On November 16, 2023, the androgen receptor inhibitor enzalutamide was approved for use in patients with nonmetastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis.¹

Supporting Efficacy Data

Approval was based on the EMBARK trial (ClinicalTrials.gov identifier NCT02319837), in which 1,068 patients were randomly assigned 1:1:1 to receive blinded enzalutamide at 160 mg once daily plus leuprolide, open-label enzalutamide at 160 mg once daily, or blinded placebo once daily plus leuprolide. All patients had prior definitive therapy with radical prostatectomy or radiotherapy with curative intent, had a prostate-specific antigen (PSA) doubling time of 9 months or less, and were not candidates for salvage radiotherapy.

Metastasis-free survival on blinded independent central review (major efficacy measure) was significantly improved with enzalutamide plus leuprolide (hazard ratio [HR] = 0.42, 95% confidence interval [CI] = 0.30–0.61, P < .0001) and enzalutamide monotherapy (HR = 0.63, 95% CI = 0.46–0.87, P = .0049) vs placebo plus leuprolide.

How It Is Used

The recommended enzalutamide dose is 160 mg once daily until disease progression or unacceptable toxicity. Enzalutamide can be administered with or without a gonadotropin-releasing hormone analog. Treatment can be suspended if there is an undetectable PSA value (< 0.2 ng/mL) after 36 weeks of therapy. Treatment may be reinitiated if the PSA value has increased to at least 2.0 ng/mL for patients who had prior radical prostatectomy or to at least 5.0 ng/mL for those who had prior primary radiation therapy.

Concomitant administration of strong CYP2C8 inhibitors (eg, gemfibrozil, sorafenib, erlotinib) and strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin) should be avoided with the use of enzalutamide. Concomitant administration of CYP3A4 (eg, imatinib, anastrozole, paclitaxel), CYP2C9 (eg, fluoxetine, losartan, phenytoin), or CYP2C19 substrates (eg, lansoprazole, omeprazole) for which a minimal decrease in concentration may lead to therapeutic failure of the substrate also should be avoided.

Safety Profile

In the EMBARK trial, the most common adverse events of any grade among patients receiving enzalutamide plus leuprolide were hot flush (69%), musculoskeletal pain (50%), fatigue (50%), fall (21%), and hemorrhage (20%); the most common adverse events among patients receiving enzalutamide alone were fatigue (54%), gynecomastia (49%), musculoskeletal pain (48%), breast tenderness (35%), hot flush (22%), and hemorrhage (21%). The most common grade 3 or 4 adverse events included musculoskeletal pain (4.8%), syncope (4.2%), fracture (4%), and ischemic heart disease (4%) in the group given enzalutamide plus leuprolide and ischemic heart disease (6%) and fatigue (4.8%) in the group given enzalutamide monotherapy.

Adverse events led to treatment discontinuation in 21% of the group receiving enzalutamide plus leuprolide, most commonly fatigue (3.4%), and in 18% of the group receiving enzalutamide monotherapy, most commonly fatigue (3.7%). Adverse events led to death in six patients (1.7%) given enzalutamide plus leuprolide, most commonly infection (n = 2), and in eight patients (2.3%) given enzalutamide monotherapy, most commonly arterial thromboembolism (n = 2).

Enzalutamide has warnings or precautions for seizure, posterior reversible encephalopathy syndrome, hypersensitivity, ischemic heart disease, falls and fractures, and embryofetal toxicity. 

REFERENCE

1. Xtandi (enzalutamide) tablets and capsules for oral use prescribing information, Astellas Pharma US, Inc, November 2023. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/203415s018,213674s005lbl.pdf. Accessed January 4, 2024.