Perioperative Apalutamide Plus ADT Cuts Metastasis Risk in High-Risk Prostate Cancer
Phase 3 PROTEUS: perioperative apalutamide plus ADT met both dual primary endpoints in high-risk localized prostate cancer, raising pCR/MRD rates to 8.9% vs 1.0% and cutting metastasis or death risk by 20%.
Adding apalutamide to androgen deprivation therapy (ADT) before and after radical prostatectomy significantly improved disease control in patients with high-risk localized or locally advanced prostate cancer, according to the final analysis of the phase 3 PROTEUS trial presented at the ASCO Annual Meeting 2026 and simultaneously published in The New England Journal of Medicine. The trial met both of its dual primary endpoints, with apalutamide plus ADT producing a pathologic complete response/minimal residual disease rate of 8.9% versus 1.0% with placebo plus ADT — a rate roughly nine times higher (OR, 10.17; 95% CI, 5.27-19.64; P <.0001) — and a 20% reduction in the risk of metastasis or death (HR, 0.80; 95% CI, 0.67-0.96; P =.02). Five-year metastasis-free survival was 78.2% in the apalutamide arm versus 73.5% with placebo, and both endpoints were evaluated by blinded independent central review after a median follow-up of 61.7 months.
Between July 15, 2019, and June 30, 2022, researchers randomly assigned 2,109 patients with high-risk localized or locally advanced prostate cancer to 6 cycles of neoadjuvant apalutamide or placebo alongside ADT, followed by radical prostatectomy and then 6 further cycles of adjuvant apalutamide or placebo. In all, 1,057 patients were assigned to apalutamide and 1,052 to placebo. The median age was 66 years; about 96% of patients in each arm had a Gleason score of 8 or higher, approximately 64% had tumor stage T2 or lower, and the median baseline PSA level was around 15 ng/mL.
Key secondary endpoints also favored apalutamide. Event-free survival was significantly improved (HR, 0.71; 95% CI, 0.63-0.80; P <.0001); the point at which 50% of patients experienced an event was 57.1 months versus 38.4 months. Time to subsequent therapy was extended to 74.2 months versus 41.5 months (HR, 0.65; 95% CI, 0.57-0.73; P <.0001), and 82.8% of apalutamide recipients were metastasis-free at 60 months compared with 76.2% of placebo recipients (HR, 0.68; 95% CI, 0.55-0.83; P =.0002). Testosterone recovery occurred within a median of 8.1 months, with no significant differences between treatment arms.
Apalutamide was associated with a higher proportion of grade 3-4 treatment-related adverse events (27.5% vs 18.9%), as well as TRAEs leading to dose reduction (11.2% vs 2.3%) and dose interruption (12.0% vs 4.4%). There were 7 deaths in the apalutamide arm and 1 with placebo. Investigators concluded that apalutamide plus ADT was well tolerated, with no new safety signals.
The data were selected to open the plenary session at ASCO 2026 and were published simultaneously in the New England Journal of Medicine. The trial was supported by Janssen Research & Development, LLC. Apalutamide is currently FDA approved in non-metastatic castration-resistant and metastatic castration-sensitive prostate cancer, and the immediate regulatory question is whether the manufacturer pursues a supplemental new drug application for the perioperative setting. PROTEUS has not yet reported mature overall survival data.