The Efficacy and Safety of Docetaxel Combined With Platinum for Metastatic Hormone-sensitive Prostate Cancer

Study Overview
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Brief Summary
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This randomized controlled trial was designed to evaluate the efficacy and safety of Docetaxel combined with Platinum-based drugs compared with Docetaxel alone for metastatic hormone-sensitive prostate cancer patients carrying DNA repair mutation.

Official Title
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A Randomized Controlled Trial to Evaluate the Efficacy and Safety of Docetaxel Combined With Platinum-based Drugs Compared With Docetaxel Alone for Metastatic Hormone-sensitive Prostate Cancer Patients Carrying DNA Repair Mutation

Conditions
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Hormone Sensitive Metastatic Prostate Cancer, DNA Damage Repair Deficiency, Chemotherapy Effect, Chemotherapeutic Toxicity

Intervention / Treatment
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* Drug: Docetaxel
* Drug: Prednisolone Acetate
* Drug: Platinum-based drugs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be ≥ 40 and ≤75 years of age. All patients must have been histologically diagnozed of prostate cancer. Metastatic disease confirmed by imaging: positive bone scan, or soft tissue or visceral metastases confirmed by abdominal/pelvic/chest contrast CT or MRI or PSMA PET-CT scan. Participants who were treated with androgen deprivation therapy (ADT) (LHRH agonist/antagonist or orchectomy) with or without first-generation anti-androgens within 12 weeks prior to random assignment must maintain serum testosterone castration levels, i.e., ≤50 ng/dL (≤ 1.75 nmol/L) during the study period. First-generation anti-androgens must be discontinued at least 1 day before the start of study therapy. Participants must carry one of the following DNA repair gene mutation: 1) HRR-related genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L; 2) Lynch syndrome-related genes: EPCAM, MLH1, MSH2, MSH6, PMS2. Eastern Cooperative Oncology Group (ECOG) physical condition score ≤1. Patients must have adequate hematologic function, hepatic function and renal function within 28 days prior to registration. Patients must participate voluntarily and sign an informed consent form(ICF), indicating that they understand the purpose and required procedures of the study, and are willing to participate in. Patients must be willing to obey the prohibitions and restrictions specified in the research protocol. Sexually active male subjects and their partner must agree the use of condoms as an effective contraceptive method and to avoid sperm donation during the whole treatment and within 4 weeks after the end of treatment. Exclusion Criteria: Patients with neuroendocrine, small cell, or signet ring cell histological features are not eligible. Patients with brain/meningeal metastases are not eligible.. Patients previously received any of the following treatments are not eligible: 1) LHRH agonists/antagonists within 12 weeks prior to the start of study therapy; 2) Second generation androgen receptor (AR) inhibitors, such as enzaluamine, dalotamide, apatamide, etc; 3) Cytochrome P17 enzyme inhibitors (e.g., abiraterone acetate or oral ketoconazole) as antitumor therapy for PCa; 4) Chemotherapy (including docetaxel) or immunotherapy for PCa; 5) Systemic corticosteroids > 10 mg/day equivalent dose of prednisone within 28 days prior to random assignment. Patients who were known to have hypersensitivity to any research drug or similar drug are not eligible. Patients received local treatments such as pre-focal treatment,radiotherapy and palliative endoscopic resection Patients with severe or uncontrolled concurrent infections are not eligible. Patients must not have New York Heart Association Class III or IV congestive heart failure at the time of screening. Patients must not have any thromboembolic event, unstable angina pectoris, myocardial infarction within 6 months prior to registration. Patients must not have uncontrolled severe hypertension, persistent uncontrolled diabetes, oxygen-dependent lung disease, chronic liver disease, or HIV infection. Patients must not have had other malignancies other than prostate cancer in the past 5 years, but cured basal cell or squamous cell skin cancers can be enrolled. Patients with mental illness, mental disability or inability to give informed consent are not eligible.

Ages Eligible for Study
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Minimum Age: 40 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Docetaxel plus platinum<br>Docetaxel combined with platinum-based drugs will be applied every 3 weeks for 6 cycles. | Drug: Docetaxel<br>* Docetaxel will be given intravenously 75 mg/m2 every 3 weeks for 6 cycles.<br>Drug: Prednisolone Acetate<br>* 5mg Prednisolone Acetate will be given orally twice a day during treatment.<br>Drug: Platinum-based drugs<br>* Platinum-based drugs will be given intravenously 70 mg/m2 every 3 weeks for 6 cycles. Cisplatin or carboplatin will be carefully chosen according to each patient's Creatinine Clearance.<br>|
| Active Comparator: Docetaxel alone<br>Docetaxel alone will be applied every 3 weeks for 6 cycles. | Drug: Docetaxel<br>* Docetaxel will be given intravenously 75 mg/m2 every 3 weeks for 6 cycles.<br>Drug: Prednisolone Acetate<br>* 5mg Prednisolone Acetate will be given orally twice a day during treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Metastatic Castration-Resistant Prostate Cancer (mCRPC) | Time from treatment initiation to Metastatic Castration-Resistant Prostate Cancer (mCRPC). Patients with metastatic prostate cancer develop PCa progression during androgen deprivation therapy (or after bilateral orchiectomy), meet any of the following criteria was defined as mCRPC. 1)PSA progression (defined as elevated PSA levels(≥1ng/ml) for no less than 2 measurements at least 1 week apart); 2) Radiographic progression in soft tissues, with or without PSA progression, according to RECIST 1.1 criteria; 3) Bone progression (defined as 2 or more new bone lesions on bone scans) with or without PSA progression, according to PCWG. | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The survival rate of participants during follow-up time. | up to 5 years | 
| rPFS | Radiographic progression-free survival. The survival of participants without radiographic progression. | up to 5 years | 
| Time to PSA progression | PSA progression is defined as elevated PSA levels(≥2ng/ml) for no less than 2 measurements at least 1 week apart. | up to 5 years | 
| Time to subsequent anti-tumor therapy | Time from end of treatment to the time when subsequent anti-tumor therapy is needed. | up to 5 years | 
| Adverse events | All grades of adverse events will be recorded according to NCI CTCAE (v.5.0) | up to 3 years |