Prostagram magnetic resonance imaging in a screening population: Prostate Imaging-Reporting and Data System or Likert?

OBJECTIVE: To compare biopsy recommendation rates and accuracy of the Prostate Imaging-Reporting and Data System, version 2 (PI-RADSv2) with the Likert scale for detection of clinically significant and insignificant prostate cancer in men screened within the Imperial Prostate 1 Prostate Cancer Screening Trial Using Imaging (IP1-PROSTAGRAM). PATIENTS AND METHODS: Men aged 50-69 years were screened with Prostagram MRI. Scans were prospectively reported using both PI-RADSv2 (excluding dynamic contrast-enhanced sequence score) and 5-point Likert scores by expert uro-radiologists. Systematic and targeted transperineal biopsy was recommended if the scan was scored ≥ 3, based on either reporting system. The proportion of patients recommended for biopsy and detection rates for Grade Groups (GGs) 1 and ≥ 2 were compared. Receiver operating characteristic (ROC) analysis was performed to compare performance. RESULTS: A total of 406 men underwent Prostagram MRI. The median (interquartile range) age and prostate-specific antigen level were 57 (53-61) years and 0.91 (0.56-1.74) ng/mL, respectively. At MRI score ≥ 3, more patients were recommended for biopsy based on Likert criteria (94/406; 23%, 95% confidence interval [CI] 19.2%-27.6%) compared to PI-RADSv2 (72/406; 18%, 95% CI 14.2%-21.9%; P = 0.03). For MRI scores ≥ 4, PI-RADSv2 and Likert scales led to 43/406 (11%, 95% CI 7.9%-14.1%) and 35/406 (9%, 95% CI 6.2%-11.9%) men recommended for biopsy (P = 0.40). For GG ≥ 2 detection, PIRADSv2 and Likert detected 22% (95% CI 11.4%-30.8%, 14/72) and 16% (95% CI 9.5%-25.3%, 15/94), respectively (P = 0.56). For GG1 cancers detection these were 11% (95% CI 4.3%-19.6%, seven of 72) vs 11% (95% CI 4.7%-17.8%, nine of 94; P = 1.00). The accuracy of PI-RADSv2 and Likert scale was similar (area under the ROC curve 0.64 vs 0.65, P = 0.95). CONCLUSIONS: In reporting non-contrast-enhanced Prostagram MRI in a screening population, the PI-RADSv2 and Likert scoring systems were equally accurate; however, Likert scale use led to more men undergoing biopsy without a subsequent increase in significant cancer detection rates. To improve reporting of Prostagram MRI, either the PI-RADSv2 or a modified Likert scale or a standalone scoring system should be developed.

Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity: A Multicenter Randomized Controlled Trial.

OBJECTIVE: The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation. SUMMARY BACKGROUND DATA: This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery. METHODS: In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months. RESULTS: There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44-2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8-39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group. CONCLUSIONS: The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions. TRIAL REGISTRATION: ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.

Patients' Preferences for Cytoreductive Treatments in Newly Diagnosed Metastatic Prostate Cancer: The IP5-MATTER Study.

