patients and 37 per cent of placebo patients. Discontinuations due to AEs were reported for 6 per cent of Xtandi-treated patients. In Terrain, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3 and 4 ARs were reported in 39 per cent of Xtandi patients and 38 per cent of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8 per cent of Xtandi patients and 6 per cent of bicalutamide patients.

In Prosper, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31 per cent of Xtandi patients and 23 per cent of placebo patients. Discontinuations with an AE as the primary reason were reported for 9 per cent of Xtandi patients and 6 per cent of placebo patients.

In Arches, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher AEs were reported in 24 per cent of Xtandi-treated patients. Permanent discontinuation due to AEs as the primary reason was reported in 5 per cent of Xtandi patients and 4 per cent of placebo patients.

Lab abnormalities: Lab abnormalities that occurred in equal or greater than 5 per cent of patients and more frequently (greater than 2 per cent) in the Xtandi arm compared with 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 per cent of Xtandi patients and 5 per cent of placebo patients. Hypertension led to study discontinuation in less than 1 per cent 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 Astellas Pharma Inc.

Astellas is a pharmaceutical company conducting business in more than 70 countries around the world. It is promoting the focus area approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on biology and modality. Furthermore, it is also looking beyond its foundational Rx focus to create Rx plus health care solutions that combine its expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of health care change to turn innovative science into value for patients.

About Pfizer Oncology

At Pfizer Oncology, it is committed to advancing medicines wherever it believes it can make a meaningful difference in the lives of people living with cancer. Today, it has an industry-leading portfolio of 24 approved innovative cancer medicines and biosimilars across more than 30 indications, including breast, genitourinary, colorectal, blood and lung cancers, as well as melanoma.

About the Pfizer/Astellas collaboration

In October, 2009, Medivation Inc., which is now part of Pfizer, and Astellas entered into a commercial agreement to jointly develop and commercialize Xtandi (enzalutamide) in the United States, while Astellas has responsibility for manufacturing and all additional regulatory filings globally, as well as commercializing the product outside of the United States. Pfizer receives alliance revenues as a share of U.S. profits and receives royalties on sales outside of the U.S.

(1) Prostate Cancer: Types of Treatment (12-2022) at the Cancer website. Obtained on March 16, 2023.

(2) American Society of Clinical Oncology. Asco Answers: Prostate Cancer (2021). Obtained on March 16, 2023.

(3) J.F. Ward and J.W. Moul. Rising prostate-specific antigen after primary prostate cancer therapy. Nat. Clin. Pract. Urol., April, 2005; 2(4): 174-182; doi: 10.1038/ncpuro0145; PMID: 16474760.

(4) Emmanuel S. Antonarakis et al. "The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up." BJU International, Vol. 109, 1 (2012): 32-39. doi: 10.1111/j.1464-410X.2011.10422.

(5) Channing J. Paller, et al. "Management of patients with biochemical recurrence after local therapy for prostate cancer." Hematology/oncology clinics of North America, Vol. 27, 6 (2013): 1,205-1,019, viii. doi: 10.1016/j.hoc.2013.08.005.

(6) Data on file. Northbrook, Ill.: Astellas Inc.

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