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Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial

['Chris C. Parker', 'The Institute Of Cancer Research', 'Royal Marsden Nhs Foundation Trust', 'London', 'United Kingdom', 'Nicholas D. James', 'Christopher D. Brawley', 'Mrc Clinical Trials Unit At Ucl', 'Ucl', 'Noel W. Clarke']

Date: 2022-06

Abstract Background STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). Methods and findings Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. Conclusions Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. Trial registration ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544.

Author summary Why was this study done? Prostate cancer is the most common cancer in males.

Radiotherapy (RT) to the prostate is widely used as a radical treatment for nonmetastatic prostate cancer.

A comparison was added to the STAMPEDE protocol to assess whether RT to the prostate would also be helpful for males with metastatic prostate cancer. A benefit in survival was targeted.

The trial previously reported a clinically relevant, statistically significant overall survival (OS) benefit for patients with a low metastatic burden but not for men with a high metastatic burden.

This long-term analysis assesses survival with substantially longer follow-up and more events and looked also at complications of local disease. What did the researchers do and find? A randomised controlled trial of adding RT to the prostate to standard of care (SOC) was incorporated into the STAMPEDE protocol.

More than 2,000 patients joined the comparison between 2013 and 2016.

The data set was frozen in 2021 and analysed using standard methods.

There was a clear improvement in survival with prostate RT in the low metastatic burden group.

There was no improvement in survival with prostate RT in the high metastatic burden group.

Symptomatic local progression and the need for later local intervention were improved with RT in the low metastatic burden group.

In the low metastatic burden group, the improvement with RT was similar whether the RT was given with a daily schedule (over 4.5 weeks) or a weekly schedule (over 6 weeks).

The adverse effects of RT were manageable without any impact on long-term quality of life (QoL). What do these findings mean? Prostate RT is a relatively cheap, widely accessible, and well-tolerated treatment.

Prostate RT is indicated in patients with newly diagnosed prostate cancer with a low metastatic burden.

RT to the prostate is not routinely indicated for patients with a high metastatic burden.