BACKGROUND AND OBJECTIVE: Cytoreductive treatments for patients diagnosed with de novo synchronous metastatic hormone-sensitive prostate cancer (mHSPC) confer incremental survival benefits over systemic therapy, but these may lead to added toxicity and morbidity. Our objective was to determine patients' preferences for, and trade-offs between, additional cytoreductive prostate and metastasis-directed interventions. METHODS: A prospective multicentre discrete choice experiment trial was conducted at 30 hospitals in the UK between December 3, 2020 and January 25, 2023 (NCT04590976). The individuals were eligible for inclusion if they were diagnosed with de novo synchronous mHSPC within 4 mo of commencing androgen deprivation therapy and had performance status 0-2. A discrete choice experiment instrument was developed to elicit patients' preferences for cytoreductive prostate radiotherapy, prostatectomy, prostate ablation, and stereotactic ablative body radiotherapy to metastasis. Patients chose their preferred treatment based on seven attributes. An error-component conditional logit model was used to estimate the preferences for and trade-offs between treatment attributes. KEY FINDINGS AND LIMITATIONS: A total of 352 patients were enrolled, of whom 303 completed the study. The median age was 70 yr (interquartile range [IQR] 64-76) and prostate-specific antigen was 94 ng/ml (IQR 28-370). Metastatic stages were M1a 10.9% (33/303), M1b 79.9% (242/303), and M1c 7.6% (23/303). Patients preferred treatments with longer survival and progression-free periods. Patients were less likely to favour cytoreductive prostatectomy with systemic therapy (Coef. -0.448; [95% confidence interval {CI} -0.60 to -0.29]; p < 0.001), unless combined with metastasis-directed therapy. Cytoreductive prostate radiotherapy or ablation with systemic therapy, number of hospital visits, use of a "day-case" procedure, or addition of stereotactic ablative body radiotherapy did not impact treatment choice. Patients were willing to accept an additional cytoreductive treatment with 10 percentage point increases in the risk of urinary incontinence and fatigue to gain 3.4 mo (95% CI 2.8-4.3) and 2.7 mo (95% CI 2.3-3.1) of overall survival, respectively. CONCLUSIONS AND CLINICAL IMPLICATIONS: Patients are accepting of additional cytoreductive treatments for survival benefit in mHSPC, prioritising preservation of urinary function and avoidance of fatigue. PATIENT SUMMARY: We performed a large study to ascertain how patients diagnosed with advanced (metastatic) prostate cancer at their first diagnosis made decisions regarding additional available treatments for their prostate and cancer deposits (metastases). Treatments would not provide cure but may reduce cancer burden (cytoreduction), prolong life, and extend time without cancer progression. We reported that most patients were willing to accept additional treatments for survival benefits, in particular treatments that preserved urinary function and reduced fatigue.

Perceived patient burden and acceptability of MRI in comparison to PSA and ultrasound: results from the IP1-PROSTAGRAM study.

BACKGROUND: The IP1-PROSTAGRAM study showed that a short, non-contrast MRI detected more significant cancers with similar rates of biopsy compared to PSA. Herein, we compare the expected and perceived burden of PSA, MRI and ultrasound as screening tests. METHODS: IP1-PROSTAGRAM was a prospective, population-based, paired screening study of 408 men conducted at seven UK primary care practices and two imaging centres. The screening tests were serum PSA, non-contrast MRI and ultrasound. If any test was screen-positive, a prostate biopsy was performed. Participants completed an Expected Burden Questionnaire (EBQ) and Perceived Burden Questionnaire (PBQ) before and after each screening test. RESULTS: The overall level of burden for MRI and PSA was minimal. Few men reported high levels of anxiety, burden, embarrassment or pain following either MRI or PSA. Participants indicated an overall preference for MRI after completing all screening tests. Of 408 participants, 194 (47.5%) had no preference, 106 (26.0%) preferred MRI and 79 (19.4%) preferred PSA. This indicates that prior to screening, participants preferred MRI compared to PSA (+6.6%, 95% CI 4.4-8.4, p = 0.02) and after completing screening, the preference for MRI was higher (+21.1%, 95% CI 14.9-27.1, p < 0.001). The proportion of participants who strongly agreed with repeating the test was 50.5% for ultrasound, 65% for MRI and 68% for PSA. A larger proportion of participants found ultrasound anxiety-inducing, burdensome, embarrassing and painful compared to both MRI and PSA. CONCLUSIONS: Prostagram MRI and PSA are both acceptable as screening tests among men aged 50-69 years. Both tests were associated with minimal amounts of anxiety, burden, embarrassment and pain. The majority of participants preferred MRI over PSA and ultrasound. REGISTRATION: This study was registered on clinicaltrials.gov at https://clinicaltrials.gov/ct2/show/NCT03702439 .

An Evaluation of Screening Pathways Using a Combination of Magnetic Resonance Imaging and Prostate-specific Antigen: Results from the IP1-PROSTAGRAM Study.

