Evaluation of triplet therapy combined with robot‐assisted cytoreductive prostatectomy for high‐volume metastatic prostate cancer: a multicentre randomised controlled trial protocol

Abstract

Background

Prostate cancer (PCa) is the second most common cancer in men. For patients with high‐volume metastatic PCa (mPCa) who are fit for docetaxel, a triplet therapy regimen consisting of androgen deprivation therapy (ADT), chemotherapy, and an androgen receptor pathway inhibitor (ARPI) is recommended. Adding local radiotherapy to triplet therapy has been shown to alleviate symptoms and reduce disease progression. However, the benefit of combining triplet therapy with local surgery remains unclear and warrants further investigation in the present study.

Study Design

This is an open‐label, prospective, two‐arm, multicentre, randomised controlled trial.

Endpoints

Primary endpoints are progression‐free survival (PFS) and the 1‐year PFS rate. Disease progression is defined as prostate‐specific antigen (PSA) progression, radiological progression, or unequivocal clinical progression. Secondary endpoints include overall survival (OS) and health‐related quality of life (HRQoL).

Patients and Methods

Patients aged 18–75 years with high‐volume mPCa will receive ADT (triptorelin 15 mg every 3 months), four–six cycles of chemotherapy (docetaxel 75 mg/m² every 3 weeks), and an ARPI (rezvilutamide 240 mg once daily). Patients achieving a PSA level ≤0.2 ng/mL and deemed suitable candidates for surgery will be enrolled. A total of 88 eligible patients will be randomised in a 1:1 ratio. The control group will continue treatment with triptorelin and rezvilutamide, while the experimental group will receive robot‐assisted cytoreductive prostatectomy in addition to triptorelin and rezvilutamide. Baseline PSA levels will be recorded and re‐examined at each chemotherapy cycle and every 3 months thereafter. Radiological evaluations will be performed every 6 months. Clinical progression will be assessed based on pain severity, performance status, and the need to initiate new anticancer therapy. HRQoL will be evaluated every 3 months. PFS and OS will be estimated using Kaplan–Meier curves and compared with the log‐rank test.

Trial Registration

Chinese Clinical Trial Registry: ChiCTR2600121819

Abbreviations

ADT

androgen deprivation therapy

ARPI

androgen receptor pathway inhibitor

BMI

body mass index

CRP

cytoreductive prostatectomy

CTC

circulating tumour cell

DSMC

Data and Safety Monitoring Committee

EAU

European Association of Urology

ECOG

Eastern Cooperative Oncology Group

EORTC

European Organisation for Research and Treatment of Cancer

NCCN

National Comprehensive Cancer Network

OS

overall survival

(m)PCa

(metastatic) prostate cancer

PET

positron emission tomography

PFS

progression‐free survival

PLND

pelvic lymph node dissection

PS

performance status

PSMA

prostate‐specific membrane antigen

QLQ‐C30

Quality of Life Questionnaire Core 30

QLQ‐PR25

Quality of Life Questionnaire Prostate Cancer 25 Items

(HR)QoL

(health‐related) quality of life

RCT

randomised controlled trial

RT

radiotherapy

SOC

standard of care

TME

tumour microenvironment

ULN

upper limit of normal

Background

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, with an estimated 1 466 680 new cases and 396 792 deaths worldwide in 2022 [1]. The risk of PCa increases with age, and the median age at diagnosis is 67 years [2]. About 10% of newly diagnosed PCa cases present with distant metastases [2]. The most common site of metastasis is bone (82%), followed by non‐regional lymph nodes (34%) and visceral organs (5%) [3]. Metastasis significantly worsens prognosis, with median overall survival (OS) of 24 months for bone metastases, 16 months for visceral metastases, and 14 months for combined bone and visceral metastases [4]. Although the median OS of patients with de novo metastatic PCa (mPCa) has improved substantially with the adoption of novel treatment paradigms [5], the incidence of mPCa has continued to rise in recent years [6], imposing a considerable economic burden on healthcare systems and society [7]. The European Association of Urology (EAU) [8] and National Comprehensive Cancer Network (NCCN) guidelines [9] recommend androgen deprivation therapy (ADT) combined with an androgen receptor pathway inhibitor (ARPI) or triplet therapy consisting of ADT, an ARPI, and docetaxel chemotherapy as first‐line treatment options for mPCa. The recommendation for triplet therapy in patients who are fit for docetaxel is supported by the findings of the PEACE‐1 (ClinicalTrials.gov identifier: NCT01957436) [10] and ARASENS (NCT02799602) [11] phase III trials.

