77 Quick summary: Results from the international PROTEUS phase three clinical trial demonstrate that a new perioperative treatment regimen combining apalutamide with hormone therapy significantly reduces the risk of metastasis or death by 20% in patients with high risk localised prostate cancer. Patients receiving this intensive combination therapy before and after radical surgery were nine times more likely to show minimal residual disease and experienced a delayed need for subsequent treatments by an average of thirty three months. These paradigm changing findings carry immense weight for healthcare practice and public policy, offering clinical oncologists a proven pathway to alter the standard of care and directly improve survival outcomes and long term mental well being for thousands of individuals facing aggressive cancer diagnoses. A new treatment regimen combining apalutamide with hormone therapy before and after prostate surgery has significantly reduced the risk of metastasis or death in high-risk patients, meeting both primary endpoints of an international phase 3 clinical trial. The findings were presented by principal investigator Mary-Ellen Taplin, MD, a medical oncologist at Dana-Farber Cancer Institute, in a plenary session at the American Society for Clinical Oncology (ASCO) Annual Meeting in Chicago and were published simultaneously in the New England Journal of Medicine. More than 330,000 people are diagnosed with prostate cancer each year, and up to 20% have an aggressive form considered high-risk for relapse after primary therapy. Current standard treatment includes radical prostatectomy and radiotherapy combined with androgen-deprivation therapy (ADT), yet up to 50% of patients relapse within 5 years. “Reducing the risk of prostate cancer recurrence and death with improved initial treatment regimens has been a longstanding unmet need for men with localised high-risk prostate cancer,” said Taplin. “The PROTEUS study was designed to help men whose cancer is still considered curable but has a high chance of recurring or spreading.” PROTEUS was a randomised, double-blind, placebo-controlled phase 3 study of 2,109 patients with newly diagnosed high-risk localised or locally advanced prostate cancer. Participants received either apalutamide plus ADT or placebo plus ADT for 6 months in the perioperative period before and after radical prostatectomy with pelvic lymph-node dissection. The two primary endpoints were pathologic response at surgery and metastasis-free survival, assessed using both conventional imaging (bone scan and CT scan) and PSMA-PET imaging. Apalutamide is already approved for metastatic castration-sensitive prostate cancer and non-metastatic castration-resistant prostate cancer. Prior Dana-Farber research led by Taplin had also shown that intensive ADT before surgery showed promise in this patient population, supporting the perioperative approach explored here. After a median follow-up of 61.7 months, the apalutamide plus ADT combination reduced the risk of metastasis or death by 20%, with a 5-year metastasis-free survival probability of 78.2% compared to 73.5% with hormone therapy alone. Patients in the apalutamide group were 9 times more likely to have little or no cancer present at surgery, and 8.9% experienced a pathologic complete response or minimal residual disease, versus just 1.0% in the placebo group. The regimen also delayed the need for subsequent therapy by an average of 33 months. Researchers noted that PSMA-PET imaging alongside conventional methods provided a more comprehensive assessment of disease status. “As a urologic surgeon who cares for patients with advanced prostate cancer, I am thrilled by the significant improvements in pathology and metastasis-free survival we observed in the PROTEUS trial,” said Adam Kibel, senior author of the ASCO presentation and the New England Journal of Medicine manuscript. “The outcomes of this trial have the potential to reshape the standard of care for our patients with high-risk prostate cancer.” Taplin echoed this view. “We have a paradigm-changing phase 3 clinical trial,” she said. “This type of treatment regimen that combines systemic therapy with surgery is standard in other aggressive cancers and now has proven benefit for patients with high-risk localised or locally advanced prostate cancer.” Side effects were consistent with previously reported data, although Grade 3 or 4 adverse events occurred more frequently in the apalutamide group, primarily driven by rash. These data represent the 1st phase 3 evidence supporting perioperative intensification with an androgen-receptor pathway inhibitor in this setting. Further follow-up and potential regulatory reviews will determine how quickly this approach may influence clinical guidelines for high-risk cases.