Randomized Controlled Study on the Efficacy and Safety of Intermittent Darolutamide Treatment in the Triple Therapy of Metastatic Hormone Sensitive Prostate Cancer
Phase: PHASE3
Conditions: Metastatic Prostate Cancer, Intermitent Anti-androgen Therapy
Sponsor: The First Affiliated Hospital with Nanjing Medical University

 
 
 
Official title: Randomized Controlled Study on the Efficacy and Safety of 
Intermittent Darolutamide Treatment in the Triple Therapy of metastatic hormone 
sensitive prostate cancer.  
 
Date: December 11, 2023  
 

Summary of the Plan  
Research Title: 
Randomized Controlled Study on the Efficacy and Safety of Intermittent 
Darolutamide Treatment in the Triple Therapy of metastatic hormone sensitive 
prostate cancer. 
Plan Number: 
 
Version Number 
2.0 
 Version Date 
November 21, 2023 
Study Drug: 
Darolutamide  
Principal 
Investigator:  
Hua Lixin  
Participating 
Center: 
Jiangsu People's Hospital  
Research 
Objective:  
To evaluate the efficacy and safety of intermittent use of darolutamide compared to 
long-term use in combination with ADT and docetaxel in the treatment of mHSPC 
patients. 
Study Endpoints: 
• 
 Primary Endpoint: • Radiographic Progression Free Survival (rPFS) 
Secondary Endpoints: • Overall Survival (OS) • Time to castration-resistant 
prostate cancer (Time to mCRPC) • Time to pain progression (TTPP) • 
Safety • Quality of Life (QOL) 
Study 
Population:  
 Patients enrolled are those with metastatic hormone-sensitive prostate cancer 
(mHSPC) 
Study 
Design 
and 
Treatment 
Regimen 
Patients will firstly receive 6 months of darolutamide in combination with 
docetaxel and ADT treatment. 
1. When the patient reaches: 
1. PSA ≤ 0.2ng/ml 
2. Or PSA > 0.2ng/ml but with more that 90% decrease comparing 
baseline 
3. Without newly discovered metastatic lesions.  
They will be randomly assigned in a 1:1 ratio to either continuous 
treatment group or intermittent treatment group  
(1) 
Continuous 
treatment 
group: 
Darolutamide: 
600mg, 

bid+ADT: Leuprorelin (3.6mg qm or 10.8mg q3m) or goserelin 
80mg qm until mCRPC; (2) Intermittent treatment group: Only 
ADT as background treatment without Darolutamide. PSA check 
every three months, when the patient's PSA > 1ng/ml (or PSA > 
1ng/ml and PSA has risen by more than 20% comparing 
baseline), restart the darolutamide, until mCRPC. 
2. When the patient: 
1. PSA > 0.2ng/ml and has not decreased by 90% compared to 
baseline 
2. Or has new metastatic lesions, they will exit the study. 
Imaging assessment will be conducted every 3 months  
 
Key 
Inclusion 
Criteria  
 
Patients must meet all of the following criteria to be eligible for this study: 
1. Male aged ≥18 years; 
2. Histologically or cytologically confirmed prostate adenocarcinoma; 
3. Metastatic disease (confirmed by conventional imaging); 
4. ECOG performance status of 0-1; 
5. Suitable for ADT and docetaxel treatment; 
6. Good bone marrow, kidney, and liver function: 
1. (1) Hematological examination (no blood transfusion or use of 
hematopoietic growth factors within 7 days before screening): 
1. Hemoglobin (HB) ≥ 90g/L; 
2. Absolute neutrophil count (ANC) ≥ 1.5×109/L; 
3. Platelets (PLT) ≥ 80×109/L; 
2. (2) Blood biochemistry examination (no blood transfusion or 
albumin within 7 days before screening): 
1. Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase (AST) ≤ 2.5 × ULN 
2. Total bilirubin (TBIL) ≤ 2.0 × ULN; 
3. Serum creatinine (Cr) ≤ 2.0×ULN; 
7. Willing to participate in this study, sign an informed consent form, and 