The treatment of the primary tumour in mPCa has been a subject of ongoing debate for several years [12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]. In the HORRAD trial (International Standard Randomised Controlled Trial Number [ISRCTN] Registry identifier: ISRCTN06890529) [12], the addition of radiotherapy (RT) to ADT in patients with mPCa was associated with a prolonged time to PSA progression, although no OS benefit was observed. The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial [13] confirmed that RT to the primary tumour did not improve OS in unselected patients. However, in subgroup analyses stratified by the ChemoHormonal therapy versus Androgen Ablation Randomized Trial for Extensive Disease in prostate cancer (CHAARTED) criteria [23], adding RT to the standard of care (SOC) significantly improved OS and failure‐free survival in patients with low‐volume disease, with acceptable toxicity and no detrimental effect on quality of life (QoL) [13, 18]. The STOPCAP meta‐analysis [14], which pooled data from the HORRAD and STAMPEDE trials, demonstrated that the survival benefit of adding prostate RT to ADT was restricted to men with four or fewer bone metastases. The PEACE‐1 trial [15] showed that combining prostate RT with SOC significantly prolonged progression‐free survival (PFS) and castration resistance‐free survival in patients with low‐volume mPCa, and that RT reduced the incidence of serious genitourinary events irrespective of metastatic burden without increasing overall treatment‐related toxicity. Similarly, a systematic review of nine retrospective studies reported that pelvic RT effectively relieved local symptoms in patients with PCa, such as pain, haematuria, and urinary obstruction [19]. Both the EAU [8] and NCCN guidelines [9] recommend adding prostate RT for patients with low‐volume mPCa. In patients with high‐volume disease, local RT may also be considered given its efficacy in reducing disease progression and ameliorating local symptoms, as well as its wide availability, favourable safety profile, and cost‐effectiveness [20].

Cytoreductive prostatectomy (CRP) conferred significant OS and cancer‐specific survival benefits comparable to those of prostate RT and superior to those of no local treatment in patient with newly diagnosed low‐volume mPCa, according to an analysis of data from a multicentre prospective cancer registry [16]. In a randomised controlled trial (RCT), men with oligometastatic PCa (defined as five or fewer bone or extrapelvic lymph node metastases without detectable visceral metastases) who received ADT plus local treatment (primarily CRP) had significantly higher radiographic PFS and OS rates than those treated with ADT alone [17]. The RAMPP randomised trial (NCT02454543), which enrolled 132 patients with oligometastatic PCa, demonstrated that the addition of CRP to SOC significantly reduced cancer‐specific mortality [21]. Results from 13 European centres showed that CRP in patients with oligometastatic PCa was associated with favourable short‐term survival outcomes, satisfactory functional results, and acceptable complication rates [22]. Therefore, as part of a multimodal treatment strategy, CRP represents a feasible option for men with low‐volume mPCa [24]. However, whether the addition of CRP to SOC confers a survival benefit and improves QoL in patients with high‐volume mPCa remains unclear.

Several biological mechanisms provide a rationale for adding CRP to SOC for patients with mPCa [25, 26, 27, 28, 29]. Multifocal whole‐genome sequencing has demonstrated that clonal tumour cells in patients with PCa can disseminate via both primary‐to‐metastasis and metastasis‐to‐metastasis routes [25]. Primary tumour‐derived circulating tumour cells (CTCs) contribute to metastasis not only through directly seeding but also by remodelling the pre‐metastatic niche, creating a favourable microenvironment for tumour cell invasion and colonisation [26]. Primary tumours can secrete inflammatory interleukins that attract CTCs back to their site of origin, where they alter the tumour microenvironment (TME) by releasing cytokines and matrix metalloproteinases, thereby driving aggressive local tumour growth and promoting intratumoral angiogenesis [27]. Disseminated tumour cells from secondary distant sites can also return to their tumour of origin to remodel the TME and promote primary tumour growth [27], or facilitate metastatic outgrowth by secreting paracrine interleukin‐6, which activates MYC (a proto‐oncogene) through Signal Transducer and Activator of Transcription 3 (STAT3) signalling [28]. Besides, a population‐based analysis encompassing 38 921 prostate biopsies showed that higher tumour volume was associated with an increased mutational burden and worse genomic features in patients with Grade Group 2–5 PCa [29]. Thus, reducing tumour burden through cytoreductive strategies may theoretically prevent or delay the development of new metastatic lesions. This hypothesis is supported by data from two prospective trials, which demonstrated that patients with PCa who experienced a decline in CTC counts had improved survival outcomes [30].

