In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
In August 31, enzalutamide (Xtandi) was approved for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.1,2
Approval was based on results of the multicenter AFFIRM trial, in which 1,199 patients with metastatic castration-resistant prostate cancer who had received prior docetaxel were randomly assigned to receive enzalutamide at 160 mg orally once daily (n = 800) or placebo (n = 399).2,3 (For additional discussion of the AFFIRM trial, see here.) Patients with a history of or risk factors for seizure or who were taking medications known to decrease seizure threshold were excluded from the trial. All patients continued androgen deprivation therapy, and patients were permitted to start or continue corticosteroid treatment during the study.
Approximately 70% of patients were aged 65 years or older, 91% had an ECOG performance status of 0 or 1, 51% had received more than two prior hormonal treatments, 27% had received two or more prior chemotherapy regimens, 38% had more than 20 bone lesions, and 77% had no visceral disease at baseline. In total, 48% of the enzalutamide group and 46% of placebo group received corticosteroids during the study. Median durations of treatment were 8.3 months with enzalutamide and 3.0 months with placebo and median follow up was 14.4 months. New systemic chemotherapy after progression was received by 42% of enzalutamide patients and 61% of placebo patients.
At the prespecified interim analysis, median overall survival, the primary endpoint of the trial, was significantly prolonged in the enzalutamide group (18.4 vs 13.6 months), with risk of death reduced by 37% compared with placebo (hazard ratio = 0.63, 95% confidence interval = 0.53–0.75, P < .0001). Median times to PSA progression (8.3 vs 3.0 months), radiographic progression (8.3 vs 2.9 months), and first skeletal-related event (16.7 vs 13.3 months) were also significantly prolonged with enzalutamide (all P < .001).
How It Works
Enzalutamide is an androgen receptor–signaling inhibitor that acts at several steps in the signaling pathway.2,3 It competitively inhibits androgen binding to androgen receptors and differs from currently available antiandrogen agents in that it inhibits androgen receptor nuclear translocation, DNA binding, and coactivator recruitment. It has a greater affinity for the androgen receptor and has no known agonistic effects. Enzalutamide decreases proliferation and induces cell death of prostate cancer cells in vitro and induces tumor shrinkage in xenograft models (compared with growth retardation with conventional agents). A major metabolite of the drug, N-desmethyl enzalutamide, exhibits activity in vitro similar to the parent compound.
How It Is Given
Enzalutamide is given at 160 mg orally once daily, with or without food. Recommended dose modifications include withholding of treatment for 1 week or until symptoms resolve to grade 2 or better in patients experiencing grade 3 or higher toxicity or an intolerable adverse reaction. Treatment can be resumed at the same dose or, if warranted, at a reduced dose of 120 mg or 80 mg.
Concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If coadministration cannot be avoided, the enzalutamide dose should be reduced to 80 mg once daily. If treatment with the CYP2C8 inhibitor is stopped, the enzalutamide dose should be returned to the dose prior to the dose reduction. Use of CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index (eg, celecoxib [Celebrex], omeprazole) should be avoided, since enzalutamide may decrease their plasma exposure; additional international normalized ratio (INR) monitoring is needed if enzalutamide is coadministered with warfarin (CYP2C9 substrate).
According to the drug’s approved product labeling, the most common adverse events in enzalutamide recipients (> 20%) in the AFFIRM trial were asthenic conditions (51% vs 44% in placebo recipients), back pain (26% vs 24%), diarrhea (22% vs 17%), arthralgia (20% vs 17%), and hot flushes (20% vs 10%).2 Grade 3 or 4 adverse events occurred in 47% of the enzalutamide group and in 53% of the placebo group. The most common (> 2%) were asthenic conditions (9.0% vs 9.3%), spinal cord compression and cauda equine syndrome (6.6% vs 3.8%), back pain (5.3% vs 4.0%), arthralgia (2.5% vs 1.8%), lower respiratory tract and lung infection (2.4% vs 1.3%), and hypertension (2.1% vs 1.3%).
Laboratory abnormalities were relatively uncommon; grade 3 or 4 abnormalities included neutropenia in 1% of the enzalutamide arm, thrombocytopenia in 0.5% of the enzalutamide arm and 1% of the placebo arm, and ALT elevation in 0.3% of the enzalutamide arm and 0.5% of the placebo arm. Discontinuation of treatment due to adverse events occurred in 16% of the enzalutamide group and 18% of the placebo group.
Death from infection or sepsis occurred in 1.0% with enzalutamide and 0.3% with placebo, with infection-related serious adverse events occurring in approximately 6% of patients in both groups. Falls or injuries related to falls occurred in 4.6% of enzalutamide recipients and 1.3% of placebo recipients. The falls were not related to loss of consciousness or seizure. Fall-related injuries were more severe in the enzalutamide group and included nonpathologic fractures, joint injuries, and hematomas.
Grade 1 or 2 hallucinations (visual, tactile, or undefined) occurred in 1.6% with enzalutamide and 0.3% with placebo; most patients were on opioid-containing medications at the time of the hallucination. Seizures occurred in 0.9% of patients on the enzalutamide arm and in no patients on the placebo arm. Those with seizure were discontinued from the study, and all seizures resolved.
Enzalutamide carries warnings/precautions for seizure. The drug lowers the seizure threshold, possibly through inhibition of the γ-aminobutyric acid–gated chloride channel. There is no clinical trial experience with enzalutamide in patients with a history of seizure or predisposing factors for seizure or in patients using concomitant medications that may lower the seizure threshold. Thus, the safety of enzalutamide in patients with predisposing factors for seizure is unknown.
The estimated cost of enzalutamide is $7,450 per month. ■
1. U.S. Food and Drug Administration: Approved drugs. Enzalutamide (XTANDI capsules). Available at http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm317997.htm. Accessed September 11, 2012.
2. XTANDI® (enzalutamide) capsules prescribing information. Astellas Pharma US, Inc, August 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203415lbl.pdf. Accessed September 11, 2012.
3. Scher HI, Fizazi K, Saad F, et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. August 15, 2012 (early release online).
The androgen receptor–signaling inhibitor enzalutamide (Xtandi) is reported to differ from conventional antiandrogen agents in that it inhibits androgen receptor nuclear translocation, DNA binding, and coactivator recruitment, has a greater affinity for the androgen receptor, and induces tumor...