CytoREductive prostAtectomy for Poly-metastatic Hormone sensiTIVE Prostate Cancer

Systemic Therapy Combined With Cytoreductive Prostatectomy for the Treatment of de Novo Poly-metastatic Hormone Sensitive Prostate Cancer: A Prospective, Open-label Randomized Controlled Trial

The goal of this clinical trial is to compare systemic therapy combined with cytoreductive prostatectomy with standard of care (SOC) in de novo poly-metastatic hormone sensitive prostate cancer (de novo pmHSPC). The main questions it aims to answer are:

1. To explore the clinical benefit and safety of systemic therapy combined with cytoreductive prostatectomy for patients with de novo pmHSPC.
2. To explore the characteristics of the subgroup of patients who could benefit more from the above treatment.
3. To explore the relationship between stage efficacy and clinical prognosis.
4. To explore the correlation between molecular imaging such as PSMA-PET/CT and its changes with treatment efficacy.

Participants will undergo systemic therapy combined with cytoreductive prostatectomy.

Researchers will compare systemic therapy combined with cytoreductive prostatectomy with SOC to see the pros and cons of the two strategies.

1. Subject Management

1. Recruitment of subjects The subjects are recruited from the outpatient clinic of the Department of Urology of Renji Hospital, Shanghai Jiao Tong University School of Medicine; the specific time was from the beginning of the recruitment of subjects to the end of reaching the target of the recruitment of subjects. If the attending physician's initial judgment meets the criteria for NAC, recruitment will be carried out after communicating with the patient and his/her family.

2. Informed consent process After the attending physician (investigator) finds patients who initially meet the enrollment criteria of this trial, he/she should give a written and verbal explanation to the subjects about the background, nature, significance, steps, benefits, risks, compensation, injury compensation, and withdrawal of the study, and he/she must obtain an informed consent form signed by each subject (or subject's legal representative). The informed consent form is dated, and the informed consent form and its copy are kept separately by the investigator and the subject.

3. Checking the enrollment criteria As soon as possible after the preliminary identification of subjects, the attending physician and the investigator will check the enrollment criteria together, make a formal decision to recruit or not to recruit into the group and inform the subjects, and explain the reasons for not recruiting into the group in detail and record them.

4. Examination of medical history and records of combined medications During the initial screening and verification of the enrollment criteria, the attending physician will obtain the subject's past history, current medical history, personal history, as well as comorbid medications, and previous medications. If necessary, the history and co-medication records will be declared by the patient himself/herself or under the supervision of the attending physician while signing the informed consent form.

5. Assignment of screening number At the time of signing the informed consent, each patient is assigned a screening number, the rules for the preparation of the screening number are specified separately, and should ensure the principles of continuity, traceability and de-specialization.

6. Assignment of treatment/randomization group numbers Sequence generation: the data manager should use SAS statistical software (SAS Institute. Cary, NC, USA) to generate the allocation sequence in a stratified block randomization with block length set to 4. All subjects were randomly (1:1) assigned to trial and control groups. Factors for stratification included tumor stage (M1a/M1b/M1c) and baseline alkaline phosphatase level (greater/less than ULN). Randomized assignment sequences were performed using sequentially coded sequestration, and interventions should in principle be assigned as soon as possible after generation of the randomized assignment sequence. Sequences should not be accessed by anyone other than the restricted data manager prior to allocation of the intervention.

   Implementation: Generation of the randomized allocation sequence and allocation of the intervention by the data manager, and the generation of the sequence and the allocation of the intervention should be performed by different managers; recruitment of subjects by the attending clinical physician (investigator).

7. Trial Adherence Management During the course of the trial, patients' adherence to the trial will be examined and documented by the supervising physician at each visit and as deemed necessary by the investigator. If necessary, subjects may be instructed to complete a medication diary, which will be checked by the supervising physician and the investigator at each visit. Adherence reports are submitted to the Ombudsman for review as deemed necessary.

2. Intervention Trial group: Systemic therapy plus cytoreductive prostatectomy Control group: Standard of care.

3. Efficacy measurement Efficacy measurements of the specified items and frequencies are performed according to the visit requirements, and the efficacy is observed and recognized strictly according to the criteria set out in the outcomes, and the investigators and evaluators should form an efficacy report and include it in the case report form. PET-CT and PSMA-PET/CT examinations were for the exploratory purpose of this study, so they could be performed on a voluntary basis at the subjects' own expense and with their fully informed consent. The performance or failure of the examination and its results should not affect the performance of other treatments, nor should it affect the performance of other visits and programs.

In order to ensure the objectivity and comparability of the assessment of outcome indicators, the grouping information was hidden from the imaging evaluators and laboratory technicians, and for the scale-based visits, the patient self-assessment was used as the primary method, supplemented by the evaluation under the guidance of the professional staff, and the grouping information was hidden from the supervisory staff when the latter method was used.

4. Data Management

1. Data entry The investigator loads the data into the case report form in a timely, complete, correct and legible manner based on the subject's original observation record. The questionnaire after review and signature by the supervisor should be sent to the Clinical Research Data Manager in a timely manner. The entry is done using the appropriate database system of two-person dual-machine entry, after which the database is compared twice, during which if any problems are found, the supervisor is promptly notified and the researcher is asked to make an answer. The exchange of all kinds of questions and answers between them should be in the form of a questionnaire, which should be kept for reference.
2. Content and manner of data verification and management When all the case report forms have been double-entered and checked for accuracy, a database check report will be written by the data manager, which will include study completion (including list of dislodged subjects), inclusion/exclusion criteria check, completeness check, logical consistency check, outlier data check, time-window check, combined medication check, and adverse event check. At the audit meeting, the principal investigator, representatives of the sponsor, supervisors, data managers and statisticians will make a resolution on the issues raised in the subjects' signing of the informed consent form and the database checking report, write an audit report, and the database will be locked at the same time.
3. Data archiving The case report form, after data entry and verification are completed as required, will be filed and stored in numbered order and filled with search catalogs, etc., for examination. Electronic data files including databases, examination procedures, analytical procedures, analytical results, codebooks and description documents should be classified and kept with multiple backups on different disks or recording media for proper preservation and prevention of damage. All original files should be kept for the period within the corresponding regulations.