Citation: Parker CC, James ND, Brawley CD, Clarke NW, Ali A, Amos CL, et al. (2022) Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial. PLoS Med 19(6): e1003998. https://doi.org/10.1371/journal.pmed.1003998 Academic Editor: James Derek Brenton, University of Cambridge, UNITED KINGDOM Received: January 4, 2022; Accepted: April 22, 2022; Published: June 7, 2022 Copyright: © 2022 Parker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: Data will be available to successful applications for clearly specified research projects following the MRC CTU at UCL standard data sharing processes: https://www.mrcctu.ucl.ac.uk/our-research/other-research-policy/data-sharing/ Discussion with the trial team is encouraged to determine whether the relevant data to support the application are available. Email to: [email protected]. Funding: Research support for this comparison and other comparisons in the STAMPEDE protocol was awarded by Cancer Research UK (CRUK_A12459) www.cancerresearchuk.org (for this comparison, co-authors CCP, DPD, MDM, MKBP, MR, MRS, NDJ; and additionally for other comparisons DG, DM, GA, REL, RM, WC); Medical Research Council (MRC_MC_UU_12023/25, MC_UU_00004/01 and MC_UU_00004/02) www.ukri.org/councils/mrc (to authors MKBP, MRS, REL); and Swiss Group for Clinical Cancer Research, www.sakk.ch (to co-author SG). Other research support for the STAMPEDE protocol was awarded by Astellas www.astellas.com, Clovis Oncology www.clovisoncology.com, Janssen www.janssen.com, Novartis www.novartis.com, Pfizer www.pfizer.com, Sanofi-Aventis www.sanofi.com. CCP, DPD and NDJ are supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CCP reports personal fees from Bayer, personal fees from Janssen, personal fees from Clarity Pharmaceuticals, personal fees from Myovant, personal fees from ITM Oncologics, outside the submitted work NDJ received research funding to the institution from Astellas, Astra Zeneca &Janssen; receipt of honoraria/fees on the advisory board for Astra Zenenca, Clovis, Janssen, Merck, Novartis & Sanofi; received fees as a speaker for Bayer & Novartis NWC received honoraria from Astellas & Janssen; took a consulting/advisory role for Astellas, Janssen, Ferring, Bayer & Sanofi; was paid speakers fees b Janssen & Astellas; received funding for the institution from Astra Zeneca; received meeting and travel expenses from Janssen, Astellas, Sanofi, Astra Zeneca, Ferring & Ipsen GA reports personal fees from Sanofi Aventis, during the conduct of the study; personal fees and non-financial support from Astellas, personal fees and non-financial support from Medivation, personal fees from Novartis, personal fees from Millennium Pharmaceuticals, personal fees and non-financial support from Abbott Laboratories, personal fees and non-financial support from Essa Pharmaceuticals, personal fees and non-financial support from Bayer Healthcare Pharmaceuticals, personal fees from Takeda, grants from AstraZeneca, grants from Arno Therapeutics, grants from Innocrin Pharma, grants, personal fees and non-financial support from Janssen, personal fees from Veridex, personal fees and non-financial support from Roche/Ventana, personal fees and non-financial support from Pfizer, personal fees from The Institute of Cancer Research (ICR), outside the submitted work; and The Institute of Cancer Research (ICR) receives royalty income from abiraterone I receive a share of this income through the ICR’s Rewards to Discoverers Scheme SC received consulting fees from Telix, remedy & Huma; received payment for speaker fees and/or manuscript writing and/or educational events from Astra Zeneca, Novartis/AAA, Clovis, Janssen, Bayer, Pfizer, Beigene & Astellas; they were a member of the data safety monitoring/advisory board for Astra Zeneca, Novartis/AAA, Clovis, Janssen, Bayer, Pfizer, Beigene & Astellas DPD received payment to the institution from C33589/A19727 Advances in Physics for Precision Radiotherapy; previous employer, The Institute of Cancer Research receives loyalty income from abiraterone, receives personal share of this income through ICR’s Rewards