Evaluating the Efficacy and Safety of Cytoreductive Prostatectomy Combined With Triple or Dual Systemic Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer
Phase: PHASE3
Conditions: Metastatic Prostate Cancer, Therapy, Directly Observed
Sponsor: The First Affiliated Hospital with Nanjing Medical University

Official title：Evaluating the Efficacy and Safety of Cytoreductive Prostatectomy
combined with Triple or Dual Systemic therapy in patients with Metastatic
Hormone-Sensitive Prostate Cancer
Date: March 20, 2024

Research Purpose: The primary research purpose is to evaluate:
The radiographic progression-free survival (rPFS) of metastatic hormone-sensitive
prostate cancer (mHSPC) patients treated with androgen deprivation therapy (ADT) +
second-generation antiandrogens ± chemotherapy combined with cytoreductive
prostatectomy (CRP).
Secondary research purposes include:
1)
Evaluating the safety of CRP in mHSPC patients during the perioperative period.
2)
Asse
ssing other efficacy indicators of ADT + second-generation antiandrogens ±
chemotherapy combined with CRP in treating mHSPC, including time to PSA
recurrence, time to castration-resistant prostate cancer (CRPC), overall survival
(OS), overall survival rate, postoperative complication rate, and quality of life
score assessed by the EORTC QLQ-C30 questionnaire.
Study Endpoints
1) The primary endpoint is rPFS.
Secondary endpoints include:
Safety endpoints: AE incidence, severity, abnormal laboratory indicators.
Efficacy endpoints: Time to PSA recurrence, time to CRPC, OS, overall survival rate,
postoperative complication rate, and quality of life score assessed by the EORTC
QLQ-C30 questionnaire.
Study Population: Patients with metastatic hormone-sensitive prostate cancer
(mHSPC). Sample Size Determination: Subjects will be randomly assigned in a 1:1
ratio to receive either cytoreductive prostatectomy (CRP) combined with ADT+
second-generation
antiandrogens
±
chemotherapy
(Group
A)
or
ADT+
second-generation antiandrogens ± chemotherapy (Group B). Each group plans to
enroll 100 cases, for a total of 200 cases.
Study Design: This trial is a multicenter, prospective, randomized controlled clinical
study aimed at evaluating the effectiveness and safety of cytoreductive prostatectomy
combined with ADT + second-generation antiandrogen ± chemotherapy in the
treatment of metastatic hormone-sensitive prostate cancer. The plan is to include 200
eligible subjects.
Group A: Subjects will orally take one of the second-generation antiandrogen
drugs (240 mg of apalutamide once daily; 240 mg of Rezvilutamide once daily; 600
mg of darolutamide twice daily; 240 mg of enzalutamide once daily; 1000 mg of
abiraterone once daily + 5 mg of prednisone twice daily), while also receiving LHRH
analogs or LHRH antagonists for ADT treatment for at least 6 months. PSA and
serum testosterone concentrations will be measured at 4 weeks, 3 months, and 6
months. Imaging examinations will be performed again at 6 months to assess the
treatment response to ADT. Patients with PSA levels below 1.0 ng/ml, relief or
stabilization of bone metastases, and no new lymph node or visceral metastases will
be considered for CRP treatment.