In this study, we will investigate the effectiveness of triplet therapy combined with robot‐assisted CRP in patients with high‐volume mPCa. The primary endpoints are PFS and the 1‐year PFS rate. The secondary endpoints include OS and health‐related QoL (HRQoL). We hypothesise that the combination of triplet therapy and CRP will improve both survival and HRQoL in this patient population.

Study Design

This is an open‐label, prospective, two‐arm, multicentre RCT. Ethical approval has been obtained from the Medical Ethics Committee of the Seventh Affiliated Hospital of Sun Yat‐sen University (KY‐2025‐500‐02). Any modifications to the research protocol or the informed consent document will require formal approval from the committee prior to their implementation in the study. The trial has been registered with the Chinese Clinical Trial Registry (ChiCTR2600121819). The study will be conducted in accordance with local regulations, the Declaration of Helsinki, and Good Clinical Practice guidelines. Written informed consent will be obtained from all patients after they have received a full explanation of the study purpose, potential risks and benefits, and their rights to confidentiality and withdrawal at any time. Study findings will be disseminated through peer‐reviewed journals and conference presentations.

An independent Data and Safety Monitoring Committee (DSMC) comprising two clinicians with expertise in PCa treatment, a statistician, a pharmacologist, and an ethicist will be established to oversee the safety and efficacy of the trial. DSMC members will not be directly involved in the conduct of the study. The DSMC will meet at least every 6 months to review study progress and safety data. In the event of unacceptable toxicity or other significant safety concerns, the DSMC may recommend early termination of the trial. The principal investigator will consider the DSMC's recommendations and make the final decision. This study protocol was developed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines.

Endpoints

Primary Endpoints

The primary endpoints are PFS (defined as the time from randomisation to the first documented disease progression or death from any cause [31]) and the 1‐year PFS rate. According to the 2026 EAU guidelines [8], disease progression in mPCa is defined by castrate levels of serum testosterone (<50 ng/dL or 1.7 nmol/L) in combination with either PSA progression, radiological progression, or unequivocal clinical progression. PSA progression is defined as three consecutive rises in PSA, each measured at least 1 week apart, resulting in two 50% increases over the nadir and a final PSA level >2 ng/mL [8]. Radiological progression is defined as the appearance of two or more new bone lesions on bone scan or prostate‐specific membrane antigen (PSMA)‐positron emission tomography (PET) [32], or a new soft tissue lesion as assessed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [33]. Unequivocal clinical progression refers to clinically meaningful deterioration attributable to cancer progression, including worsening cancer‐related pain, decline in performance status (PS), or the need to initiate new systemic or local anticancer therapy [32]. We will use the Brief Pain Inventory (BPI) [34] to assess pain severity on a scale from 0 to 10, where 0 indicates no pain and 10 represents the worst pain imaginable. PS will be evaluated using the Eastern Cooperative Oncology Group (ECOG) criteria [35], which grades patients on a scale from 0 to 5, with higher scores indicating greater functional impairment. The 1‐year PFS rate is defined as the proportion of patients who remain free from disease progression at 12 months.

Secondary Endpoints

The secondary endpoints include OS and HRQoL. OS is defined as the time from randomisation to death from any cause [36]. HRQoL will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ‐C30) [37] and Prostate Cancer 25 Items (QLQ‐PR25) [38]. The EORTC QLQ‐C30 is a validated 30‐item instrument designed to assess physical, emotional, and social functioning as well as symptoms in patients with cancer [37]. The EORTC QLQ‐PR25 is a 25‐item module specifically developed and validated for patients with PCa, covering urinary symptoms, bowel symptoms, sexual functioning, and treatment‐related side effects [38].

Eligibility Criteria

Inclusion Criteria

• Aged 18–75 years.

• Diagnosed with high‐volume mPCa (defined as visceral metastases or four or more bone lesions with at least one beyond the vertebral bodies and pelvis [23]).

• Histologically confirmed adenocarcinoma (accounting for ~95% of all PCa cases [39]).

• Fully informed of the purpose and risks of the study and provided signed written informed consent.

• An ECOG PS score of 0 or 1.

• A PSA level ≤0.2 ng/mL after four to six cycles of docetaxel chemotherapy. In a RCT evaluating the association between PSA and OS in men with mPCa, a PSA ≤0.2 ng/mL at 7 months was identified as a prognostic marker for longer OS [40].

Exclusion Criteria

• Presence of chemotherapy contraindications [41], including allergy to docetaxel, neutrophil count <1500 cells/mm³, bilirubin >upper limit of normal (ULN), alanine aminotransferase and/or aspartate aminotransferase >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN.

