Neoadjuvant Chemo-hormonal Therapy Combined With Radical Prostatectomy for Locally Advanced Prostate Cancer

Study Overview
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Brief Summary
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To evaluate of the value of radical prostatectomy and extended pelvic lymph node dissection in locally advanced prostate cancer after neoadjuvant hormonal therapy with or without docetaxel chemotherapy.

Detailed Description
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Using larger sample prospective randomized controlled study design, and comparing neoadjuvant HT combined with docetaxel chemotherapy to neoadjuvant HT followed by RP and extended lymph node dissection to determine whether neoadjuvant HT combined with docetaxel chemotherapy can more effectively improve biochemical progression-free survival of locally advanced prostate cancer patients. Further analysis was performed to determine whether the treatment regimen helped to prolong the radiologic progression-free survival (rPFS) or OS in these patients. The pathological changes of tumor before and after neoadjuvant treatment were also analyzed. To search for the important risk factors influencing the long-term prognosis of these patients, the safety characteristics of patients in different treatment groups were analyzed. Therefore, it can provide the basis for the formulation of the optimal treatment plan for locally advanced prostate cancer, prolong the survival time of patients and improve the quality of life. Study design: Prospective，Multicenter, Open-label, Parallel group, Randomized (2:2:1) Controlled , Clinical Trial Study group: Newly diagnosed, untreated cT3a-cT4 or any cT, cN1 in locally advanced hormone-sensitive prostate cancer. Study group number: 475 cases, Randomized 2:2:1

Official Title
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A Prospective, Multicenter, Three-arm, Randomized, Controlled Study Comparing the Efficacy of Neoadjuvant Hormonal Therapy Combined With Systemic Chemotherapy (NCHT), Neoadjuvant Hormonal Therapy (NHT) and Radical Prostatectomy Only in Locally Advanced Prostate Cancer

Conditions
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Prostate Cancer, Chemotherapy Effect, Hormone Sensitive Prostate Cancer, Locally Advanced Prostate Carcinoma