have good compliance 
 
Exclusion 
Criteria: 
1. No metastatic disease; 
2. Prior treatment with: a) Second-generation ARis or other experimental 
ARis b) CYP17 enzyme inhibitors such as abiraterone acetate or oral 
ketoconazole for anti-tumor treatment of prostate cancer c) Chemotherapy 
or immunotherapy prior to randomization for prostate cancer 
3. Received radiotherapy within 2 weeks before starting 6 months of 
darolutamide + docetaxel + ADT treatment; 
4. Stroke, myocardial infarction, severe/unstable angina, coronary/peripheral 
artery bypass surgery, congestive heart failure (New York Heart 
Association class III or IV); 
5. History of malignant tumors; 
6. Planned receipt of other anti-tumor treatment during the study treatment 
period; 
7. Known allergy to the above drug components; 
8. Difficulty swallowing, chronic diarrhea, intestinal obstruction, and various 
factors affecting drug intake and absorption; 
9. Refusal to sign the informed consent form; 
10. Investigator's opinion that the participant is not suitable for inclusion. 
 
Assessment 
Criteria: 
Safety assessment: Adverse events will be evaluated using NCI-CTC AE 5.0 
criteria. Efficacy assessment: Response will be evaluated using RECIST 1.1 
criteria. 
Safety Indicators 
Blood and biochemical tests (ALT, AST, TB, DB, BUN, Cr, electrolytes), 12-lead 
electrocardiogram, coagulation function, etc. 
Termination 
of 
Treatment 
Standard: 
1. When one of the following occurs after 6 months of treatment with 
Darolutamide + Docetaxel + ADT: a. PSA > 0.2ng/ml and has not 
decreased by 90% compared to baseline b. Presence of newly discovered 
metastatic lesions 
2. The patient has completed the prescribed treatment and follow-up plan. 
3. Disease progression (PD) is determined based on the efficacy evaluation 
criteria, i.e., progression to mCRPC. Definition of progression to mCRPC: 

Either of the following conditions is met: a. Biochemical progression: 
Testosterone < 50ng/dl or 1.7nmol/l, PSA > 2ng/ml, continuous increase 
of more than 50% compared to baseline b. Radiographic progression: 
Bone scan reveals ≥2 new bone lesions or RECIST assessment shows 
enlargement of soft tissue lesions 
4. The investigator considers it necessary to terminate the treatment in the 
best interest of the patient. 
5. Occurrence of intolerable or unexpected adverse reactions or serious 
adverse events. 
6. Inability to complete the treatment according to the trial protocol even 
after dose adjustment for grade 3/4 adverse events. 
7. Patients with treatment delay > 4 weeks. 
8. Medical or ethical reasons affecting the continuation of the study. 
9. Poor patient compliance. 
10. Use of other anti-tumor drugs that affect efficacy assessment (e.g., 
chemotherapy, targeted therapy, or biologic therapy). 
11. Death. 
12. Other situations deemed necessary for the patient to withdraw from the 
study. 
 
Withdrawal from 
the Study 
Reasons for subject withdrawal from the study may include: 
1. Subject withdrawal of informed consent, refusal to continue follow-up. 
2. Discovery of subject's ineligibility after enrollment. 
3. Medical imaging or clinical features indicating disease progression. 
4. Occurrence of clinical adverse events, abnormal laboratory tests, or 
comorbidities, and the investigator deems continued participation not in 
the subject's best interest. 
5. Subject experiences a pregnancy event during the study. 
6. Loss to follow-up or death. 
7. Other reasons deemed by the investigator as unable to continue the 
treatment. 
 
Termination 
of 
the Study 
Termination of the trial refers to the premature cessation of the entire trial as per 

the protocol. The purpose of terminating the trial early is mainly to protect the 
rights of the subjects, ensure the quality of the trial, and avoid unnecessary 
economic losses. Early termination of the clinical trial should be promptly 
communicated to all involved parties. 
1. Discovery of unexpected, significant, or unacceptable risks to the subjects. 
2. Major errors in the trial protocol identified during the trial execution. 
3. Ineffectiveness of the investigational drug treatment or continuation of the 
trial is deemed meaningless. 
4. Severe delays in subject enrollment or frequent protocol deviations, 
making trial completion extremely difficult. 
 
