FDA Grants Priority Review to Enzalutamide for Nonmetastatic CRPC

The FDA has granted a priority review to a supplemental new drug application (sNDA) for enzalutamide (Xtandi) for the treatment of men with nonmetastatic castration-resistant prostate cancer (CRPC). Enzalutamide, developed by Pfizer and Astellas, is an antiandrogen agent.

The sNDA is based on data from the phase III PROSPER trial in which the combination of enzalutamide (Xtandi) and androgen deprivation therapy (ADT) reduced the risk of metastases or death by 71% 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 enzalutamide plus ADT versus 14.7 months with ADT alone (HR, 0.29; 95% Ci, 0.24-0.35; P <.0001).

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, MD, 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 III PROSPER trial, 1401 patients with asymptomatic M0 CRPC were randomized to receive ADT plus enzalutamide at 160 mg daily (n = 933) or a matching sugar pill placebo (n = 468). ADT consisted of a gonadotropin-releasing hormone agonist/antagonist. All patients in the study had testosterone levels of ≤50 ng/dL, a prostate-specific antigen (PSA) doubling time of ≤10 months, and a PSA of ≥ 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 enzalutamide was 18.4 months compared with 11.1 months for the placebo group.

There was a 93% reduction in the risk of PSA progression in the enzalutamide arm compared with ADT alone (HR, 0.07; 95% CI, 0.05-0.08; P <.0001). The median time to PSA progression in the enzalutamide 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 enzalutamide versus ADT alone. Men enrolled in the enzalutamide arm required a new therapy after a median of 39.6 months compared with 17.7 months in the placebo group, representing a 79% reduction in the risk of requiring a new therapy (HR, 0.21; 95% CI, 0.17-0.26; P <.0001).

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 enzalutamide (HR, 0.80; 95% CI, 0.06-1.09; P = .1519).

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

AEs led to treatment discontinuation for 9% of patients in the enzalutamide arm compared with 6% in the placebo group. Five percent of patients in the enzalutamide arm experienced major cardiovascular events compared with 3% in the ADT alone arm. There were 3 seizures reported in the enzalutamide 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, MD, senior vice president and global therapeutic area head, Oncology Development, Astellas, said in a statment. "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 enzalutamide 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.

References

Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36 (suppl 6S; abstr 3).