In men with metastatic castration-resistant prostate cancer (mCRPC) at risk for seizures, the androgen receptor inhibitor enzalutamide (Xtandi) didn’t raise seizure incidence when used at a dose of 160 mg/day, researchers found in a manufacturer-sponsored study.
Confirmed seizure incidence in the Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer Patients Treated With Enzalutamide (UPWARD) was 2.6 per 100 patient-years, according to Susan Slovin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues.
That’s about the same as the incidence previously calculated in a large retrospective analysis in the U.S., at 2.8 per 100 patient-years in patients with mCRPC and seizure risk factors who never took the drug, Slovin and colleagues reported online in JAMA Oncology.
“These data suggest that enzalutamide did not increase seizure incidence in men with mCRPC and seizure risk factors and is an option for patients with seizure risk factors,” the researchers wrote. “However, it should be used with caution and input from neurology specialists.”
“The risk profile presented, along with the previously established efficacy profile, suggests that enzalutamide can benefit patients with seizure risk factors, who should be closely monitored throughout the duration of treatment to ensure continued benefit and safety,” they added.
Jim Hu, MD, MPH, of New York Presbyterian/Weill Cornell Medicine in New York City, who wasn’t involved in the study, noted that the results contrast to those of a prior study, but they do suggest that “enzalutamide does not predispose to seizure. This demonstrates that enzalutamide may be safely used in men with metastatic prostate cancer who have risk factors for seizure.”
UPWARD was initiated following requests for additional safety information from the FDA and the European Medicines Agency. Although enzalutamide is known to prolong survival in men with mCRPC, phase I and II studies reported seizures in 3 of 140 (2%) enzalutamide-treated patients at doses greater than 360 mg/day.
Controlled clinical trials such as AFFIRM, PREVAIL, TERRAIN, and STRIVE have shown that with 160 mg of oral enzalutamide daily, only 0.5% of patients experienced seizure. However, patients with a history of seizure or risk factors were excluded from these trials, the researchers noted.
For UPWARD, they evaluated 423 patients at 73 sites in 20 countries, all of whom had at least one risk factor for seizure, including medications that lowered seizure threshold (57.2%); history of brain injury (26.5%); and history of cerebrovascular accident or transient ischemic attack (22.2%).
All patients received oral enzalutamide at a dose of 160 mg/day for an initial 4-month treatment period, and were given the option to extend treatment for one year.
Overall, 4 out of 366 evaluable patients (1.1%) had at least one confirmed seizure within 4 months of starting enzalutamide. The seizures were considered enzalutamide-related in 3 of the 4 patients. In addition, 3 patients (0.8%) had a seizure in the 4-month period after the study ended.
All 423 patients were included in the safety analysis. The majority (84.4%) experienced at least one treatment-emergent adverse event: 33.3% had at least one serious treatment-emergent adverse event, and 6.9% had at least one drug-related serious adverse event.
A total of 66 patients (15.6%) permanently discontinued treatment as a result of a drug-related AE, and three of these patients had a seizure, the researchers reported.
During the 4-month study period or within 30 days of the treatment ending, there were 38 deaths (9%), four of which were considered possibly drug-related. One patient died of cerebral hemorrhage, one of mCRPC progression, one experienced sudden cardiac death, and another had general deterioration. No seizure-related deaths were reported.
Study limitations included the fact that a randomized controlled trial wasn’t feasible, and that predisposing risk factors for seizure such as a history of seizure or of brain arteriovenous malformations were underrepresented, the researchers said.
“The risk profile presented, along with the previously established efficacy profile, suggests that enzalutamide can benefit patients with seizure risk factors, who should be closely monitored throughout the duration of treatment to ensure continued benefit and safety,” they concluded.
This study was funded by Astellas Pharma and Medivation (acquired by Pfizer in September 2016), the co-developers of enzalutamide. Both sponsors participated in the design and conduct of the study as well as analysis and interpretation of the data, approval of the manuscript, and decision to submit for publication. Lead author Slovin reported a relationship with Bayer AG. A number of co-authors also reported relationships with industry, including Astellas Pharma, Medivation, and Pfizer.