Sample size: 
80 cases  

Data analysis: 
 
General analysis: Unless otherwise specified, this study will summarize 
the corresponding descriptive statistics based on the data type. Measures 
of central tendency such as mean, standard deviation (SD), median, 
minimum, and maximum will be used for quantitative data. Frequency and 
percentage will be used for categorical and ordinal data. Kaplan-Meier 
method will be used for time-event data to estimate the median time and 
the 95% confidence interval of the overall population. 
 
Efficacy analysis: Data statistics will be conducted for PSA remission, 
complete remission rate (CR), partial remission rate (PR), objective 
remission rate (ORR), disease control rate (DCR). Kaplan-Meier method 
will be used to estimate the time and 95% confidence interval of the event 
endpoints (rPFS and OS), and to plot survival curves. 
 
Safety analysis: Safety analysis will be based on all treated subjects. 
Adverse events will be graded according to NCI-CTCAE version 5.0, and 
descriptive statistics will be the primary summary method. AE, SAE, and 
other data will be statistically summarized according to groups. Abnormal 
changes in laboratory test results before the trial but after treatment, and 
their relationship with the investigational drug, will be described. The 
mean, standard deviation, median, minimum, and maximum values of 
vital signs and laboratory indicators before and after medication will be 
calculated, and paired t-tests will be used for comparison. 
 
Projected 
progress of the 
trial 
November 2023 - November 2028 Completion of enrollment within 12 months 
after the implementation of clinical research approval Follow-up period: 4 
years 
 
 
 

Informed Consent Form 
 
We invite you to participate in a multicenter, randomized, open-label clinical study 
titled " Randomized Controlled Study on the Efficacy and Safety of Intermittent 
Darolutamide Treatment in the Triple Therapy of metastatic hormone sensitive 
prostate cancer". The study is led by Jiangsu Provincial People's Hospital and 
involves several renowned hospitals nationwide, including Jiangsu Cancer Hospital. 
Approximately 200 eligible subjects over the age of 40 who voluntarily participate 
will be enrolled in the study across these hospitals. The research has been reviewed 
and approved by the Ethics Committee of Jiangsu Provincial People's Hospital, and 
Dr. Huali Xin, the Director of Urology Department at our hospital, is responsible for 
this project. Our center plans to enroll 150 subjects. It is crucial for you to read and 
understand this informed consent form before agreeing to participate in this study. 
This document explains the research objectives, procedures, potential benefits, and 
risks you may face. It also outlines other treatment options available to you and your 
rights. You have the right to withdraw from the study at any stage. If you decide to 
participate, you will receive a copy of the informed consent form signed by both you 
and the researchers. 
Why conduct this research? 
Prostate cancer is the second most common malignant tumor in men globally in terms 
of incidence and the sixth most common cause of cancer-related deaths. The 
incidence of prostate cancer in China is lower than in Western countries, but it has 
been rapidly increasing in recent years. According to the latest statistics from the 
National Cancer Center, in 2015, there were approximately 60,300 new cases of 
prostate cancer and 26,600 deaths in China, ranking it as the 7th most common and 
10th most lethal cancer in males. The incidence of prostate cancer is even higher in 
major cities, such as Beijing, Shanghai, and Guangzhou, where the incidence rates in 
2009 were 19.30/100,000, 32.23/100,000, and 17.57/100,000, respectively, ranking 
them as the 5th, 5th, and 7th most common cancers among urban males. With the 
aging population and Westernized lifestyle, it is expected that the incidence of 
prostate cancer in China will continue to rise rapidly. Additionally, unlike Western 
countries, where only 10-15% of initial cases of prostate cancer are metastatic, in 
China, 20-30% of initial cases are already metastatic. Androgen deprivation therapy 
(ADT) with or without first-generation androgen receptor (AR) antagonists (such as 
bicalutamide, nilutamide) is the standard first-line treatment for metastatic prostate 
cancer. Although most patients initially respond to treatment, the disease progresses 
from metastatic hormone-sensitive prostate cancer (mHSPC) to metastatic 
castration-resistant prostate cancer (mCRPC) after an average of 18-24 months. The 
main mechanisms leading to castration resistance are continued adrenal androgen 
secretion, intratumoral androgen synthesis, AR overexpression, and acquired AR 
signaling pathway reactivation due to functional mutations. 