• Diagnosis of concomitant malignancies.

• Presence of severe major organ diseases, poorly controlled blood glucose, or inability to tolerate surgery.

• Any other clinical or laboratory conditions that would make the patient unsuitable for study participation.

• Concurrent enrolment in another therapeutic trial.

• Any psychological, familial, sociological, or geographical condition that may hamper compliance with the study protocol and follow‐up schedule.

Methods

Interventions

Patients with high‐volume mPCa admitted to the Seventh Affiliated Hospital of Sun Yat‐sen University, Dalang Hospital, or Changan Hospital will be offered triplet therapy if deemed fit for docetaxel chemotherapy. ADT will be administered with triptorelin (15 mg every 3 months), and rezvilutamide (240 mg once daily) will be used as the ARPI [8]. Docetaxel will be administered at 75 mg/m² every 3 weeks, with oral dexamethasone 8 mg given 12, 3, and 1 h before each docetaxel infusion. Prednisone 10 mg daily will be prescribed throughout the chemotherapy period. In the event of Grade 4 haematological toxicity or Grade ≥3 non‐haematological toxicity, the docetaxel dose will be reduced to 60 mg/m². After completion of four to six cycles of chemotherapy, participants who meet the eligibility criteria will be enrolled and randomised in a 1:1 ratio. The control group will continue treatment with triptorelin and rezvilutamide, while the experimental group will receive robot‐assisted CRP in addition to triptorelin and rezvilutamide (Fig. 1). Pelvic lymph node dissection (PLND) will be performed concurrently with robot‐assisted CRP, as evidence suggests that PLND at the time of CRP is associated with reduced cancer‐specific and overall mortality in the setting of mPCa, without increasing the risk of perioperative complications [42]. Both CRP and PLND will be performed by Jun Pang, an experienced high‐volume urologist with extensive expertise in robot‐assisted prostate surgery, at the Seventh Affiliated Hospital of Sun Yat‐sen University. We use the Clavien–Dindo classification to grade the severity of any surgical complications that arise [43]. All participants with bone metastasis are to receive denosumab or bisphosphonates, along with calcium and vitamin D supplementation, to reduce the risk of fractures, spinal cord compression, or other skeletal‐related events. A standard operating procedure will be developed prior to study initiation to provide step‐by‐step instructions for staff on the proper conduct of the study.

Fig. 1.

Study flowchart.

Sample Size Calculation

The sample size was calculated based on the primary endpoint of PFS, using the log‐rank test implemented in PASS V.15 (NCSS, Kaysville, USA). Under a superiority design with a 1:1 randomisation ratio, a one‐sided significance level of 0.05, a statistical power of 80%, and an assumed hazard ratio of 0.50 [10] for disease progression in the experimental group relative to the control group, a total of 70 patients were required. To account for an anticipated dropout rate of ~20%, the target sample size was increased to 88 patients. Of these, 68 patients will be recruited from The Seventh Affiliated Hospital of Sun Yat‐sen University and 10 patients each from Dalang Hospital and Changan Hospital.

Randomisation

A randomisation sequence comprising 88 allocations was generated by a clinical research assistant using SPSS®, version 31 (IBM Corp., Armonk, NY, USA). The study investigator will assign participants in a 1:1 ratio using sealed envelopes containing the randomisation sequence and group allocations.

Blinding

Given the nature of the intervention, blinding of the study participants and clinical staff was deemed not feasible. Thus, this study is open‐label.

Study Visits

The study will be conducted over a 2‐year period (July 2025 to June 2027). Specific milestones will be achieved and documented as outlined in Table 1. Baseline PSA levels will be recorded and subsequently re‐examined at each chemotherapy cycle and every 3 months thereafter. Pain severity and HRQoL will be assessed every 3 months until disease progression, death, or study completion. Radiological evaluations will be performed every 6 months. In case of Grade 3 or 4 haematological toxicity, colony‐stimulating factors will be administered. The investigators may perform additional examinations and treatments at their discretion. To promote retention and adherence, participants will receive ¥100 upon completion of the baseline enrolment visit and an additional ¥100 for each subsequent return visit. Any physical injury or harm directly resulting from study participation will be promptly evaluated and treated, and compensation will be provided in accordance with applicable laws and regulations.

Table 1.

Timeline and follow‐up of the study.

