Enzalutamide Approved for Non-Metastatic Castration-Sensitive Prostate Cancer with Biochemical Recurrence

Low mag prostate cancer micrograph.

The FDA has approved enzalutamide (Xtandi®, Astellas Pharma US, Inc.) for nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR).  

Why it matters: “Within 10 years following definitive therapy for prostate cancer, 20% to 50% of patients have BCR characterized by a rise in prostate-specific antigen (PSA) levels,” wrote Dr. Stephen Freedland, Director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Medical Center, and colleagues, in their published results of the EMBARK trial (NCT02319837), on which approval was based. “Level 1 clinical evidence regarding the treatment of biochemically recurrent prostate cancer is limited; therefore, patients generally receive a treatment strategy involving risk stratification. The objective of the EMBARK trial was to evaluate the efficacy and safety of enzalutamide plus leuprolide and enzalutamide monotherapy, as compared with leuprolide alone, in patients with prostate cancer who have had high-risk biochemical recurrence.”

What they studied: Efficacy was studied in the phase 3, controlled clinical trial in which 1,068 patients with nmCSPC with high-risk BCR were enrolled. At the time of enrollment, eligible patients had received prior definitive therapy with radical prostatectomy and/or radiotherapy with curative intent, had a PSA doubling time of ≤9 months, and were not candidates for salvage radiotherapy. Patients were randomized 1:1:1 to receive either 160 mg of blinded enzalutamide plus leuprolide once daily, 160 mg open-label single-agent enzalutamide once daily, or blinded placebo plus leuprolide once daily.

The key end point measured was metastasis-free survival as assessed by blinded independent central review. Key secondary end points measured were metastasis-free survival for enzalutamide monotherapy compared to placebo plus leuprolide and overall survival.

What they found: Enzalutamide plus leuprolide saw a significantly meaningful improvement in metastasis-free survival compared with placebo plus leuprolide, with a median not reached in either arm. Enzalutamide monotherapy, as well, saw a statistically significant improvement in metastasis-free survival compared with placebo plus leuprolide. Overall survival data was immature, with the overall population seeing 12% deaths at the time of the metastasis-free survival analysis.

Adverse events: The most common adverse events experienced in ≥20% of patients who received enzalutamide plus leuprolide were hot flush, musculoskeletal pain, fatigue, fall, and hemorrhage. The most common adverse events in patients who received enzalutamide monotherapy were fatigue, gynecomastia, musculoskeletal pain, breast tenderness, hot flush, and hemorrhage.

What’s next: Overall survival data are immature and will be reported in future analyses.

Conclusion: “The results of this trial showed that enzalutamide had clinical benefits in patients with high-risk biochemical recurrence after definitive treatment. No new safety signals were observed,” concluded Dr. Freedland and colleagues. “Enzalutamide plus leuprolide and enzalutamide monotherapy both resulted in significantly longer metastasis-free survival and a longer time to PSA progression and receipt of next antineoplastic therapy than leuprolide alone while maintaining overall quality of life.”

Instructions: The recommended dosage is 160 mg of enzalutamide orally, once daily, with or without food, and with or without gonadotropin-releasing hormone (GnRH) analog. Treatment should continue until disease progression or unacceptable toxicity. Treatment with enzalutamide may be suspended if PSA is undetectable (<0.2 ng/mL) after 36 weeks of therapy. Treatment may be reinitiated when PSA has increased to ≥2.0 ng/mL for patients who had prior radical prostatectomy, or when PSA has increased to ≥5.0 ng/mL for patients who received previous primary radiation therapy.

For More Information

Freedland SJ, de Almeida Luz M, De Giorgi U, et al (2023). Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med, 389:1453-1465. DOI: 10.1056/NEJMoa2303974

LBA02-09 EMBARK: A phase 3 randomized study of enzalutamide or placebo plus leuprolide acetate and enzalutamide monotherapy in high-risk biochemically recurrent prostate cancer. J Urol, 210(1):224-226. DOI:10.1097/JU.0000000000003518

Clinicaltrials.gov (2023). Safety and efficacy study of enzalutamide plus leuprolide in patients with nonmetastatic prostate cancer (EMBARK). NLM identifier: NCT02319837.

Xtandi® (enzalutamide) prescribing information (2023). Astellas Pharma US, Inc. Available at: https://www.astellas.us/docs/us/12A005-ENZ-WPI.pdf

US Food and Drug Administration (2023). FDA approves enzalutamide for non-metastatic castration-sensitive prostate cancer with biochemical recurrence. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-non-metastatic-castration-sensitive-prostate-cancer-biochemical-recurrence

Image credit: Nephron. Licensed under CC BY-SA 3.0 DEED

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