The primary objective of this study is to evaluate the efficacy and safety of 
intermittent use of darolutamide compared to long-term use in combination with ADT 
and docetaxel in the treatment of mHSPC patients. 
 
What do you need to do if you participate in the study? 
This study is a multicenter, randomized, positive drug-controlled, open-label clinical 
trial. It evaluates the efficacy and safety of intermittent use of darolutamide compared 
to long-term use in combination with ADT and docetaxel in the treatment of mHSPC 
patients. The Continuous treatment group: Darolutamide: 600mg, bid+ADT: 
Leuprorelin (3.6mg qm or 10.8mg q3m) or goserelin 80mg qm until mCRPC; while 
the Intermittent treatment group: Only ADT as background treatment without 
Darolutamide., who will be randomly assigned in a 1:1 ratio to the experimental and 
control groups, with stratification factors including: 1. ECOG performance status > 0; 
2. Presence of visceral metastasis. Participants are allowed to receive a maximum of 3 
months of ADT treatment (with or without antiandrogen therapy) before cycle 1 day 1 
(C1D1) of the study. Up to 4 weeks prior to C1D1, participants can undergo 
transurethral resection of the prostate or receive palliative radiotherapy or surgery for 
symptomatic metastatic disease (e.g., spinal cord compression or bone pain). 
Participants who have undergone prior ADT treatment must not have evidence of soft 
tissue disease progression (according to RECIST 1.1 criteria) or clinically significant 
prostate-specific antigen (PSA) increase (defined as ≥50% increase from the lowest 
level after reaching castration levels of testosterone) before C1D1. Participants who 
have received antiandrogen therapy prior to enrollment must discontinue it before 
C1D1 and beyond. 
 
This study includes a screening period of up to 28 days to determine if subjects meet 
the eligibility criteria and complete the baseline assessments. During the treatment 
period of the study, subjects will receive investigational drug treatment according to 
the assigned group, until disease progression, intolerable toxicity, withdrawal of 
informed consent, or the investigator determines it necessary to withdraw the subject 
from the study. 
Throughout the entire treatment period, subjects will continue to receive androgen 
deprivation therapy (ADT) (either through medication or surgical castration). Subjects 
receiving medication-based castration will follow the instructions in the drug package 
insert. Efficacy assessments for soft tissue and bone imaging will be conducted based 
on RECIST 1.1 criteria (see appendix) and the adjusted PCWG3 criteria (see section 
8.1.1). An Independent Review Committee (IRC) will review the imaging evaluations 
from each study center. 
Survival follow-up will begin after the last dose of medication on day 30 and will 
occur every 2 months through clinical or telephone follow-up. During these 

follow-ups, information regarding survival status, bone-related events (if they did not 
occur prior to the survival follow-up), and subsequent anti-tumor treatments will be 
collected until subjects experience death, loss to follow-up, withdrawal of informed 
consent, or termination of the study by the sponsor. 
If you agree to participate in this study, please sign this informed consent form. Prior 
to your inclusion in the study, your doctor will inquire about and record your medical 
history, and you will undergo screening tests such as MRI, CT, and hematology to 
confirm your eligibility based on inclusion criteria. 
After enrollment, you will be randomly assigned to either the experimental group or 
the control group in a 1:1 ratio. The Continuous treatment group: Darolutamide: 
600mg, bid+ADT: Leuprorelin (3.6mg qm or 10.8mg q3m) or goserelin 80mg qm 
until mCRPC; while the Intermittent treatment group: Only ADT as background 
treatment without Darolutamide. Throughout the treatment period, you will need to 
undergo regular examinations and evaluations according to the study protocol. After 
completion of treatment, a survival follow-up will occur every 2 months. 
3. What are the criteria for participating in this study? (Inclusion criteria) In 
order to participate in this study, you need to meet the following criteria: 
8. Male aged ≥18 years; 
9. Histologically or cytologically confirmed prostate adenocarcinoma; 
10. Metastatic disease (confirmed by conventional imaging); 
11. ECOG performance status of 0-1; 
12. Suitable for ADT and docetaxel treatment; 
13. Good bone marrow, kidney, and liver function: 
3. (1) Hematological examination (no blood transfusion or use of 
hematopoietic growth factors within 7 days before screening): 
1. Hemoglobin (HB) ≥ 90g/L; 
2. Absolute neutrophil count (ANC) ≥ 1.5×109/L; 
3. Platelets (PLT) ≥ 80×109/L; 
4. (2) Blood biochemistry examination (no blood transfusion or albumin 
within 7 days before screening): 
1. Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 2.5 × ULN 
2. Total bilirubin (TBIL) ≤ 2.0 × ULN; 
3. Serum creatinine (Cr) ≤ 2.0×ULN; 
14. Willing to participate in this study, sign an informed consent form, and have 
good compliance 