BACKGROUND: The use of prostate-specific antigen (PSA) testing to screen for prostate cancer has been fraught with under- and overdiagnosis. Short, noncontrast magnetic resonance imaging (MRI) might detect more grade group ≥2 cancers with similar rates of biopsy. OBJECTIVE: To evaluate strategies that combined PSA and MRI to select men based in the community for a prostate biopsy. DESIGN, SETTING, AND PARTICIPANTS: IP1-PROSTAGRAM was a prospective, population-based, paired cohort study of 408 men aged 50-69 yr conducted at seven UK primary care practice and two imaging centres (from October 10, 2018 to May 15, 2019). INTERVENTION: All participants underwent screening with a PSA test, MRI (T2-weighted and diffusion), and transrectal ultrasound (b-mode and elastography). If any test was screen positive, a systematic 12-core biopsy was performed. Additional image-fusion targeted biopsies were taken if the MRI or ultrasound was positive. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We conducted an analysis, set out in the statistical plan a priori, comparing 13 different pathways including PSA-alone, MRI-alone, and a range of PSA thresholds and MRI scores. The performance of each pathway was evaluated focusing on the trade-offs between biopsy referral rates and detection of grade group ≥2 cancers. A targeted biopsy was performed only where the PROSTAGRAM MRI showed a lesion score of 3, 4, or 5. RESULTS AND LIMITATIONS: The standard PSA pathway (PSA ≥3 ng/ml + systematic biopsy) would lead to 10% of men being referred for a biopsy and a 1.0% detection rate of grade group ≥2 cancers. Pathways that relied on MRI alone set at a threshold score of 3 for a biopsy led to higher biopsy rates, but with benefit of high cancer detection rates. The pathway that combined an initial low PSA threshold (≥1.0 ng/ml) and MRI score ≥4 accurately identified a high rate of grade group ≥2 cancers (2.5%, 95% confidence interval 1.3-4.6) while recommending fewer patients for a biopsy (7.1%, 95% confidence interval 4.9-10.2). The results are pertinent to only one screening round, the impact of repeat screening rounds is not evaluated, and the required MRI capacity is currently lacking. CONCLUSIONS: Our results highlight the trade-off that exists between reducing excessive numbers of biopsies and maintaining grade group ≥2 cancer detection rates. A pathway that combines PSA ≥1 ng/ml and MRI score ≥4 maintains the detection of grade group ≥2 cancers while recommending fewer men for biopsies and would be the preferred strategy to evaluate in future studies at the first screening round. PATIENT SUMMARY: The IP1-PROSTAGRAM study shows that PROSTAGRAM magnetic resonance imaging in men with a prostate-specific antigen level of ≥1.0 ng/ml could be a promising pathway to evaluate in future screening trials.

Direct mail from primary care and targeted recruitment strategies achieved a representative uptake of prostate cancer screening.

BACKGROUND AND OBJECTIVES: Prostate cancer screening studies has previously not been able to reflect a diverse group of participants. We evaluated a range of recruitment strategies and their ability to recruit from the Black population and areas of deprivation. METHODS: IP1-PROSTAGRAM was a prospective, population-based, paired screening study of 408 participants conducted at seven UK primary care practices and two imaging centres. All participants underwent screening with a prostate specific antigen (PSA) test, magnetic resonance imaging (MRI), and transrectal ultrasound. A number of recruitment strategies were embedded including direct mail, media campaigns, and a targeted recruitment strategy to increase participation among harder-to-reach groups. RESULTS: A total of 1,316 expressions of interest were received (20th September 2018 to 15th May 2019). The direct mail strategy generated 317 expressions of interest from 1707 invitation letters. Overall 387 expressions of interest were received following the targeted strategy and 612 from media campaigns. The recruitment target was met 19 months ahead of the schedule. Of the 411 participants, ethnicity was White (38.0%), Black (32.4%), Asian (23.0%), and Other/Mixed (4.4%) ethnic groups. This higher recruitment of Black men was driven by the targeted recruitment strategy. A comparison of recruitment methods showed marked differences between ethnicities recruited (P < 0.001). The proportion of Black participants recruited by direct mail (8%) was similar to the prevalence of Black local population (9%) whereas, targeted recruitment was 88% (115) and media recruitment 1.7% (1). The Index of Multiple Deprivation (IMD) distribution was similar to the local population with marginal higher recruitment from more deprived areas; proportion increasing from 26% to 40% from least to most deprived IMD quintiles (Quintiles 4/5 vs. 1/2). Direct mail recruited a close-to-normal distribution for deprivation with targeted recruitment trending towards recruiting from most deprived areas. CONCLUSION: Direct mail and targeted strategies designed to engage a diverse population can achieve a representative uptake from Black participants and those from a lower socioeconomic group.