	Screening	Treatment	Follow‐up
		At each chemotherapy cycle	Every 3 months	Every 6 months
Patient consent	×
Demographics	×
History and physical	×	×	×
PS score	×	×	×
BMI	×	×	×
Blood cell counts	×	×	×
Blood biochemistry	×	×	×
PSA	×	×	×
Testosterone	×	×	×
CT/MRI	×			×
Bone scan/PSMA‐PET	×			×
Pain assessment	×	×	×
HRQoL	×	×	×

Data Collection and Management

A case report form has been prepared for data collection. Baseline data will be recorded based on medical records or specific worksheets, mainly including sociodemographic characteristics (age, marriage status, occupation, education level, etc.), health characteristics (body mass index [BMI], PS score, signs and symptoms, HRQoL, history of previous treatments, smoking habits, alcohol consumption, comorbidities, etc.), laboratory tests (blood cell counts, blood biochemistry, PSA, testosterone, etc.), and radiographic examinations (chest and abdominal CT and pelvic MRI, bone scan, PSMA‐PET). Disease stage, grade, and EAU risk groups will also be recorded. Laboratory tests and radiographic examinations will be repeated during the follow‐up as scheduled, as well as the assessment of pain severity and HRQoL. All data will be cross‐checked independently by two investigators, and the data on hard copies will be stored in a locked cabinet, while soft copies will be stored in an encrypted hard disk. All data collected will be used for research purposes only, and only the investigators will have access to the data. All data will be destroyed 5 years after the completion of the study.

Statistical Analyses

Two investigators will participate in the statistical process. Frequencies of events will be analysed using Pearson's chi‐squared test or Fisher's exact test, and continuous variables will be analysed by Student's t‐test or non‐parametric tests in case of a non‐normal distribution. The median PFS and OS will be estimated with the Kaplan–Meier method, and survival will be compared between groups using the log‐rank test. Patients without progression, documented death or lost to follow‐up at the time of analysis will be censored at the time of the latest assessment. A Cox proportional hazards regression model will be used to analyse the association between the survival time of the patients and the predictor variables, and the hazard ratio will be given with its 95% CI. Missing data will be statistically analysed using the last observation carried forward method. All statistical analyses will be performed using Stata release 18 (StataCorp., College Station, TX, USA). A two‐tailed P ≤ 0.05 will be considered statistically significant.

Discussion

This trial is the first multicentre RCT to evaluate the effectiveness of triplet therapy combined with robot‐assisted CRP for the treatment of high‐volume mPCa. The results are expected to provide critical evidence supporting the addition of CRP to the current standard treatment strategy, with the aim of improving survival outcomes and QoL in patients with high‐volume mPCa. Perioperative complications are expected to be minimal, as previous studies encompassing robot‐assisted, laparoscopic, and open approaches have shown that CRP carries acceptable complication rates [22]. Moreover, the robot‐assisted approach adopted in this trial has been linked to lower perioperative morbidity than either laparoscopic or open surgery [44]. The involvement of an experienced, high‐volume urologist in all procedures further enhances surgical safety.

This study has some limitations. First, although the current follow‐up period is adequate for evaluating the primary endpoints (PFS and the 1‐year PFS rate), it may be insufficient to provide robust estimates for the secondary endpoint of OS. To address this, we plan to continue patient follow‐up beyond the completion of this project and will provide updated OS results in future reports. Second, the relatively limited sample size reduces statistical power for subgroup analyses, limiting our ability to identify patient subgroups, such as those defined by BMI category, smoking status, or baseline PSA levels, that may derive greater benefit from the intervention. Third, the open‐label design of this trial introduces performance, detection, and expectation biases, which may not only influence clinicians’ management decisions and outcome assessments but also affect patients’ adherence and health‐related behaviours.

Author Contributions

Xiangwei Yang, Zhuobin He, Jian Chen, and Jun Pang conceived and designed the study. Jun Pang secured funding and obtained ethical approval. Hanqi Lei, Binyuan Yan, Linze Chen, and Hong Liu contributed to the refinement of the study design. Xiangwei Yang, Zhuobin He, and Jian Chen drafted the initial manuscript and contributed to the statistical analysis plan and data interpretation. Jun Pang critically reviewed and revised the manuscript. Hanqi Lei and Binyuan Yan are responsible for study administration and data collection. All authors read and approved the final version of the manuscript.

Funding

The study was supported by the Funding of Shenzhen Clinical Research Center for Urology and Nephrology (LCYSSQ20220823091403008). The funding body has no role in the design or conduct of the study, the collection, analysis, or interpretation of data, or the reporting of the trial.

Disclosure of Interests

All authors have no conflict of interests to declare.

Data Availability Statement

No datasets have been generated or analysed at this stage of the study. Following publication of the primary results, anonymised participant data and the statistical code used for analysis will be made available by the corresponding author upon reasonable request.