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.
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.
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.
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.).
The New England journal of medicine. 2026 May 31 [Epub ahead of print]
Mary-Ellen Taplin, Martin Gleave, Neal D Shore, Angela Lopez-Gitlitz, Alexander Kretschmer, Eleni Efstathiou, Paul L Nguyen, Ronaldo Damião, Toshiyuki Kamoto, Ashley Ross, Alberto Briganti, Boris A Hadaschik, Axel Heidenreich, Álvaro Juárez Soto, Huihui Ye, Geoffrey Gotto, Brendan Rooney, Shaozhou Ken Tian, Lisa Wetherhold, Branko Miladinovic, Sharon A McCarthy, Christopher P Evans, Adam S Kibel, PROTEUS Investigators
Dana-Farber Cancer Institute, Boston., Department of Urologic Sciences, University of British Columbia, Vancouver, Canada., START Carolinas, Myrtle Beach, SC., Johnson & Johnson, Los Angeles., Johnson & Johnson, Spring House, PA., Knight Cancer Institute, Oregon Health and Science University, Portland., Mass General Brigham, Boston., Universidade do Estado do Rio de Janeiro, Rio de Janeiro., University of Miyazaki, Miyazaki City, Japan., Northwestern University Feinberg School of Medicine, Chicago., Urological Research Institute, Comprehensive Cancer Center, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan., University of Duisburg-Essen, Essen, Germany., Uro-Oncology, Robot-Assisted and Specialized Urologic Surgery, University Hospital of Cologne, Cologne, Germany., Hospital Universitario de Jerez de la Frontera, Cadiz, Spain., Labcorp Biopharma Laboratory Services, Torrance, CA., University of Calgary, Calgary, AB, Canada., Johnson & Johnson, High Wycombe, United Kingdom., Johnson & Johnson, San Diego, CA., University of Nevada, Reno.