to Discoverer’s Scheme; honoraria for consultancy from Janssen; EP1933709B1 – Location and Stabilisation Device., European patent issued, Pending in Canada and India SG reports personal fees from Orion, personal fees from Janssen Cilag, personal fees from ProteoMedix, personal fees from Amgen, personal fees from MSD, other from Tolero Pharmaceuticals, other from Astellas Pharma, other from Janssen, other from MSD Merck Sharp&Dome, other from Bayer, other from Roche, other from Pfizer, other from Telixpharma, other from Amgen, other from Bristol-Myers Squibb, other from AAA International SA, other from Orion, other from Silvio Grasso Consulting, from Tolremo, outside the submitted work; In addition, Gillessen has a patent WO2009138392 issued and Menarini Silicon Biosystems (Advisory Board 2019) - not compensated Aranda (Advisory Board 2019) - not compensated RJJ received research funding to the institution from Bayer, Astellas & Pfizer; received honoraria on the advisory board for Janssen, Astellas, Bayer, Pfizer; received speaker fees from Janssen, Astellas, Bayer & Pfizer REL received an institutional grant from the MRC CG received research funding to the institution from Janssen, Clovis Oncology, Sanofi, Astellas, Medical Research Council & Cancer Research UK DF received speaker fees and/or manuscript writing and/or educational events from BMS, IPSEN, EUSA, Pfizer, ESAI; they received travel expenses from Janssen & IPSEN MDM is an advisory board member for Endocyte & Clovis AB received payment for lecture/presentation/speaker bureau/manuscript writing or educational event from Boston Scientific AJB received speaker fees and travel support from Janssen DF received payment for lectures for Janssen, Pfizer & BMS; support for attending conferences/meetings from Genisiscare & BMS AMH received research grants from CRUK and NIHR; support attending meetings from the European Association of Urologists; is a member of the European Association of Urologists & the Prostate Cancer Guidelines Group MK received travel, accommodation and conference fees as expenses from Bayer, travel and accommodation fees for Prostate cancer summits from Janssen AL received expenses for attending meetings and/or travel from Astellas, Bayer, BMS & MSD JMOS received speaker fees from AAA, Astellas, Bayer, Janssen, Novartis, Sanofi and participated as an advisory board member and/or member of the data safety monitoring board for AAA, Astellas, Bayer, Janssen, Novartis & Sanofi NNS received travel/meeting payments from Janssen JT received support for conference attendance from Janssen, Roche & Bayer; participated on the advisory board for Astra Zeneca, Astellas & Bayer MKBP received research funding to the Unit he directs from Acoria Pvt Ltd, Akagera, Amgen, Aspirin Foundation, Astellas, AstraZeneca, Baxter, Bayer, BMS US, Bri-Bio, Cepheid, Cipla, Clovis Inc, CSL Behring, Eli-Lilly, Emergent Biosolutions, Gilead Sciences, GlaxoSmithKline, Grifols, Janssen Products LP, Janssen-Cilag, Johnson & Johnson, Micronoma, Modus Theraputics, Mylan, Novartis, Pfizer, Sanofi, Serum Institute of India, Shionogi, Synteny Biotechnology, Takeda, Tibotec, Transgene, ViiV Healthcare, Virco and Xenothera MRS received research funding to the institution from Astellas, Clovis, Janssen, Novartis, Pfizer, Sanofi-Aventis; received speaker fees from Lilly Oncology & Janssen; independent member of data monitoring committees. All other authors have nothing to declare. Abbreviations: ADT, androgen deprivation therapy; AE, adverse event; CONSORT, Consolidated Standards of Reporting Trials; CTCAE, Common Terminology Criteria for Adverse Events; FPM, flexible parametric model; GnRH, gonadotrophin-releasing hormone; HR, hazard ratio; IQR, interquartile range; ITT, intention-to-treat; LIFS, local intervention–free survival; NSAID, nonsteroidal anti-inflammatory drug; OS, overall survival; PH, proportional hazard; QoL, quality of life; RMST, restricted mean event-free (“survival”) time; RT, radiotherapy; SLEFS, symptomatic local event-free survival; SOC, standard of care; WHO, World Health Organization

