Clinical Data for Nonmetastatic CRPC

Matthew R. Smith, MD, PhD:The PROSPER study was a global randomized controlled trial of enzalutamide in men with nonmetastatic CRPC and a greater risk for disease progression based on the PSA doubling time of less than 10 months. Patients were randomized in a 2:1 manner to either enzalutamide or placebo. The primary study endpoint was metastasis-free survival. Compared to placebo, enzalutamide resulted in a 71% reduction in risk of metastasis or death. Enzalutamide was generally well tolerated, with relatively few patient discontinuations due to adverse events.

Apalutamide and enzalutamide are structurally similar novel antiandrogens. Apalutamide, in nonclinical studies, has a lower CNS penetration. It may have certain safety advantages. It’s important to note, though, that there have been no head-to-head studies of apalutamide and enzalutamide. Apalutamide is currently approved for the treatment of nonmetastatic CRPC. That approval was based on the results of the SPARTAN study, and the FDA approved apalutamide in that setting on February 14, 2018. The PROSPER study was very similar to the SPARTAN trial, and FDA review of enzalutamide for nonmetastatic CRPC is ongoing.

The package insert for apalutamide in nonmetastatic CRPC includes 2 important safety considerations. Apalutamide was associated with a higher rate of falls and fractures, and all patients receiving apalutamide should be assessed for their fracture risk and consider drug therapy to prevent fractures, according to national guidelines. Seizures are also listed on the package insert. About 0.2%, or 2 in 1000 patients, were observed to have seizures in the apalutamide pivotal trial. And any patient who experiences seizure activity during apalutamide treatment should permanently discontinue the medication.

The ARAMIS study is the third study of a potent antiandrogen in nonmetastatic CRPC. The ARAMIS study is a global randomized controlled trial of darolutamide in men with nonmetastatic CRPC and greater risk for disease progression based on the same PSA doubling time cutoff of less than 10 months. In contrast to PROSPER and SPARTAN, the darolutamide trial does not blind patients or providers to PSA results on study. So, it will be interesting to see what that feature of the trial, how that will impact subject retention in the study. The study completed accrual in February 2018, and results are expected based on event-driven analyses.

Transcript edited for clarity.