If you require more detailed inclusion criteria for participating in this study or if you 
have any unclear phrases or information, please consult your research doctor. 
4. Who should not participate in the study? (Exclusion criteria) You should not 
participate in this study if you have any of the following conditions: 
5. No metastatic disease; 
6. Prior treatment with: a) Second-generation ARis or other experimental ARis b) 
CYP17 enzyme inhibitors such as abiraterone acetate or oral ketoconazole for 
anti-tumor treatment of prostate cancer c) Chemotherapy or immunotherapy 
prior to randomization for prostate cancer 
7. Received radiotherapy within 2 weeks before starting 6 months of 
darolutamide + docetaxel + ADT treatment; 
8. Stroke, myocardial infarction, severe/unstable angina, coronary/peripheral 
artery bypass surgery, congestive heart failure (New York Heart Association 
class III or IV); 
9. History of malignant tumors; 
10. Planned receipt of other anti-tumor treatment during the study treatment 
period; 
11. Known allergy to the above drug components; 
12. Difficulty swallowing, chronic diarrhea, intestinal obstruction, and various 
factors affecting drug intake and absorption; 
13. Refusal to sign the informed consent form; 
14. Investigator's opinion that the participant is not suitable for inclusion. 
5. When can the study be terminated if I participate? 
1. If you agree to participate in this study, you can terminate the study after 
completing the research tasks under the guidance of the research team. 
2. During the study, you may terminate it midway under the following 
circumstances: a) Withdrawing informed consent (participants decide to 
withdraw for any reason); b) Any clinical adverse events, abnormal laboratory 
test results, or comorbidities identified by the researchers that are not in the 
best interest of the participants to continue receiving treatment and 
participating in the study; c) Inability to follow the study protocol. 
6. What are the available treatment options? If you do not agree to participate in 
this study, you can choose from ADT monotherapy, ADT combined with 
abiraterone, or ADT combined with docetaxel. To determine which treatment 
option is more suitable for you, you can further consult with the specialist in 
the outpatient department. 
7. What are the risks of participating in the study? The use of darolutemide, ADT, 
and docetaxel in this study may have potential side effects, including: 

 
Diarrhea: Participants should be closely monitored for signs and clinical 
symptoms of colitis, such as diarrhea, abdominal pain, bloody or mucous 
stools, and fever. In symptomatic participants, infection should be ruled out, 
and if the symptoms persist and/or are severe, an endoscopic evaluation should 
be considered. It is recommended that participants with diarrhea drink plenty 
of water. If adequate fluid intake cannot be achieved through oral intake, fluid 
and electrolyte replacement should be administered intravenously. 
 
Anemia: Blood transfusion and hematopoietic growth factors may be used 
under the guidance of the researchers. 
 
Neutropenia: Granulocyte colony-stimulating factor (G-CSF) can be used to 
treat grade 3-4 febrile neutropenia. 
 
Bone pain: Bisphosphonates can be used to reduce the occurrence of bone 
disease, bone pain, and fractures under the guidance of the researchers. In 
addition, non-opioid analgesics can be used for symptomatic treatment. 
 
Anti-infective drugs: Participants with documented complications of infection 
can be administered oral or intravenous antibiotics or other anti-infective 
drugs according to standard hospital treatment protocols. 
 