Group B: Subjects will orally take one of the second-generation antiandrogen drugs
(240 mg of apalutamide once daily; 600 mg of darolutamide twice daily; 240 mg of
enzalutamide once daily; 1000 mg of abiraterone once daily + 5 mg of prednisone
twice daily), while also receiving LHRH analogs for ADT treatment. During the
subjects' treatment, dose adjustments can be made in the event of intolerable toxic
reactions (see dose adjustment plan for details). If the symptoms are not relieved after
dose
adjustment,
the
experimental
drug
treatment
should
be
discontinued.
Stratification factors include: 1) Visceral metastases; 2) Tumor burden. High tumor
burden is defined as meeting at least one of the following conditions: 1) Bone scan
indicating ≥6 bone metastases (with at least one outside the pelvis or spine); 2)
CT/MRI revealing visceral metastases (excluding lymph nodes).
Inclusion Criteria:
Patients must meet all of the following criteria to be included in this trial: (1) Male
aged ≥18 and ≤75; (2) Histologically confirmed prostate adenocarcinoma; (3)
Evidence of metastasis confirmed by magnetic resonance imaging (MRI)/computed
tomography (CT) scan, bone scan, or histology; (4) Clinical stage M1a (distant lymph
node positive), M1b (bone metastasis), or M1c (visceral organ metastasis); (5)
Prostate cancer has not received local treatment (e.g., prostate radiotherapy,
cryotherapy, etc.); (6) The surgeon believes the prostate can be removed; (7) Initiation
of Androgen Deprivation Therapy (LHRH agonist/LHRH antagonist) treatment, with
or without combined anti-androgen therapy, for no more than 12 weeks prior to
randomization; (8) ECOG performance status of 0 or 1; (9) Laboratory tests meet the
following requirements:Hematology: neutrophil absolute count ≥1.5×10^9/L, platelet
count ≥100×10^9/L, hemoglobin ≥9.0g/dL;
Renal function: serum creatinine≤1.5×ULN;Hepaticfunction:alanine aminotransferase
(ALT) and aspartate aminotransferase (AST) ≤2.5×ULN, total bilirubin (TBIL)
≤1.5×ULN;
Left
ventricular
ejection
fraction
at
least
50%;
(10)
Voluntary
participation with the subject's own informed consent.
Exclusion Criteria: Patients with any of the following cannot be included in this
study: (1) The surgeon believes the disease is unresectable; (2) Initiation of Androgen
Deprivation Therapy (ADT) treatment, with or without combined anti-androgen
therapy, for more than 12 weeks; (3) Life expectancy less than 2 years; (4) Active
spinal cord compression; (5) History of prior local treatment for prostate cancer; (8)
Planned receipt of other anti-tumor therapy during the study treatment period; (9)
Known allergy to the above drug components; (10) Difficulty swallowing, chronic
diarrhea, intestinal obstruction, and other factors affecting drug intake and absorption;
(11) Diseases with a possibility of experiencing seizures within 12 months prior to
C1D1 (including transient ischemic attack, stroke, and consciousness disorders
requiring hospitalization); (12) Active cardiac disease within 6 months prior to C1D1,
including severe/unstable angina, myocardial infarction, symptomatic congestive
heart failure; (13) Other malignant tumors within 5 years before C1D1 (excluding
completely cured in situ cancer and tumors judged by the investigator to progress
slowly); (14) Unwillingness to adopt effective contraception during the entire study
treatment period and within 30 days after the last dose; (15) Presence of comorbidities
(such
as
poorly
controlled
hypertension,
severe
diabetes,
neurological
or
psychological disorders, etc.) or other situations that may have serious consequences;
(16) Refusal to sign the informed consent; (17) Investigator believes the individual is
not suitable for inclusion.
Termination of Research Treatment Criteria:

Researchers may decide to terminate the investigational drug treatment for
subjects in the following circumstances:
1. The subject withdraws informed consent to continue the research treatment;
2. The subject meets the criteria for radiographic disease progression (as
determined by RECIST 1.1 and modified PCWG3 criteria);
3. Bone-related events (such as radiation or surgery for bones, pathological
fractures, spinal cord compression, or changes in anti-tumor treatment to
relieve bone pain);
4. Any clinical adverse reactions, abnormal laboratory tests, or concurrent
diseases, etc., which the researcher believes continuing the research is not in
the best interest of the patient;
5. Other necessary situations where the researcher believes it is necessary to
withdraw from the study.
Safety assessment:
Safety assessment is conducted using the NCI-CTC AE 5.0 standard. From the time of
the subject's signing of the informed consent form until 30 days after the last dose, all
adverse events (AEs) of the subjects are observed and recorded, including clinical
symptoms, vital sign abnormalities, abnormalities in laboratory tests, and their
correlation with the investigational drug. Subjects undergo safety assessments during
the screening period, baseline, and post-dosing, including physical examinations,
ECOG performance status assessment, laboratory tests, and electrocardiogram
examinations. Unscheduled visits may be conducted based on the occurrence of
subject AEs, in addition to the scheduled visits as per the protocol.
Efficacy assessment:
1. rPFS;
2. Time to biochemical progression-free survival;
3. Time to castration-resistant prostate cancer (CRPC);
4. Overall survival (OS), overall survival rate;
5. Incidence of postoperative complications;
6. Quality of life assessment using the EORTC QLQ-C30 questionnaire.
Statistical methods:
Data Set Analysis
Full Analysis Set (FAS): The most complete and representative set of subjects,
including all randomized subjects as much as possible.

Per Protocol Set (PPS): Within the FAS, it includes subjects with primary
endpoint data, good compliance, and no major protocol violations.
Safety Set (SS): The set of subjects who have received the investigational drug at
least once and have safety assessment data.
- Efficacy Analysis
FAS and PPS will be used, with priority given to FAS results. The secondary
efficacy endpoints for each group will be calculated separately.
Study timeline: The study aims to complete enrollment within 3 years and the overall
trial within 5 years.

