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

A Phase II Prospective, Open-Label Clinical Study of Darolutamide ± ADT as Neoadjuvant Therapy in High-Risk/Very High-Risk Localized Prostate Cancer

This is a two-Parallel cohort, prospective study, aimed to explore Efficacy and safety of neoadjuvant Darolutamide with or without ADT in high-risk/very high-risk localized-stage prostate cancer. Two parallel cohorts will enroll 30 patients with high-risk/very high-risk localized-stage prostate cancer according to the criteria, respectively. Eligible patients in cohort 1 will receive 600 mg of Darolutamide orally daily, and patients in cohort 2 will receive 600 mg of Darolutamide orally daily combined with ADT. The selection of the two parallel cohorts will be determined by the clinician. Considering that ADT treatment will bring typical adverse-reactions such as hot flashes, gynecomastia, fatigue, and sexual dysfunction, the clinician will decide the enrollment cohort based on the patient's specific clinical condition. After both cohorts receive 3-6 months of neoadjuvant treatment, these patients will receive robotic-assisted laparoscopic prostatectomy (RALP) ± standard lymph node dissection (LND), and the specific surgical plan will be formulated by the clinician. Patients will receive postoperative adjuvant therapy as same as the original prescription according to different conditions (the application of postoperative adjuvant radiotherapy is determined by the clinician). Follow-up: (1) PSA and testosterone levels: Monitor monthly for the first 6 months. Monitor every 3 months within 2 years. Monitor every 6 months thereafter. (2) Radiological evaluation: Monitor every 6 minutes within 2 years after surgery, and every 12 minutes thereafter.

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.

Inclusion Criteria:

1. Informed consent was provided before the initiation of either study procedure
2. Age between 18 and 80 years of age (including 18 and 80 years of age)
3. ECOG performance status of 0-1 points, without severe cardiovascular and psychiatric disorders
4. Histologically confirmed adenocarcinoma of the prostate
5. Any one of the following conditions:

1) Clinical T stage ≥cT3; 2) Gleason score 8-10; 3) baseline PSA ≥20ng/ml; 4) presence of regional lymph node cN1; 6. No previous topical therapy and chemotherapy, ARi2nd 7. Patients previously treated with conventional ADT for ≤6 months (±ARi1st) 8. Subjects meet the criteria for resectability.The resectability criteria were defined as: clear lateral border of prostate and clear and non-invasive bladder neck on rectal digital examination

a, and no urethral or external sphincter invasion of the prostate apex 9. The subject has not received local treatment of the primary lesion of prostate cancer in the past and has no contraindications to radical prostatectomy 10. Male subjects have undergone surgical sterilization or used acceptable contraceptive methods (defined as barrier contraception containing spermicide) during the duration of the study and 3 months after the last study drug administration to prevent their partner from getting pregnant 11. Blood donor subjects are not allowed to donate blood during the study period and during the 3 months after the last study drug administration 12. During the duration of the study (including treatment and planned visits and examinations), subjects voluntarily and able to comply with the protocol

Exclusion Criteria:

1. Staff members involved in planning and/or conducting this study (research center staff).
2. Previously participated in the current study.
3. Participated in another clinical study involving an investigational product (IP) in the past month.
4. Previously underwent surgical castration or chemotherapy.
5. Previously received PARP inhibitor treatment.
6. Subjects with known hypersensitivity to ADT drugs/darolutamide or any excipient in the product.
7. Subjects with psychiatric or physical conditions that, in the investigator's judgment, would prevent them from safely receiving treatment.
8. Subjects with any laboratory test abnormalities that, in the investigator's judgment, would put them at risk if they participated in the study.
9. Subjects with persistent toxicity from prior cancer treatment (> CTCAE Grade 2), except for alopecia.
10. Patients with known active hepatitis (i.e., hepatitis B or hepatitis C) due to the risk of bloodborne or other bodily fluid transmission.
11. Immunocompromised subjects, such as those known to be HIV seropositive.
12. Unwilling or unable to comply with protocol requirements and scheduled visits.