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Official title: A Multi-center, Randomized, Open-label Clinical Trial Comparing a 6-month vs Long-term Course of Rezvilutamide With ADT Plus Chemotherapy in High Tumor Burden mHSPC
Date: July 13, 2023  
| Project name              | A Multi-center, Randomized, Open-label Clinical Trial  Comparing a 6-month vs Long-term Course of Rezvilutamide  With ADT Plus Chemotherapy in High Tumor Burden  mHSPC .                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
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| Primary                   | To explore whether a 6-month course of Rezvilutamide in the  triple therapy regimen is non-inferior to long-term  Rezvilutamide treatment in improving radiographic  progression-free survival (rPFS) in patients with high tumor  burden metastatic hormone-sensitive prostate cancer (mHSPC).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| Objective:                | Secondary Objectives: To evaluate and compare the time to prostate-specific antigen  (PSA) progression, time to next bone-related event, time to  initiation of subsequent anti-prostate cancer treatment, and  objective response rate (ORR) between the 6-month course of  Rezvilutamide and long-term androgen deprivation therapy  (ADT) plus docetaxel treatment in patients with high tumor  burden mHSPC. To assess and compare the incidence of adverse events between  the 6-month course of Rezvilutamide and long-term ADT plus  docetaxel treatment in patients with high tumor burden  mHSPC. Exploratory Objectives: To observe the circulating tumor cell status at 6 months, 12  months, 18 months, and 24 months in patients with high tumor  burden mHSPC receiving the triple therapy regimen. |
| Primary Study  Endpoints: | Radiographic progression-free survival (rPFS) Secondary Study Endpoints: Time to prostate-specific antigen (PSA) progression Time to next bone-related event (including fractures, spinal  cord compression, radiation therapy, or surgery targeting the  bones) Time to initiation of subsequent anti-prostate cancer treatment Objective response rate (ORR) Quality of life assessment scores Exploratory Study Endpoint: Circulating tumor cell detection rate                                                                                                                                                                                                                                                                                                                                                |  
| Patients with mHSPC have a confirmed pathology of prostate  adenocarcinoma with high tumor burden, which is defined by  having at least one of the following conditions:   |                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                     |
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| Study                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                     |
| Subjects                                                                                                                                                                   | 1)                                                                                                                                                                                                                                                                                                                                                                                                                      | Bone scan showing ≥4 bone metastatic lesions (with at least  one site outside the pelvis or spine). |
| 2)                                                                                                                                                                         | CT/MRI revealing visceral metastatic lesions (excluding  lymph nodes).                                                                                                                                                                                                                                                                                                                                                  |                                                                                                     |
| Numbers                                                                                                                                                                    | In this study, a total of 100 cases were included.                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                     |
| Study design                                                                                                                                                               | The study design is a single-center, randomized, positive  drug-controlled, open-label clinical trial. The subjects were randomized and stratified based on the following factors: 1. ECOG performance status (whether greater than 0). 2. Presence of visceral metastatic lesions (excluding lymph  nodes).                                                                                                            |                                                                                                     |
| Drugs                                                                                                                                                                      | Rezvilutamide Luteinizing hormone-releasing hormone analogs (LHRHa) Docetaxel  Rezvilutamide: 240 mg, once daily, oral administration. Luteinizing hormone-releasing hormone analogs (LHRHa):  Subcutaneous injection, every 1 or 3 months. Docetaxel: 75 mg/m2 body surface area, intravenous infusion,  Day 1, every 21 days for 6 cycles. Prednisone: 5 mg, twice daily, oral administration, from Day 1  to Day 21. |                                                                                                     |
| Drugs  regimen                                                                                                                                                             | Inclusion criteria: 1. Age ≥ 18 years, male. 2. Eastern Cooperative Oncology Group (ECOG)  performance status score of 0-1. 3. Histologically or cytologically confirmed prostate                                                                                                                                                                                                                                       |                                                                                                     |
| Patients                                                                                                                                                                   | adenocarcinoma without evidence of neuroendocrine or                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                     |
| selection                                                                                                                                                                  | small cell features.                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                     |
| 4.                                                                                                                                                                         | High tumor burden, defined as having at least one of the  following conditions: 1) Bone scan showing ≥4 bone  metastatic lesions (with at least one site outside the  pelvis or spine). 2) CT/MRI revealing visceral                                                                                                                                                                                                    |                                                                                                     |  
| metastatic lesions (excluding lymph nodes).                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                    |
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| 5.                                                                                                                                                                                                                                                                                                                                                             | Planned to receive or maintain androgen deprivation  therapy (ADT) during the study period, either by  continuous LHRHa treatment or previous bilateral  orchiectomy (surgical castration), concurrently with 6  cycles of docetaxel chemotherapy. |
| 6.                                                                                                                                                                                                                                                                                                                                                             | Organ function levels must meet the following  requirements:                                                                                                                                                                                       |
|                                                                                                                                                                                                                                                                                                                                                               | Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L.                                                                                                                                                                                                    |
|                                                                                                                                                                                                                                                                                                                                                               | Platelets (PLT) ≥ 100 × 10^9/L.                                                                                                                                                                                                                    |
