Prior to this year, there were no approved treatment options for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), and the majority continued to receive androgen deprivation therapy (ADT) alone, despite limited benefit. In these patients, a rapidly rising prostate specific antigen (PSA) level is associated with a higher risk of metastasis and shorter survival. The androgen receptor inhibitor enzalutamide is approved for patients with metastatic CRPC on the basis of an improved overall survival (OS). The randomized phase III PROSPER trial evaluated the addition of enzalutamide (160 mg daily) to ADT in 1,401 patients with nmCRPC and a PSA doubling time of 10 months or less.
Addition of enzalutamide to ADT significantly improved median metastasis-free survival (MFS), from 14.7 months with ADT and placebo to 36.6 months with enzalutamide and ADT (HR 0.29, P<.001). Fewer patients in the enzalutamide group required subsequent antineoplastic therapy (15% vs 48%), and those who did had a longer time to next therapy (39.6 months vs 17.7 months; HR 0.21, P<.001). Time to PSA progression was also significantly prolonged in the enzalutamide plus ADT group compared to ADT plus placebo (37.2 months vs 3.9 months; HR 0.07, P<.001). OS data are not yet mature. At the time of this analysis, 11% of patients in the enzalutamide group and 13% in the placebo group had died.
Adverse events (AEs) were consistent with the known safety profile of enzalutamide. Grade 3 or higher AEs occurred in 31% of patients receiving enzalutamide plus ADT, compared to 23% of patients receiving ADT plus placebo. AEs of special interest occurring more commonly in patients receiving enzalutamide included hypertension (12% vs 5%), major cardiovascular events (5% vs 3%), and mental impairment (5% vs 2%).
The investigators concluded that the addition of enzalutamide to ADT results in a clinically meaningful decrease in risk of metastasis in men with nmCRPC at high risk of progression, making it a viable alternative to watchful waiting or hormone therapy alone in appropriate patients. In an accompanying editorial, Matthew Smith, MD, PhD (Massachusetts General Hospital, Boston, Massachusetts, United States), commented that results from the PROSPER trial confirm observations in the recently published SPARTAN trial, which investigated apalutamide in this setting. Both of these trials support early use of antiandrogen therapy in men with nmCRPC, particularly in those at high risk for metastasis. The United States Food and Drug Administration (FDA) approved this indication for high-risk nmCRPC for enzalutamide on July 13 and for apalutamide in February of this year.
N Engl J Med. 2018;378:2465-2474.
N Engl J Med. 2018;378:2531-2532.