Introduction Prostate radiotherapy (RT) is recommended for men with newly diagnosed, low-burden, metastatic prostate cancer, but not for men with high-burden disease [1]. This recommendation is based largely on the initial results of the STAMPEDE trial, reported in 2018 [2]. In this randomised controlled trial of 2,061 men with newly diagnosed metastatic prostate cancer, prostate RT improved overall survival (OS) for men with low metastatic burden (hazard ratio [HR] 0.68, 95% CI 0.52 to 0.90; p = 0.007), with no evidence of a meaningful effect on survival in men with high metastatic burden (HR 1.07, 95% CI 0.90 to 1.28; p = 0.420). That initial analysis, triggered by a preplanned number of events, was done after a median follow-up of 37 months and was based on 761 events. Here, we report the final analysis of OS, with an additional 2 years follow-up. We hypothesised that prostate RT would reduce the complications of local disease progression, such as urinary or bowel obstruction. If so, this could benefit men with metastatic disease, regardless of disease burden. Here, we report data on freedom from local interventions (e.g., urinary catheter, ureteric stents, nephrostomies, and colostomy). Any benefits of prostate RT need to be weighed against the risk of treatment-related adverse events (AEs). We report, for the first time, data from the trial on quality of life (QoL). The trial was stratified according to the choice of 1 of 2 RT dose-fractionation schedules, nominated prior to randomisation; 36 Gy in 6 fractions over 6 weeks, or 55 Gy in 20 fractions over 4 weeks. The 2 schedules were chosen in the expectation that they would be similarly effective. With the benefit of additional follow-up, and more events in the final analysis, we have tested for any differential impact on OS by choice of RT schedule.

