Xtandi Granted Priority Review for Prostate Cancer Treatment

The Food and Drug Administration granted Xtandi (enzalutamide) a priority review to a supplemental new drug application for the treatment of patients with nonmetastatic castration-resistant prostate cancer, according to the companies developing the drug, Pfizer and Astellas.

The sNDA is based on data from the phase 3 PROSPER trial in which the combination of Xtandi and androgen deprivation therapy (ADT) reduced the risk of metastases or death by 71 percent compared with ADT alone for patients with nonmetastatic CRPC. In the double-blind study, the median metastasis-free survival (MFS) was 36.6 months with Xtandi plus ADT versus 14.7 months with ADT alone.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision by July 2018.

“Treatment options have been limited for men with nonmetastatic CRPC, in whom the only evidence of progressive disease is a rapidly rising PSA,” Mace Rothenberg, M.D., chief development officer, Oncology, Pfizer Global Product Development, said in a statement. “Xtandi is already established as a standard of care for men with metastatic CRPC. This milestone marks an important step toward our ability to bring Xtandi to CRPC patients in an earlier setting.”

In the phase 3 PROSPER trial, 1,401 patients with asymptomatic M0 CRPC were randomized to receive ADT plus Xtandi at 160 mg daily (933 patients) or a matching sugar pill placebo (468 patients). ADT consisted of a gonadotropin-releasing hormone agonist/antagonist. All patients in the study had testosterone levels of less than 50 ng/dL, a prostate-specific antigen (PSA) doubling time of less than 10 months, and a PSA of at least 2 ng/mL.

The primary endpoint of the study was MFS within 112 days of treatment discontinuation. Secondary endpoints of the study focused on PSA, time to next antineoplastic therapy, and overall survival (OS). Median duration of treatment with Xtandi was 18.4 months compared with 11.1 months for the placebo group.

There was a 93 percent reduction in the risk of PSA progression in the Xtandi arm compared with ADT alone. The median time to PSA progression in the Xtandi group was 37.2 months compared with 3.9 months for ADT alone.

The time to next antineoplastic therapy was extended by a median of 21.9 months with Xtandi versus ADT alone. Men enrolled in the Xtandi arm required a new therapy after a median of 39.6 months compared with 17.7 months in the placebo group, representing a 79 percent reduction in the risk of requiring a new therapy.

The initial results from the PROSPER trial were available 2 years earlier than estimates, which predicted data maturation in 2020. At the time of the analysis, OS data were not yet mature, with medians unavailable for each arm. At this early stage, however, there was a trend toward improvement in OS with the addition of Xtandi.

There were significantly more adverse events (AEs) in the Xtandi group compared with placebo (87 percent vs 77 percent). Grade 3 or higher AEs were experienced by 31 percent of men in the Xtandi arm compared with 23 percent of those in the placebo group. The grade 3 or higher AEs that were more common in the Xtandi group versus placebo, respectively, were hypertension (5 percent vs 2 percent) and fatigue (3 percent vs 1 percent).

AEs led to treatment discontinuation for 9 percent of patients in the Xtandi arm compared with 6 percent in the placebo group. Five percent of patients in the Xtandi arm experienced major cardiovascular events compared with 3 percent in the ADT alone arm. There were three seizures reported in the Xtandi arm compared with none in the placebo group.

"Once cancer spreads and metastasizes, men with castration-resistant prostate cancer face a daunting prognosis and challenging odds," Steven Benner, M.D., senior vice president and global therapeutic area head, Oncology Development, Astellas, said in a statement. "We're pleased to see the FDA's priority review designation as we work to potentially bring Xtandi to men living with nonmetastatic CRPC."

The FDA initially approved Xtandi as a treatment for men with metastatic CRPC following docetaxel in 2012. This approval was expanded to include treatment with the antiandrogen prior to chemotherapy in 2014.