Seizures: In the event of status epilepticus, intravenous diazepam 10 mg, rapid 
intravenous infusion of 20% mannitol, or intravenous dexamethasone 10-20 
mg should be administered to prevent and treat brain edema. Blood glucose, 
electrolytes, arterial blood gas, and body temperature should be checked, and 
symptomatic treatment should be provided if abnormalities are detected. 
We will monitor your hematological and non-hematological toxicities through regular 
examinations, observe the efficacy of the drug, and take appropriate measures for 
symptomatic treatment of adverse events. If you experience any discomfort or adverse 
reactions, please contact the research doctor promptly. Since enzalutamide, ADT, and 
docetaxel are conventional treatments for prostate cancer in clinical practice, there is a 
possibility of experiencing these side effects/adverse reactions even if you do not 
participate in this clinical study. In addition, any treatment may be ineffective, and the 
disease may continue to progress due to treatment failure or the presence of other 
comorbidities. 
8. 
What are the potential benefits of participating in the research? By 
participating in this study, there is a possibility that your condition may 
improve (or it may not). This research also helps determine which treatment 
methods can effectively and safely treat other patients with similar conditions 
to yours. 
9. 
Are there any costs associated with participating in the research? 
The cost of medications and related examinations used in the study, as well as 
outpatient fees, transportation costs, medication costs, and examination fees, 
are the responsibility of the patient. There are no other subsidies. If any harm 

occurs as a result of the trial, appropriate treatment and compensation will be 
provided according to relevant national regulations. 
10. Compensation: a) Compensation for participating in the study There 
will be no financial compensation for participating in this study or 
reimbursement of treatment-related costs. 
11. Is personal information kept confidential? The results of this 
research project may be published in medical journals with the understanding 
and assistance of you and other participants. However, we will keep your 
research records confidential as required by law. The personal information of 
research participants will be strictly protected, and your personal information 
will not be disclosed unless required by relevant laws. When necessary, 
government authorities, hospital ethics committees, and other relevant 
researchers may have access to your data according to regulations. 
12. Am I required to participate in the research? Participating in this 
study is completely voluntary. You have the right to refuse participation or 
withdraw from the study at any stage without discrimination or retaliation, and 
your medical treatment and rights will not be affected. If you decide to 
withdraw from this study, please contact your doctor for appropriate diagnosis 
and treatment of your condition. 
13. What other treatment options are available if I don't participate in 
this research? If you do not agree to participate in this study, you can choose 
between ADT monotherapy, ADT combined with abiraterone, or ADT 
combined with docetaxel. To determine which treatment option is more 
suitable for you, you can further consult with the attending expert in the 
outpatient clinic. 
14. Who can I consult if I have questions? If you have any questions 
regarding research information and participant rights or if any research-related 
harm occurs, you can contact the researchers and the ethics committee along 
with their contact details. Researchers: Lixin Hua; Shangqian Wang, phone: 
13770561625; Medical Ethics Committee of Jiangsu People's Hospital, phone: 
025-68306360. 
  
 
 

Informed Consent Form 
Signature page 
 
Subject's Declaration: I have read the introduction to this study and my research 
personnel have fully explained and clarified the purpose, procedures, potential risks, 
and potential benefits of participating in this study, and have answered all my relevant 
questions. I voluntarily agree to participate in this study. 
I agree □ or refuse □ to allow my research data and biological samples to be used for 
other studies besides this research. 
Subject's Printed Name: Subject's Signature: Date: __________ Year __________ 
Month __________ Day Subject's Contact Phone Number: Mobile Number: 
_______________ 
Legal Guardian's Printed Name: (if applicable) Relationship with the subject: 
Legal Guardian's Signature: Date: __________ Year __________ Month __________ 
Day Reason for the legal guardian's signature: 
Witness's Printed Name: (if applicable) Witness's Signature: Date: __________ Year 
__________ Month __________ Day Reason for witness's signature: 
Doctor's Statement: I have explained the relevant details of this study to the volunteer 
participating in this study and provided them with an original signed informed consent 
form. I confirm that I have provided a detailed explanation of the study, particularly 
regarding the ethical principles and requirements of risks and benefits, free 
participation, compensation, harm and compensation, voluntary participation, and 
confidentiality. 
Doctor's Signature: Date: __________ Year __________ Month __________ Day 
Doctor's Contact Phone Number: 
Medical Ethics Committee, Jiangsu Provincial People's Hospital, Contact Phone 
Number: 025-68306360