Methods Study participants Eligible patients had prostate cancer that was newly diagnosed, with no previous radical treatment, had metastatic disease confirmed on a bone scintigraphic scan and soft tissue imaging, and were within 12 weeks after starting androgen deprivation therapy (ADT). Patients were required to have no contraindications to RT and no clinically significant cardiovascular history. Participants were recruited at secondary care sites in the UK and Switzerland. The trial was registered as NCT00268476 (ClinicalTrials.gov) and ISRCTN78818544 (ISRCTN.com). The trial was done in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki and had relevant ethics (West Midlands–Edgbaston Research Ethics Committee) and regulatory approvals. All patients gave written informed consent. The rationale and design, including sample size calculations, have been described previously [2,3]. Full details are in the protocol at www.stampedetrial.org. Procedures All patients received lifelong hormone therapy as gonadotrophin-releasing hormones (GnRHs) agonists or antagonists or orchidectomy. In addition, docetaxel was permitted after it became available for this setting in the UK. Docetaxel, when used, was given as six 3 weekly cycles of 75mg/m2 with or without prednisolone 10 mg daily. External beam RT to the prostate was given as 1 of 2 schedules nominated prior to randomisation: 36 Gy in 6 consecutive weekly fractions of 6 Gy or 55 Gy in 20 daily fractions of 2.75 Gy over 4 weeks. Treatment was given with the patient supine, with a full bladder and an empty rectum. The planning target volume consisted of the prostate only with an 8-mm margin posteriorly and a 10-mm margin elsewhere. RT was to commence as soon as practicable after randomisation, and, if the patient was having docetaxel as part of standard of care (SOC), within 3 to 4 weeks after the last docetaxel dose. Patients were followed up 6 weekly until 6 months after randomisation, 12 weekly to 2 years, 6 monthly to 5 years, and then annually. Toxicities and symptoms were reported at regular follow-up visits or when an AE was categorised as “serious.” These were graded with Common Terminology Criteria for Adverse Events (CTCAE) v4·0. Separately, bowel and bladder adverse effects during RT and long-term possible RT effects were recorded using the RTOG scale [4]. Participants were asked to complete the EORTC QLQ-C30 at each scheduled follow-up appointment. Metastatic burden at randomisation was evaluated retrospectively through central imaging review of whole body scintigraphy and computerized tomography (CT) or MRI staging scans. Metastatic burden was classified according to the definition used in the CHAARTED trial [5] as either high (polymetastatic; ≥4 bone metastases with ≥1 outside the vertebral bodies or pelvis and/or visceral metastases) or low (oligometastatic). Patients with only lymph node metastases, in the absence of bone or visceral disease, were therefore classified as low metastatic burden regardless of the number of nodal metastases. Randomisation and masking Patients were randomised centrally using a computerised algorithm, developed and maintained by the trials unit. Minimisation with a random element of 20% was used (80% probably of allocation to a minimising treatment), stratifying for hospital, age at randomisation (<70 versus ≥70 years), nodal involvement (negative versus positive versus indeterminate), the World Health Organization (WHO) performance status (0 versus 1 or 2), planned form of ADT (orchidectomy versus LHRH (leuteinising hormone-releasing hormone) agonist versus LHRH antagonist versus dual androgen blockade), and regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use (yes or no). Planned docetaxel use was added as a stratification factor after use was permitted as part of SOC. Allocation was 1:1 to SOC only or SOC+RT. There was no blinding to treatment allocation. Primary and secondary outcomes The primary efficacy outcome measure was OS, defined as time from randomisation to death from any cause. Secondary outcomes for this long-term efficacy analysis included local intervention–free survival (LIFS)—consisting of time from randomisation to the first report on case report forms of TURP, ureteric stent, surgery for bowel obstruction, urinary catheter, nephrostomy, colostomy, death from prostate cancer—and symptomatic local event-free survival (SLEFS), comprising any of these LIFS events or acute kidney injury, urinary tract infection, or urinary tract obstruction. Cause of death was determined by the site investigator, with some cases reclassified as prostate cancer death according to predefined criteria which suggested this to be the likely cause. Patients without the event of interest were censored at the time last known to be event free. QoL analyses focused on Global QoL % and QLQ-30 Summary Score %, as derived from patient reports at scheduled assessment time points in the first 2 years after randomisation (see S2 Text). Statistical analysis The primary outcome measure, OS, was assessed across all patients and separately within patient subgroups characterised by baseline metastatic burden (low versus high) and nominated RT schedule (daily versus weekly). Standard survival analysis methods were used to analyse time-to-event data in Stata v16.1 (College Station, Texas, United States of America). A nonparametric stratified log-rank test was used to assess any difference in survival between treatment groups; this was stratified across the minimisation factors used at randomisation (except hospital and planned form of hormone therapy) plus protocol-specific time periods defined by other arms recruiting to STAMPEDE or changes to SOC which could affect the population being randomised. Cox proportional hazards (PHs) regression models adjusting for the same stratification factors and stratified by time period were used to estimate relative treatment effect; a HR less than 1·00 favoured the research arm. Unadjusted estimates of treatment effect are also presented. Flexible parametric models (FPMs) were fitted with degrees of freedom (5.5) and adjusted for stratification factors and time periods [6]. Medians and 5-year survival estimates are presented from the FPM fitted to the data. Kaplan–Meier curves, using the KMunicate format [7], show estimated survival over time. Following the fitting of Cox models, the PHs assumption was tested using a global Grambsch–Therneau test with log-transformed time; restricted mean event-free (“survival”) time (RMST) was emphasised in the presence of nonproportionality, using a t-star of 91 months as determined by the Royston and Parmar method [6]. Cox and Fine and Gray regression models [8] were used for cause-specific and competing risk analyses, respectively; competing risks were non-prostate cancer–related death for prostate cancer–specific survival and death from any cause for SLEFS and LIFS. Evidence for different treatment effect across subgroups was assessed using the likelihood ratio p-value for an interaction term added to the relevant adjusted Cox/FPM model, or Wald test p-value from Fine and Gray model. Sensitivity analyses of local event outcomes examined the impact of excluding death from prostate cancer and a competing risks approach with death from any cause specified as a competing event. All tests are presented as 2 sided, with 95% CIs and the relevant p-value. Median follow-up was estimated using the Kaplan–Meier method with reverse censoring on death. All patients were included in the efficacy and QoL analyses according to allocated treatment on an intention-to-treat (ITT) basis; sensitivity analyses exclude patients who did not explicitly fulfill all of the eligibility criteria. AE data are shown for the safety population, in patients with at least 1 follow-up assessment and analysed according to whether RT was received within 1 year of randomisation (SOC+RT) or not (SOC). Analyses of the QoL outcomes included partly conditional and composite approaches, building on the approaches previously used in the trial [9]. For the former, missing values were multiply imputed using observed data using chained equations. Imputed values for assessments dating after a patient had died were restored to missing. Generalised estimating equations with an independence correlation matrix were used to estimate the expected value of the outcome for each treatment arm at each assessment time point. For the composite approach, observations following the death of a patient were set to 0% (corresponding to the lowest possible QoL state). Mixed linear regression with random intercept and slope (with unstructured correlation specification) was used to model the outcome. Additional cross-sectional analyses estimated the difference in average QoL associated with treatment allocation in patients alive and with data available at a given assessment time point, controlling for baseline state. This trial is reported per the Consolidated Standards of Reporting Trials (CONSORT; see S3 Text).