Intervention / Treatment
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* Drug: Neoadjuvant chemotherapy combined with hormone therapy
* Drug: Neoadjuvant hormone therapy
* Procedure: Radical Prostatectomy (RP)+ extended lymph node dissection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18≤ Aged <75 years, male; Histology or cytology diagnosis: Prostate adenocarcinoma; ECOG performance Status ≤1; Expected lifetime ≥10 years; Without clinical or radiographic metastases in 6 months (Bone scan, MRI or pelvic enhanced CT scan, PET-CT) before randomized; The patients of locally advanced prostate cancer need to satisfy at least one of the following requirements: clinical stageT3a-T4, N0, M0; any T, N1, M0; Without Androgen Blockade Treatment in 4 weeks before randomized; Without radiographic treatment towards primary tumour; Without opioids (including codeine and dextropropoxyphene) relieving relevant pain of cancer; Without azole drugs (such as fluconazole, itraconazole); Important laboratory indicators are as follows: Haemoglobin ≥90g/L ANC ≥ 1500/μL PLT≥100*10^9/L K+≥3.5mmol/L AST or ALT ≤1.5 times upper limit of normal (ULN), TBIL should be ≤ULN (except patients with certified Gilbert syndrome) and ALP≤5ULN ALB≥30g / L calculated Ccr>60 ml/min, serum creatinine ≤ ULN Without swallowing disease, able to swallow the whole piece of drugs; Without other tumour chemotherapy history, without chemotherapy and endocrine therapy contraindications; If patient's spouse is at her childbearing age, the patient needs to agree that effective contraception should be taken during the treatment and 4 months after the operation. Subjects volunteer to participate, the subject must sign an informed consent form (ICF), indicating the understanding of the purpose and the required procedures of the study, and willing to participate in the study. Subjects must be willing to comply with the prohibitions and restrictions set forth in the program. Exclusion Criteria: The pathology result of prostate is neuroendocrine prostate cancer, including small cell carcinoma; Previous cytotoxic chemotherapy or biological therapy for prostate cancer; Contraindications to prednisone, such as active infections or other disorders; Patients with chronic disease needed to be given dose of prednisone (each time 5mg, bid a day) exceed the dose in the study; High blood pressure with poor control of drugs (systolic blood pressure ≥160mmHg or diastolic blood pressure ≥95mmHg); Active or symptomatic viral hepatitis or other chronic liver disease, known infected with human immunodeficiency virus (HIV); A disease history of pituitary or adrenal dysfunction; Patients with active autoimmune disease who need hormone therapy; Heart disease with clinical significance, including: myocardial infarction or arterial thrombosis occurred in the past 6 months; severe or unstable angina; New York Heart Association grade III or IV heart disease (Appendix 4); atrial fibrillation or other arrhythmias that require treatment; Subjects who participated in other clinical studies within a month before the first use of chemotherapy; (the elution time is at least 5 times the half-life time of the study drug if the half-life time is too long.) Patients with a history of hypersensitivity to Taxanes or docetaxel Patients who are concomitantly receiving strong CYP3A4 inhibitors Other circumstances considered inappropriate by investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized 2:2:1
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NCHT Group<br>Neoadjuvant chemotherapy combined with hormone therapy, Radical Prostatectomy (RP)+ extended lymph node dissection | Drug: Neoadjuvant chemotherapy combined with hormone therapy<br>* Docetaxel 75mg/m2 IV (every 3 weeks) +Prednisone 5mg BID orally + HT (Bicalutamide Tablets, 50mg QD orally; Goserelin, 3.6mg, subcutaneous injection, q28d), 4-6 cycles<br>* Other names: NCHT;Procedure: Radical Prostatectomy (RP)+ extended lymph node dissection<br>* Radical Prostatectomy (RP)+ extended lymph node dissection: Within three months after neoadjuvant treatment. Treatment after prostatectomy: There will not have any drug treatment after surgery until disease progression. Pelvic lymph node dissection is required to reach the level of bilateral iliac artery. If the postoperative pathology indicated positive incisional margin or pelvic lymph node metastasis, pelvic adjuvant radiotherapy should be performed within 3 months after surgery.<br>* Other names: RP+ePLND;|
| Active Comparator: NHT Group<br>Neoadjuvant hormonal therapy, radical Prostatectomy (RP)+ extended lymph node dissection. | Drug: Neoadjuvant hormone therapy<br>* HT (Bicalutamide Tablets, 50mg QD orally; Goserelin, 3.6mg, subcutaneous injection, q28d), 3-6 cycles<br>* Other names: NHT;Procedure: Radical Prostatectomy (RP)+ extended lymph node dissection<br>* Radical Prostatectomy (RP)+ extended lymph node dissection: Within three months after neoadjuvant treatment. Treatment after prostatectomy: There will not have any drug treatment after surgery until disease progression. Pelvic lymph node dissection is required to reach the level of bilateral iliac artery. If the postoperative pathology indicated positive incisional margin or pelvic lymph node metastasis, pelvic adjuvant radiotherapy should be performed within 3 months after surgery.<br>* Other names: RP+ePLND;|
| Other: RP Group<br>Radical Prostatectomy (RP)+ extended lymph node dissection alone. | Procedure: Radical Prostatectomy (RP)+ extended lymph node dissection<br>* Radical Prostatectomy (RP)+ extended lymph node dissection: Within three months after neoadjuvant treatment. Treatment after prostatectomy: There will not have any drug treatment after surgery until disease progression. Pelvic lymph node dissection is required to reach the level of bilateral iliac artery. If the postoperative pathology indicated positive incisional margin or pelvic lymph node metastasis, pelvic adjuvant radiotherapy should be performed within 3 months after surgery.<br>* Other names: RP+ePLND;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| bPFS (Biochemical progression-free survival) | Biochemical recurrence-free survival (bPFS): defined as the time from randomization to biochemical recurrence. The definition of biochemical recurrence is as follows: in the case of normal testosterone levels, the PSA was >0.2 ng/ml twice for more than 4 consecutive weeks. | about 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The 1-year biochemical progression-free survival (bPFS) rate | The ratio of patients whose consecutive postoperative PSA <0.2ng/ml within 1-year. | 1 year | 
| Overall survival (OS) | The time from randomization to death due to all causes. | 5-10 years | 
| Radiographic progression-free survival (rPFS) | The time from randomization to first confirmed imaging progression or death (whichever first is counted). Imaging progression was defined as one of the following: a. Progression of soft tissue lesions as defined in the revised RECIST 1.1 (Appendix 8) found by CT or MRI. b. Confirmation of bone metastasis lesions by ECT or PET-CT examination. | 3-5 years | 
| TTPP | The time from randomization to the time when PSA increased by 25%. | 1-3 years | 
| ECOG score progression-free survival | The time from treatment to the time of ECOG score progression. | 3-5 years |