|                                                                                                                                                                                                                                                                                                                                                               | Hemoglobin (Hb) ≥ 90 g/L.                                                                                                                                                                                                                          |
|                                                                                                                                                                                                                                                                                                                                                               | Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal  (ULN).                                                                                                                                                                                       |
|                                                                                                                                                                                                                                                                                                                                                               | Alanine aminotransferase (ALT) ≤ 2.5 × ULN.                                                                                                                                                                                                        |
|                                                                                                                                                                                                                                                                                                                                                               | Aspartate aminotransferase (AST) ≤ 2.5 × ULN.                                                                                                                                                                                                      |
|                                                                                                                                                                                                                                                                                                                                                               | Blood urea nitrogen (BUN) (or urea) and creatinine (Cr)  ≤ 1.5 × ULN.                                                                                                                                                                              |
|                                                                                                                                                                                                                                                                                                                                                               | Left ventricular ejection fraction (LVEF) ≥ 50%.                                                                                                                                                                                                   |
| 7.                                                                                                                                                                                                                                                                                                                                                             | Judged by the investigator to be able to comply with the  trial protocol.                                                                                                                                                                          |
| 8.                                                                                                                                                                                                                                                                                                                                                             | Voluntarily participate in the clinical trial, understand  the study procedures, and have signed the informed  consent form.                                                                                                                       |
| Exclusion criteria: 1. Prior treatment with ADT, chemotherapy, surgery,  external beam radiation therapy, brachytherapy,  radiopharmaceuticals, or investigational local therapies  for prostate pain. However, the following cases are  allowed for inclusion:  Up to 3 months of ADT (medical or surgical  castration) with or without antiandrogen therapy |                                                                                                                                                                                                                                                    |  
| prior to Cycle 1 Day 1 (C1D1) without evidence  of radiographic disease progression (based on  RECIST 1.1 criteria) or clinically significant  PSA rise (defined as ≥50% increase from the  lowest level after reaching castration levels of  serum testosterone) before C1D1.   |                                                                                                                                                                                                                                                                                                                                                                                                                                      |
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|                                                                                                                                                                                                                                                                                 | Transurethral prostatectomy or up to one course  of palliative radiation therapy or surgery for  symptomatic treatment of metastatic disease at  least 4 weeks prior to C1D1. All adverse events  related to these treatments must have improved  to at least Grade 1 (according to NCI-CTCAE  v4.03) before starting study treatment.                                                                                               |
| 2.                                                                                                                                                                                                                                                                               | Prior use or planned use of second-generation androgen  receptor antagonists (such as enzalutamide, apalutamide,  darolutamide), abiraterone acetate, or other  investigational drugs inhibiting testosterone synthesis  for the treatment of prostate cancer during the study  period.                                                                                                                                              |
| 3.                                                                                                                                                                                                                                                                               | Received the following treatments within 4 weeks  before C1D1:  5-alpha-reductase inhibitors (e.g., finasteride,  dutasteride).  Estrogens, progestins, androgens, systemic  corticosteroids (except for temporary use for  allergic purposes).  Known herbal medicines with anti-prostate  cancer or PSA-lowering effects (e.g., saw  palmetto).  Participation in other clinical trials involving  investigational treatments. |
| 4.                                                                                                                                                                                                                                                                               | Confirmed brain tumor lesions on imaging.                                                                                                                                                                                                                                                                                                                                                                                            |
| 5.                                                                                                                                                                                                                                                                               | Planned to receive any other anticancer treatment during  the trial.                                                                                                                                                                                                                                                                                                                                                                 |
| 6.                                                                                                                                                                                                                                                                               | Known allergy or hypersensitivity to apalutamide, ADT,  or chemotherapy components.                                                                                                                                                                                                                                                                                                                                                  |