Informed Consent Form
We invite you to participate in a multicenter, randomized, open-label clinical study
titled " Clinical study assessing the efficacy and safety of cytoreductive prostatectomy
in combination with dual/triple therapy for 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 research purpose is to evaluate:

The radiographic progression-free survival (rPFS) of metastatic hormone-sensitive
prostate cancer (mHSPC) patients treated with androgen deprivation therapy (ADT) +
second-generation antiandrogens ± chemotherapy combined with cytoreductive
prostatectomy (CRP).
What do you need to do if you participate in the study?
This study is a multicenter, randomized,
open-label clinical trial. It evaluates
whether the ADT + second-generation antiandrogens ± chemotherapy combined
with CRP improves radiographic progression-free survival (rPFS) in patients with
metastatic hormone-sensitive prostate cancer (mHSPC) compared to the patients
without surgery. The experimental group will receive second-generation antiandrogen
drugs (240 mg of apalutamide once daily; 600 mg of darolutamide twice daily; 240
mg of enzalutamide once daily; 1000 mg of abiraterone once daily + 5 mg of
prednisone twice daily), while also receiving LHRH analogs or LHRH antagonists for
ADT treatment for at least 6 months. PSA and serum testosterone concentrations will
be measured at 4 weeks, 3 months, and 6 months. Imaging examinations will be
performed again at 6 months to assess the treatment response to ADT. Patients with
PSA levels below 1.0 ng/ml, relief or stabilization of bone metastases, and no new
lymph node or visceral metastases will be considered for CRP treatment or
brachytherapy. The entire study plans to enroll 200 patients with high tumor burden
mHSPC, who will be randomly assigned in a 1:1 ratio to the experimental and control
groups.
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.
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 drugs in experimental group include
Rezvilutamide, Darolutamide, Apalutamide, Abiraterone, LHRH agonist, LHRH

antagonist and docetaxel (for 6 cycles), followed by local treatment for primary tumor,
while the control group will receive the following drugs without local treatment.
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.
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:
Patients must meet all of the following criteria to be included in this trial: (1) Male
aged ≥18 and ≤75; (2) Histologically confirmed prostate adenocarcinoma; (3)
Evidence of metastasis confirmed by magnetic resonance imaging (MRI)/computed
tomography (CT) scan, bone scan, or histology; (4) Clinical stage M1a (distant lymph
node positive), M1b (bone metastasis), or M1c (visceral organ metastasis); (5)
Prostate cancer has not received local treatment (e.g., prostate radiotherapy,
cryotherapy, etc.); (6) The surgeon believes the prostate can be removed; (7) Initiation
of Androgen Deprivation Therapy (LHRH agonist/LHRH antagonist) treatment, with
or without combined anti-androgen therapy, for no more than 12 weeks prior to
randomization; (8) ECOG performance status of 0 or 1; (9) Laboratory tests meet the
following requirements:Hematology: neutrophil absolute count ≥1.5×10^9/L, platelet
count ≥100×10^9/L, hemoglobin ≥9.0g/dL;
Renal function: serum creatinine≤1.5×ULN;Hepaticfunction:alanine aminotransferase
(ALT) and aspartate aminotransferase (AST) ≤2.5×ULN, total bilirubin (TBIL)
≤1.5×ULN;
Left
ventricular
ejection
fraction
at
least
50%;
(10)
Voluntary
participation with the subject's own informed consent.
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.
Who should not participate in the study? (Exclusion criteria) You should not
participate in this study if you have any of the following conditions:
(1) The surgeon believes the disease is unresectable; (2) Initiation of Androgen
Deprivation Therapy (ADT) treatment, with or without combined anti-androgen
therapy, for more than 12 weeks; (3) Life expectancy less than 2 years; (4) Active
spinal cord compression; (5) History of prior local treatment for prostate cancer; (8)
Planned receipt of other anti-tumor therapy during the study treatment period; (9)
Known allergy to the above drug components; (10) Difficulty swallowing, chronic
diarrhea, intestinal obstruction, and other factors affecting drug intake and absorption;
(11) Diseases with a possibility of experiencing seizures within 12 months prior to
C1D1 (including transient ischemic attack, stroke, and consciousness disorders
requiring hospitalization); (12) Active cardiac disease within 6 months prior to C1D1,
including severe/unstable angina, myocardial infarction, symptomatic congestive
heart failure; (13) Other malignant tumors within 5 years before C1D1 (excluding
completely cured in situ cancer and tumors judged by the investigator to progress
slowly); (14) Unwillingness to adopt effective contraception during the entire study
treatment period and within 30 days after the last dose; (15) Presence of comorbidities
(such as poorly controlled hypertension, severe diabetes, neurological or

psychological disorders, etc.) or other situations that may have serious consequences;
(16) Refusal to sign the informed consent; (17) Investigator believes the individual is
not suitable for inclusion.
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 enzalutamide, 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 the regime in
control group.
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