On December 16, 2019, enzalutamide (Xtandi) was approved for the treatment of patients with metastatic castration-sensitive prostate cancer.^1,2

Supporting Efficacy Data

The current approval was based on findings from the phase III double-blind ARCHES trial (ClinicalTrials.gov identifier NCT02677896), in which 1,150 patients with metastatic castration-sensitive prostate cancer were randomly assigned to receive oral enzalutamide at 160 mg once daily (n = 574) or placebo (n = 576).^2,3 All patients received a gonadotropin-releasing hormone (GnRH) analog or had prior bilateral orchiectomy.

Patients had a median age of 70 years (30% ≥ 75 years), 81% were white and 14% were Asian, 66% had a Gleason score ≥ 8, 63% had high-volume disease, 82% had no prior docetaxel, 12% received concomitant bone-targeted agents, and all had an Eastern Cooperative Oncology Group performance status of 0 (78%) or 1.

The main efficacy outcome measure was radiographic progression-free survival on blinded independent central review. The median radiographic progression-free survival was not reached in the enzalutamide group vs 19.4 months in the placebo group (hazard ratio [HR] = 0.39, P < .0001). Time to initiation of a new antineoplastic therapy was significantly prolonged in the enzalutamide group (HR = 0.28, P < .0001). Overall survival data were not mature at the time of this analysis.

How It Works

Enzalutamide is an androgen receptor inhibitor that acts at a number of steps in the androgen receptor–signaling pathway. It has been shown to competitively inhibit androgen binding to androgen receptors and to consequently inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite of enzalutamide, N-desmethyl enzalutamide, exhibited similar in vitro activity as the parent compound. Enzalutamide decreased the proliferation and induced death of prostate cancer cells in vitro and reduced tumor volume in a prostate cancer mouse xenograft model.

How It Is Used

The recommended dose for the current indication is 160 mg once daily. Patients should receive a GnRH analog or have had bilateral orchiectomy.

Dose modifications for adverse events include withholding the dosing for 1 week or until symptoms improve to grade ≤ 2 in patients with grade ≥ 3 toxicity or intolerable side effects. Dosing can then be resumed at the same or reduced dose (120 mg or 80 mg once daily) if warranted.

Concomitant use of strong CYP2C8 inhibitors (eg, gemfibrozil, clopidogrel, lopinavir) should be avoided. If such use cannot be avoided, the enzalutamide dose should be reduced to 80 mg once daily; the dose used prior to initiation of the strong inhibitor should be resumed upon discontinuation of the strong inhibitor.

Concomitant use of strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St John’s wort) should be avoided. If such use cannot be avoided, the enzalutamide dose should be increased from 160 mg to 240 mg once daily and should be resumed at the dose used prior to the start of the strong inducer upon its discontinuation.

Safety Profile

The most common adverse events of any grade (≥ 10%) that have occurred more frequently (≥ 2% vs placebo) in patients receiving enzalutamide in clinical trials were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension. In the ARCHES trial, the most common (≥ 5%) adverse events of any grade in the enzalutamide group that occurred with a frequency of at least 2% vs the placebo group were hot flush (27% vs 22%), asthenic conditions (24% vs 20%), hypertension (8.0% vs 5.6%), fractures (6.5% vs 4.2%), and musculoskeletal pain (6.3% vs 4.0%). Grade ≥ 3 adverse events occurred in 24% of the enzalutamide group, with the most common including hypertension (3.3% vs 1.7%), asthenic conditions (1.7% vs 1.6%), and fractures (1.0% vs 1.0%).

The most common grade 3 or 4 laboratory abnormalities among 3,173 patients receiving enzalutamide in 4 pooled randomized, placebo-controlled trials were hyperglycemia (3.2% vs 3.1% among 2,282 patients who received) and hyponatremia (1.4% vs 1.5%).

In the ARCHES trial, adverse events led to discontinuation of enzalutamide in 4.9% of patients, with the most common causes being increased alanine aminotransferase, increased aspartate aminotransferase, and seizure (0.3% each). Adverse events led to dose reduction in 4.4% of the enzalutamide group, with the most common cause being fatigue/asthenia (2.1%). Adverse events led to death in 10 patients (1.7%) receiving enzalutamide, with causes including heart disease (n = 3), sepsis (n = 2), and pulmonary embolism (n = 2). Adverse events led to death in eight patients in the placebo group (1.4%), with causes including heart disease (n = 2) and sudden death (n = 2).

Enzalutamide has warnings/precautions for seizure (which has occurred in 0.5% of patients receiving enzalutamide and in 2.2% of those with predisposing factors), posterior reversible encephalopathy syndrome, hypersensitivity, ischemic heart disease, falls and fractures (which have occurred in 11% and 10% of patients receiving enzalutamide), and embryofetal toxicity.

Enzalutamide should be permanently discontinued in patients who develop a seizure during treatment. Patients should have optimal management of cardiovascular risk factors; treatment should be discontinued for grade 3 or 4 ischemic heart disease events. Treatment should be discontinued for hypersensitivity reactions and for patients developing posterior reversible encephalopathy syndrome. Patients should be evaluated for fracture and fall risk and treated with bone-targeted agents according to established guidelines.■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves enzalutamide for metastatic castration-sensitive prostate cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-metastatic-castration-sensitive-prostate-cancer. Accessed January 10, 2020.

2. Xtandi (enzalutamide) capsules prescribing information, Astellas Pharma Inc., December 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/203415s015lbl.pdf. Accessed January 10, 2020.

3. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al: ARCHES: A randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 37:2974-2986, 2019.