| 7.                                                                                                                                                                                                                                                                               | Presence of conditions that impede swallowing, chronic  diarrhea, intestinal obstruction, or other factors affecting  drug intake and absorption.                                                                                                                                                                                                                                                                                    |
| 8.                                                                                                                                                                                                                                                                               | History of seizures or occurrence of conditions that can  induce seizures within 12 months before C1D1  (including transient ischemic attack, stroke, traumatic  brain injury with altered consciousness requiring  hospitalization).                                                                                                                                                                                                |  
| 9.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Presence of active cardiac diseases within 6 months  before C1D1, including severe/unstable angina,  myocardial infarction, symptomatic congestive heart  failure, and ventricular arrhythmias requiring  medication.   |
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| 10. Diagnosis of any other malignancy within 5 years before  C1D1, except for completely resolved in situ cancer or  malignancies with slow progression as determined by  the investigator. 11. Active HBV or HCV infection (HBV viral load ≥  10,000 copies/mL, HCV viral load ≥ 1,000 copies/mL). 12. History of immunodeficiency (including positive HIV  test) or organ transplantation. 13. Unwillingness to use effective contraception during the  entire study treatment period and for 30 days after the  last dose. 14. Judged by the investigator to have conditions that pose a  serious risk to patient safety, may confound study  results, or may affect the patient's ability to complete the  study (such as poorly controlled hypertension, severe  diabetes, neurological or psychiatric diseases, etc.), or  any other relevant circumstances.                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                         |
| The investigator may decide to discontinue the study drug  treatment for a participant in the following circumstances: 1. The participant withdraws informed consent to continue  receiving the study treatment. 2. The participant meets the criteria for radiographic  disease progression in soft tissue and/or bone (as  determined by each study center based on RECIST 1.1  and modified PCWG3 criteria, see section 4.3.1). 3. The participant experiences clinical disease progression  accompanied by PSA progression (defined in section  8.1.2). Clinical progression is defined as worsening of  prostate cancer-related symptoms that the investigator  deems necessary to treat with any of the following: other  anticancer treatments, radiation therapy, surgery, or  intensified analgesic therapy (including the use of new  opioid analgesics or increasing the dose or frequency of  existing opioid analgesics). 4. The participant experiences any clinically significant  adverse reactions, abnormal laboratory findings, or  concurrent illnesses that, in the judgment of the  investigator, make continued participation in the study |                                                                                                                                                                                                                         |
| Criteria of  abandoning  the study                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                         |  
| not in the best interest of the participant.                                                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
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| 5.                                                                                                                                                                                                                                                                                                                                                                                                        | The investigator deems it necessary to withdraw the  participant from the study due to other reasons, such as  poor compliance, inability to express a free will due to  imprisonment or isolation, etc.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| 6.                                                                                                                                                                                                                                                                                                                                                                                                        | The participant dies or is lost to follow-up.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| The discontinuation of study treatment for a participant does not  automatically mean their withdrawal from the trial. The  investigator may decide to withdraw a participant from the  study in the following circumstances: 1. The participant withdraws informed consent for the  collection of subsequent data. 2. The participant dies or is lost to follow-up. 3. The sponsor terminates the study. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| Criteria of  candidates  quitting                                                                                                                                                                                                                                                                                                                                                                         | If any of the following situations occur, the trial must be  terminated: 1. Major errors are identified in the clinical trial protocol  that make it difficult to effectively evaluate the drug. 2. The sponsor requests termination, ensuring the rights  and safety of the participants. 3. Regulatory authorities or the ethics committee orders the  termination of the trial for specific reasons.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Criteria of  termination                                                                                                                                                                                                                                                                                                                                                                                  | General Analysis: Unless otherwise specified, this study will  employ the following methods for descriptive statistics.  Continuous variables will be summarized using mean, standard  deviation, median, maximum value, and minimum value.  Categorical variables will be summarized using frequency and  percentage. Time-to-event data will be analyzed using the  Kaplan-Meier method to estimate survival rates and median  survival time. When necessary, corresponding 95% confidence  intervals will be provided for the aforementioned analyses. Efficacy Analysis: The efficacy analysis will involve the  following methods: 1. Stratified Log-Rank test: It will be used to compare the  rPFS (progression-free survival) between groups. The  Kaplan-Meier method will be utilized to calculate the  median time to rPFS, along with the two-sided 95%  confidence interval. Additionally, a stratified Cox  proportional hazards model will be employed to analyze  the risk of the experimental group relative to the control  group. The hazard ratio and its two-sided 95% |
| Statistical  approach                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |  
| confidence interval will be reported.                                                                                |                                                                                                                                                                                                                                                           |
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| 2.                                                                                                                   | Kaplan-Meier method: This will be used to assess the  time to PSA progression, time to next bone-related  event, and time to initiation of next anti-prostate cancer  treatment. Two-sided 95% confidence intervals will be  provided for these analyses. |
| 3.                                                                                                                   | Clopper-Pearson method: It will be utilized to estimate  the 95% confidence interval for the objective response  rate (ORR).                                                                                                                              |
| Furthermore, the overall analysis will include the summary of  quality of life scores at various study visit points. |                                                                                                                                                                                                                                                           |
| Study period                                                                                                         | 3 years                                                                                                                                                                                                                                                   |