Darolutamide ± ADT as Neoadjuvant Therapy in High-Risk/Very High-Risk Localized Prostate Cancer

Purpose Main research objectives: To explore the efficacy and safety of neoadjuvant Darolutamide monotherapy and Darolutamide combined with ADT followed by radical prostatectomy in two Parallel cohorts of High-risk/very high-risk localized-stage prostate cancer patients. Secondary study objectives: To explore the efficacy and safety of neoadjuvant Darolutamide monotherapy and Darolutamide combined with ADT followed by radical prostatectomy in two Parallel cohorts of High-risk/very high-risk localized-stage prostate cancer patients. Exploratory research objectives: The predictive effect of PSMA PET (SUVmax) and CTC (Circulating tumor cells) on curative effect and the value of monitoring recurrence after radical resection; Main Outcomes: The proportion of patients achieving MRD (minimal residual disease) in two parallel cohorts. Secondary Outcomes: Pathological downstaging rate, pCR rate (pathological complete remission), positive margin rate, proportion of undetectable PSA, bPFS (biochemical progression-free survival), MFS (metastasis-free survival), quality of life questionnaire Exploratory Outcomes: Biomarkers related to efficacy; Analysis of CTC status; exploration of the correlation between SUVmax measured by PSMA-PET and prognosis. Target treatment subject population: The target population of this study is patients diagnosed with high-risk/very high-risk localized-stage prostate cancer (Meet one of the following conditions): Clinical T stage ≥cT3; Gleason score 8-10 points; baseline PSA ≥20ng/ml; regional lymph node cN1; Planned duration of treatment: The duration of neoadjuvant therapy in this study will be 3 to 6 months, and the follow-up period will be 2 years. Eligible patients will receive: Parallel cohort 1: daily oral administration of Darolutamide 600 mg; Parallel cohort 2: daily oral administration of darolutamide 600 mg combined with ADT drugs (no restriction on drug categories, including LHRH agonists/LHRH antagonists, the specific dosage is determined according to the actual situation), for 3 to 6 months. The selection of the two parallel cohorts is determined by the clinician. Considering that ADT treatment can cause typical adverse reactions such as hot flashes, gynecomastia, fatigue, sexual dysfunction, etc., the clinician will decide the enrollment cohort based on the patient's specific clinical condition. Subjects will undergo robotic-assisted laparoscopic prostatectomy (RALP) ± standard lymph node dissection (LND), followed by a 2-year follow-up. Study drugs, dosage and administration route: The study drug is Darolutamide 600 mg, taken orally twice a day; ADT drug (the specific dosage is determined according to the actual instructions). Statistical methods: Primary endpoint: Proportion of patients achieving MRD (minimal residual disease) in two parallel cohorts. Secondary study endpoints: pCR rate (pathological complete remission), pathological downstaging rate, positive resection margin rate, proportion of PSA undetectable 8 weeks after surgery, biochemical progression-free survival (bPFS), metastasis-free survival (MFS), and quality of life questionnaire. Data will be summarized using appropriate descriptive statistics. Continuous variables will be summarized using number of observations (n), mean (or geometric mean, if appropriate), standard deviation (SD), median, quartiles (Q1 and Q3), minimum and maximum. Categorical variables will be summarized using frequencies and percentages for each category. 95% CIs will be provided where appropriate.