Discussion This final analysis has confirmed that prostate RT improves OS in men with newly diagnosed, low-burden metastatic prostate cancer, but not in men with high-burden disease. The magnitude of the survival benefit is substantial and clinically relevant, particularly given that prostate RT is a relatively cheap, widely accessible, and well-tolerated treatment. These results of the final analysis confirm the findings from the initial analysis. The additional 2 years of follow-up, and the subsequent increase in the number of events for analysis, has reduced the CIs around the point estimate of the HR of the OS benefit for prostate RT. However, the point estimate itself has changed very little, improving from 0.68 to 0.64 for men in the low metastatic disease risk group. This result is consistent with that from the smaller HORRAD trial [10]. Our new data strongly support those guidelines already recommending the use of prostate RT in men with low-burden metastatic disease. We have not found any benefit for prostate RT in men with high-burden disease, either in OS or in preventing interventions for local disease progression. We found no compelling evidence of a difference in efficacy or toxicity between the 2 RT dose-schedules tested. The weekly schedule of 36 Gy in 6 fractions over 6 weeks has an obvious practical advantage in terms of convenience and may be preferred for that reason. A daily schedule might be preferred if pelvic nodal RT were to be used in addition or if RT dose escalation was thought to be appropriate. Prostate RT did not have any long-term impact on QoL either in this trial, or in the HORRAD trial [11]. The risk of toxicity from prostate RT, although low, could be further reduced by the use of more contemporary intensity modulated techniques [12]. The criteria used in the trial to classify cases as low or high burden were taken from those used in the CHAARTED trial [5]. These criteria are based on the presence or absence of visceral disease on CT scan, together with the number and the location of bone metastases on bone scan. Patients with only lymph node metastases have low-burden disease, regardless of the extent of nodal disease. There is no good reason to think that these criteria are optimal for identifying those patients with metastatic disease who stand to benefit from prostate RT. The initial analysis of STAMPEDE suggested that the survival benefit from prostate RT gradually decreased in magnitude as the number of bone metastases visible on a baseline bone scan increased [13]. One could decide to identify patients suitable for prostate RT based solely on the number of bone metastases visible on baseline bone scan, regardless of location. A count-of-metastases approach would be simpler to use in the clinic than the CHAARTED definition and would likely increase the number of men considered suitable for prostate RT. The trial has several strengths, including the randomised design, the large number of events for analysis, and recruitment from over 100 centres, which adds to the generalisability of the results. The main limitations of the study are the changes in clinical practice since the trial started, particularly with regard to imaging techniques and systemic treatment. The trial recruited between 2013 and 2016 and, while this has the benefit of long follow-up, it also means that newer imaging techniques, such as PSMA (Prostate-specific membrane antigen) PET and whole body MRI, were unavailable. It is important to note that low-burden disease in the trial was defined according to bone scan and CT scan. There is no agreed definition of metastatic disease burden based solely on PSMA PET or on whole body MRI. In patients without visceral disease but who have more than 4 bone metastases on PET or MRI, a bone scan may be required in addition, in order to determine suitability for prostate RT. If this is not practicable, and there remains uncertainty as to whether a patient has high- or low-burden disease, there is a strong argument for using prostate RT. The systemic treatment of metastatic prostate cancer has changed since the trial recruited. Standard treatment for men with low-burden metastatic disease now includes one of the newer hormone agents (abiraterone or apalutamide or enzalutamide) in addition to ADT. The effect of these agents on the survival benefit of prostate RT is unknown. Similarly, the effect of prostate RT on the survival benefit of the newer hormonal agents is also unknown. Based on current evidence, it is reasonable to assume that both prostate RT and one of the newer hormonal agents should be considered SOC for low-burden metastatic disease, in addition to ADT. The PEACE-1 Trial is testing the use of prostate RT in men receiving ADT + abiraterone. In summary, this final analysis confirms that prostate RT improves OS in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC.

Acknowledgments Large-scale trials do not happen without huge collaborations. Thanks to all central and site staff who have made the STAMPEDE trial happen. See S4 Text for full list of investigators, oversight committees, and contributors. In particular, thanks to all the people who have chosen to participate in STAMPEDE and their families and friends who have supported them. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Investigators and collaborators See Credit List included as S4 Text and on the STAMPEDE trial website: http://www.stampedetrial.org/media-section/presentation-repository/trial-recognition.

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