Feasibility of Comparative Health Research Outcome of Novel Surgery in prostate cancer (IP4-CHRONOS): statistical analysis plan for the randomised feasibility phase of the CHRONOS study.

BACKGROUND: Randomised controlled trials (RCTs) for surgical interventions have often proven difficult with calls for innovative approaches. The Imperial Prostate (IP4) Comparative Health Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS) study aims to deliver level 1 evidence on outcomes following focal therapy which involves treating just the tumour rather than whole-gland surgery or radiotherapy. Our aim is to test the feasibility of two parallel RCTs within an overarching strategy that fits with existing patient and physician equipoise and maximises the chances of success and potential benefit to patients and healthcare services. METHODS AND DESIGN: IP4-CHRONOS is a randomised, unblinded multi-centre study, including two parallel randomised controlled trials targeting the same patient population: IP4-CHRONOS-A and IP4-CHRONOS-B. IP4-CHRONOS-A is a 1:1 RCT and the other is a multi-arm, multi-stage (MAMS) RCT starting with three arms and a 1:1:1 randomisation. The two linked RCTs are discussed with patients at the time of consent and the choice of A or B is dependent on physician and patient equipoise. The primary outcome is the feasibility of recruitment, acceptance of randomisation and compliance to allocated arm. RESULTS: This paper describes the statistical analysis plan (SAP) for the feasibility study within IP4-CHRONOS given its innovative approach. Version 1.0 of the SAP has been reviewed by the Trial Steering Committee (TSC), Chief Investigator (CI), Senior Statistician and Trial Statistician and signed off. The study is ongoing and recruiting. Recruitment is scheduled to finish later in 2021. The SAP documents approved methods and analyses that will be conducted. Since this is written in advance of the analysis, we avoid bias arising from prior knowledge of the study data and findings. DISCUSSION: Our feasibility analysis will demonstrate if IP4-CHRONOS is feasible in terms of recruitment, randomisation and compliance, and whether to continue both A and B or just one to the main stage. TRIAL REGISTRATION: ISRCTN ISRCTN17796995 . Registered on 08 October 2019.

Population-Based Prostate Cancer Screening With Magnetic Resonance Imaging or Ultrasonography: The IP1-PROSTAGRAM Study.

