Perioperative Apalutamide in High-Risk Localized Prostate Cancer

BACKGROUND: Radical prostatectomy is potentially curative in patients with high-risk localized or locally advanced prostate cancer; however, relapse occurs within 5 years in up to 50% of patients. METHODS: We conducted a phase 3, double-blind, placebo-controlled trial in which patients with newly diagnosed high-risk localized or locally advanced prostate cancer were randomly assigned in a 1:1 ratio to receive androgen-deprivation therapy (ADT) plus apalutamide (240 mg per day) or ADT plus placebo for 6 cycles (28 days each) before and after radical prostatectomy with pelvic lymph-node dissection. The dual primary end points were a composite of pathological complete response or minimal residual disease (defined as a pathological stage of ypT2 or lower, with a tumor size of ≤5 mm in the greatest dimension) and metastasis-free survival, as assessed with conventional imaging or prostate-specific membrane antigen positron-emission tomography. Secondary end points included event-free survival, first subsequent treatment, and distant metastasis (assessed in time-to-event analyses), as well as safety. RESULTS: A total of 2109 patients underwent randomization: 1057 were assigned to receive ADT plus apalutamide, and 1052 to receive ADT plus placebo. The median follow-up was 61.7 months. The percentage of patients with a pathological complete response or minimal residual disease was significantly higher in the apalutamide group than in the placebo group (8.9% vs. 1.0%; odds ratio, 10.17; 95% confidence interval [CI], 5.27 to 19.64; P<0.001), as was the percentage of patients with metastasis-free survival (probability of metastasis-free survival at 5 years, 78.2% vs. 73.5%; hazard ratio for distant metastasis or death, 0.80; 95% CI, 0.67 to 0.96; P = 0.02). Event-free survival, time to the first subsequent treatment, and time to distant metastasis significantly favored ADT plus apalutamide over ADT plus placebo (P<0.001 for all between-group comparisons). Grade 3 or 4 adverse events occurred in 39.6% of the patients in the apalutamide group and in 31.0% of those in the placebo group, with the difference between the groups driven primarily by a higher incidence of rash in the apalutamide group. CONCLUSIONS: Perioperative treatment with ADT plus apalutamide was associated with better oncologic outcomes of radical prostatectomy in patients with high-risk localized or locally advanced prostate cancer than treatment with ADT plus placebo. Adverse events were more common in the apalutamide group than in the placebo group. (Funded by Johnson & Johnson; PROTEUS ClinicalTrials.gov number, NCT03767244.).