5. Analysis and statistical methods Before the start and after the end of each phase of the trial and the trial, the principal investigator, representatives of the sponsor, supervisors, data administrators and statisticians should carry out internal data analysis, including the completion of the study (including the list of dislodged subjects), analysis of the efficacy of the phase, and analysis of the adverse events, etc., and submit the analysis report to the review meeting for consideration.

According to the basic principle of Intention-to-Treat (ITT), the analysis of the main indicators should include all randomized subjects, regardless of whether they completed the trial or not. Therefore, this study used the full analysis set for analysis; when choosing the full analysis set for statistical analysis, the missing of the main indicators should be avoided as much as possible, and when the indicators are indeed missing, the deletion and the reason for deletion should be indicated in the analysis, and the mixed-effects model of repeated-measures data should be applied in the statistical analysis for processing.

Statistical analyses included stage efficacy analyses and summative efficacy analyses. Stage analysis was conducted after all subjects had completed the induction/chemotherapy phase and after all subjects in the trial group had completed the topical treatment phase. Terminal statistical analysis was conducted after all subjects had reached the primary endpoint of the study or had completed 3 years or had been discontinued/withdrawn, i.e., had completed the maintenance phase, and the trial had been completed. Statistical analyses were conducted to determine the relationship between subjects' achievement of the primary and secondary trial endpoints at each stage, and the stage-specific changes in each of the visits associated with the trial endpoints, and their potential impact on factors including, but not limited to, baseline status, receipt of the intervention, and changes in other visits. Statistical analyses were performed according to the following specifications:

Statistical descriptions of patients' baseline clinical characteristics; hypothesis testing for outcomes that manifested as categorical variables and those that manifested as ordered categorical variables using chi-square, Fisher's exact test, and rank-sum tests, as necessary; analysis of outcome indicators of a survival nature using Kaplan-Meier survival analysis; and exploration of the influence of each potentially influencing factor on the outcome using univariate and multivariate Cox regression. The impact of potential influences on outcomes was explored using univariate and multivariate Cox regression.

Inclusion Criteria:

1. Fully understand the purpose of this trial and sign a written informed consent;
2. Men aged 18-85 years;
3. have histologically or cytologically confirmed adenocarcinoma of the prostate;
4. Have multiple metastatic disease, defined as follows: according to RECIST v1.1, metastatic disease was defined as metastatic foci detected on bone scans or measurable lymph nodes or soft tissue or visceral lesions above the aortic bifurcation. Lymph nodes were defined as measurable if their short-axis diameter was ≥15 mm; soft tissue/visceral lesions were defined as measurable if their long-axis diameter was ≥10 mm. and total number of metastatic lesions ≥ 5. Patients with only regional lymph node metastases (N1, below the aortic bifurcation) were not eligible for the study.
5. At the investigator's discretion, patients must meet the indications for ADT and docetaxel;
6. Patients have not received any prior local or systemic therapy for prostate cancer primary or metastasis.
7. Eastern Cooperative Oncology Group (ECOG) score of 0-1;
8. Blood count at screening: hemoglobin ≥ 9.0 g/dL, absolute neutrophil count ≥ 1.5 x 10^9/L, and platelet count ≥ 100 x 10^9/L (patient has not received any colony-stimulating factor within 4 weeks or a transfusion or blood product within 7 days prior to blood collection)
9. Serum alanine aminotransferase and/or aspartate aminotransferase ≤ 1.5 x Upper limit of normal (ULN), total bilirubin ≤ ULN, creatinine ≤ 2.0 x ULN.

Exclusion Criteria:

1. Prior therapy: ADT, second-generation androgen receptor inhibitors, CYP17 enzyme inhibitors, any chemotherapy or immunotherapy for prostate cancer, radiotherapy (external radiation radiotherapy, brachytherapy, or radiopharmaceuticals);
2. Known hypersensitivity to any of the investigational drugs, or excipients in the preparations;
3. Contraindication to CT/MRI examination;
4. Any of the following conditions within 6 months prior to randomization: stroke, myocardial infarction, severe or unstable angina, coronary or peripheral artery bypass grafting, or congestive heart failure (New York Heart Association cardiac function class III or IV);
5. uncontrolled hypertension as evidenced by a resting systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 mm Hg after treatment
6. History of prior malignancy, except basal cell or cutaneous squamous cell carcinoma in complete remission;
7. History of gastrointestinal disorders or surgery expected to significantly interfere with the absorption of study drug(s);
8. Active acute and chronic viral hepatitis, known HIV infection;
9. Prior (28 days prior to initiation of study drug or 5 half-lives of investigational therapy from a prior study, whichever is longer) or concurrent participation in another clinical study of study drug;
10. Any other serious or unstable medical condition or condition that may interfere with their participation in the study or the evaluation of study results or may jeopardize the safety of the trial and other conditions;
11. Inability to swallow oral medications;
12. A close interest in the research center.