IMPORTANCE: Screening for prostate cancer using prostate-specific antigen (PSA) testing can lead to problems of underdiagnosis and overdiagnosis. Short, noncontrast magnetic resonance imaging (MRI) or transrectal ultrasonography might overcome these limitations. OBJECTIVE: To compare the performance of PSA testing, MRI, and ultrasonography as screening tests for prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: This prospective, population-based, blinded cohort study was conducted at 7 primary care practices and 2 imaging centers in the United Kingdom. Men 50 to 69 years of age were invited for prostate cancer screening from October 10, 2018, to May 15, 2019. INTERVENTIONS: All participants underwent screening with a PSA test, MRI (T2 weighted and diffusion), and ultrasonography (B-mode and shear wave elastography). The tests were independently interpreted without knowledge of other results. Both imaging tests were reported on a validated 5-point scale of suspicion. If any test result was positive, a systematic 12-core biopsy was performed. Additional image fusion-targeted biopsies were performed if the MRI or ultrasonography results were positive. MAIN OUTCOMES AND MEASURES: The main outcome was the proportion of men with positive MRI or ultrasonography (defined as a score of 3-5 or 4-5) or PSA test (defined as PSA ≥3 µg/L) results. Key secondary outcomes were the number of clinically significant and clinically insignificant cancers detected if each test was used exclusively. Clinically significant cancer was defined as any Gleason score of 3+4 or higher. RESULTS: A total of 2034 men were invited to participate; of 411 who attended screening, 408 consented to receive all screening tests. The proportion with positive MRI results (score, 3-5) was higher than the proportion with positive PSA test results (72 [17.7%; 95% CI, 14.3%-21.8%] vs 40 [9.9%; 95% CI, 7.3%-13.2%]; P < .001). The proportion with positive ultrasonography results (score, 3-5) was also higher than the proportion of those with positive PSA test results (96 [23.7%; 95% CI, 19.8%-28.1%]; P < .001). For an imaging threshold of score 4 to 5, the proportion with positive MRI results was similar to the proportion with positive PSA test results (43 [10.6%; 95% CI, 7.9%-14.0%]; P = .71), as was the proportion with positive ultrasonography results (52 [12.8%; 95% CI, 9.9%-16.5%]; P = .15). The PSA test (≥3 ng/mL) detected 7 clinically significant cancers, an MRI score of 3 to 5 detected 14 cancers, an MRI score of 4 to 5 detected 11 cancers, an ultrasonography score of 3 to 5 detected 9 cancer, and an ultrasonography score of 4 to 5 detected 4 cancers. Clinically insignificant cancers were diagnosed by PSA testing in 6 cases, by an MRI score of 3 to 5 in 7 cases, an MRI score of 4 to 5 in 5 cases, an ultrasonography score of 3 to 5 in 13 cases, and an ultrasonography score of 4 to 5 in 7 cases. CONCLUSIONS AND RELEVANCE: In this cohort study, when screening the general population for prostate cancer, MRI using a score of 4 or 5 to define a positive test result compared with PSA alone at 3 ng/mL or higher was associated with more men diagnosed with clinically significant cancer, without an increase in the number of men advised to undergo biopsy or overdiagnosed with clinically insignificant cancer. There was no evidence that ultrasonography would have better performance compared with PSA testing alone.

The effect of a duodenal-jejunal bypass liner on lipid profile and blood concentrations of long chain polyunsaturated fatty acids.

BACKGROUND & AIMS: Duodenal-jejunal bypass liners (DJBLs) prevent absorption in the proximal small intestine, the site of fatty acid absorption. We sought to investigate the effects of a DJBL on blood concentrations of essential fatty acids (EFAs) and bioactive polyunsaturated fatty acids (PUFAs). METHODS: Sub-study of a multicentre, randomised, controlled trial with two treatment groups. Patients aged 18-65 years with type-2 diabetes mellitus and body mass index 30-50 kg/m2 were randomised to receive a DJBL for 12 months or best medical therapy, diet and exercise. Whole plasma PUFA concentrations were determined at baseline, 10 days, 6 and 11.5 months; data were available for n = 70 patients per group. RESULTS: Weight loss was significantly greater in the DJBL group compared to controls after 11.5 months: total body weight loss 11.3 ± 5.3% versus 6.0 ± 5.7% (mean difference [95% CI] = 5.27% [3.75, 6.80], p < 0.001). Absolute concentrations of both EFAs, linoleic acid and α-linolenic acid, and their bioactive derivatives, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid, were significantly lower in the DJBL group than in the control group at 6 and 11.5 months follow-up. Total serum cholesterol, LDL-cholesterol and HDL-cholesterol were also significantly lower in the DJBL group. CONCLUSION: One year of DJBL therapy is associated with superior weight loss and greater reductions in total serum cholesterol and LDL-cholesterol, but also depletion of EFAs and their longer chain derivatives. DJBL therapy may need to be offset by maintaining an adequate dietary intake of PUFAs or by supplementation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02459561.

Metastatic prostate cancer men's attitudes towards treatment of the local tumour and metastasis evaluative research (IP5-MATTER): protocol for a prospective, multicentre discrete choice experiment study.

INTRODUCTION: Systemic therapy with androgen deprivation therapy (ADT) and intensification with agents such as docetaxel, abiraterone acetate and enzalutamide has resulted in improved overall survival in men with de novo synchronous metastatic hormone-sensitive prostate cancer (mHSPC). Novel local cytoreductive treatments and metastasis-directed therapy are now being evaluated. Such interventions may provide added survival benefit or delay the requirement for further systemic agents and associated toxicity but can confer additional harm. Understanding men's preferences for treatment options in this disease state is crucial for patients, clinicians, carers and future healthcare service providers. METHODS: Using a prospective, multicentre discrete choice experiment (DCE), we aim to determine the attributes associated with treatment that are most important to men with mHSPC. Furthermore, we plan to determine men's preferences for, and trade-offs between, the attributes (survival and side effects) of different treatment options including systemic therapy, local cytoreductive approaches (external beam radiotherapy, cytoreductive radical prostatectomy or minimally invasive ablative therapy) and metastases-directed therapies (metastasectomy or stereotactic ablative body radiotherapy). All men with newly diagnosed mHSPC within 4 months of commencing ADT and WHO performance status 0-2 are eligible. Men who have previously consented to a cytoreductive treatment or have developed castrate-resistant disease will be excluded. This study includes a qualitative analysis component, with patients (n=15) and healthcare professionals (n=5), to identify and define the key attributes associated with treatment options that would warrant trade-off evaluation in a DCE. The main phase component planned recruitment is 300 patients over 1 year, commencing in January 2021, with planned study completion in March 2022. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Health Research Authority East of England, Cambridgeshire and Hertfordshire Research Ethics Committee (Reference: 20/EE/0194). Project information will be reported on the publicly available Imperial College London website and the Heath Economics Research Unit (HERU website including the HERU Blog). We will use the social media accounts of IP5-MATTER, Imperial Prostate London, HERU and the individual researchers to disseminate key findings following publication. Findings from the study will be presented at national/international conferences and peer-reviewed journals. Authorship policy will follow the recommendations of the International Committee of Medical Journal Editors. TRIAL REGISTRATION NUMBER: NCT04590976.

Additional Treatments to the Local tumour for metastatic prostate cancer-Assessment of Novel Treatment Algorithms (IP2-ATLANTA): protocol for a multicentre, phase II randomised controlled trial.

INTRODUCTION: Survival in men diagnosed with de novo synchronous metastatic prostate cancer has increased following the use of upfront systemic treatment, using chemotherapy and other novel androgen receptor targeted agents, in addition to standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit. In this setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the addition of sequential multimodal local and metastasis-directed treatments compared with standard care alone. METHODS: A phase II, prospective, multicentre, three-arm randomised controlled trial incorporating an embedded feasibility pilot. All men with new histologically diagnosed, hormone-sensitive, metastatic prostate cancer, within 4 months of commencing ADT and of performance status 0 to 2 are eligible. Patients will be randomised to Control (standard of care (SOC)) OR Intervention 1 (minimally invasive ablative therapy to prostate±pelvic lymph node dissection (PLND)) OR Intervention 2 (cytoreductive radical prostatectomy±PLND OR prostate radiotherapy±pelvic lymph node radiotherapy (PLNRT)). Metastatic burden will be prespecified using the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) definition. Men with low burden disease in intervention arms are eligible for metastasis-directed therapy, in the form of stereotactic ablative body radiotherapy (SABR) or surgery. Standard systemic therapy will be administered in all arms with ADT±upfront systemic chemotherapy or androgen receptor agents. Patients will be followed-up for a minimum of 2 years. PRIMARY OUTCOME: PFS. Secondary outcomes include predictive factors for PFS and overall survival; urinary, sexual and rectal side effects. Embedded feasibility sample size is 80, with 918 patients required in the main phase II component. Study recruitment commenced in April 2019, with planned follow-up completed by April 2024. ETHICS AND DISSEMINATION: Approved by the Health Research Authority (HRA) Research Ethics Committee Wales-5 (19/WA0005). Study results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03763253; ISCRTN58401737.