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

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.

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 ).

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 ).

Results

Patients

Between January 22, 2013 and September 2, 2016, 2,061 patients were randomised from 117 hospitals in UK and Switzerland: 1,029 to SOC and 1,032 to SOC+RT. The data set was frozen on March 17, 2021 and included information up to November 30, 2020. shows the CONSORT flow diagram for analyses presented in this paper. shows baseline characteristics balanced across the allocated treatment groups. Table A in shows baseline characteristics in 1,939 (94%) patients who were evaluable for disease burden, 819 (40%) with low- and 1,120 (54%) with high-burden disease.

CONSORT diagram.

AE, adverse event; CONSORT, Consolidated Standards of Reporting Trials; RT, radiotherapy to the prostate, SOC, standard of care. *Alive, no withdrawal of permission for continued data collection.

Median duration of follow-up was 61.3 months (interquartile range [IQR] = 53.8 to 73.1) and was similar in both treatment groups: SOC 61.0 (IQR = 53.8 to 72.6) and SOC+RT 61.6 (IQR = 53.8 to 73.1).

OS by allocated treatment and metastatic burden

A total of 1,183 deaths were reported, 609 in patients allocated to SOC and 574 in those allocated to SOC+RT (, ).

OS in all patients.

Adjusted HR = 0.90 (95% CI 0.81 to 1.01; p = 0.081). HR, hazard ratio; OS, overall survival; RT, radiotherapy to the prostate; SOC, standard of care.

In the low metastatic burden group, 358 had died: 202/409 SOC and 156/410 SOC+RT. Median survival was 63.6 months for SOC and 85.5 months for SOC+RT (5-year survival 53% versus 65%); adjusted HR = 0.64 (95% CI 0.52 to 0.79; p < 0.001 [p = 0.00004]) (, ). There was no evidence of non-PHs.

OS in patients in the low-burden metastatic disease group.

Adjusted HR = 0.64 (95% CI 0.52 to 0.79; p < 0.001 [p = 0.00004]). HR, hazard ratio; OS, overall survival; RT, radiotherapy to the prostate; SOC, standard of care.

In the high-burden disease group, 761 had died: 375/567 SOC and 386/553 SOC+RT. Median survival was 41.2 months in SOC and 38.8 months in SOC+RT (5-year survival 35% versus 30%): adjusted HR = 1.11 (95% CI 0.96 to 1.28; p = 0.164) (, ). There was no evidence of non-PHs.

OS in patients in the high-burden metastatic disease group.

Adjusted HR = 1.11 (95% CI 0.96 to 1.28; p = 0.164). HR, hazard ratio; OS, overall survival; RT, radiotherapy to the prostate; SOC, standard of care.

There was clear evidence of differential treatment effect according to metastatic burden: interaction test p < 0.001 [p = 0.00005].

Similar results were obtained from cause-specific and competing risk analyses (). A participant audit found 36 (<2%) patients with baseline data or documented protocol deviation inconsistent with the comparison’s full eligibility criteria. Sensitivity analyses found no impact from excluding these patients (Tables B and C in ). Analysis of time from randomisation to reported second-line treatments indicates no confounding of RT treatment effect on OS by postprogression abiraterone or enzalutamide therapy ().

Exploration of OS by elected RT schedule

In 980 patients nominated prior to randomisation for weekly RT, 575 had died: 282/482 SOC and 293/498 SOC+RT. Median survival was 52.2 months for SOC and 49.9 months for SOC+RT (5-year survival: 44% versus 42%); adjusted HR = 1.00 (95% CI 0.85 to 1.18); p = 0.974 (, ). In 1,081 patients nominated prior to randomisation for daily RT, 608 died: 327/547 SOC and 281/534 SOC+RT. Median survival was 47.8 months in SOC and 55.5 months in SOC+RT (5-year survival 41% versus 47%); adjusted HR = 0.83 (95% CI 0.71 to 0.97; p = 0.022) (, ). There was no good evidence of interaction in the treatment effect by RT schedule: interaction p = 0.088.

OS in patients nominated for weekly RT (36 Gy/6 f) prior to randomisation.

Adjusted HR = 1.00 (95% CI 0.85 to 1.18; p = 0.974). HR, hazard ratio; OS, overall survival; RT, radiotherapy to the prostate; SOC, standard of care.

OS in patients nominated for daily RT (55 Gy/20 f) prior to randomisation.

Adjusted HR = 0.83 (95% CI 0.71 to 0.97; p = 0.022). HR, hazard ratio; OS, overall survival; RT, radiotherapy to the prostate; SOC, standard of care.

Given that RT improved OS in the low metastatic burden patients, RT schedule was further explored in this subgroup. In 360 patients nominated for weekly RT, 162 had died: 94/190 SOC and 68/170 SOC+RT; adjusted HR = 0.67 (95% CI 0.49 to 0.93; p = 0.015 [p = 0.0155]). In 459 patients nominated for daily RT, 196 had died: 108/219 SOC and 88/240 SOC+RT; adjusted HR = 0.62 (95% CI 0.47–0.83; p = 0.001 [p = 0.00112]). There was no good evidence of interaction in the treatment effect by RT schedule: interaction p = 0.732.

SLEFS by allocated treatment

A total of 1,209 (59%) patients were reported as experiencing at least 1 symptomatic local event: 608 SOC and 601 SOC+RT. In 789 cases (400 SOC and 389 SOC+RT), death from prostate cancer was the only event recorded. summarises the reported incidence of each type of event. There was no evidence of a difference in time to first reported event by treatment arm: adjusted HR = 1.00 (95% CI 0.90 to 1.13; p = 0.931); median symptomatic local event–free survival 43.8 months SOC, 43.3 months SOC+RT (5-year SLEFS survival 39% versus 40%) (, ).

A total of 1,086 (53%) patients had 1 or more local intervention events reported, 556 SOC and 530 SOC+RT, of which death from prostate cancer was the only event in 78% and 81% of cases. Median local intervention event–free survival was 51.1 months in SOC and 53.6 months in SOC+RT (5-year survival 44% versus 47%); adjusted HR = 0.94 (95% CI 0.83 to 1.06; p = 0.286) (, , Table D in ). Table E in presents the results of sensitivity analyses.

AEs by allocated treatment

Urinary-related late AEs of grade 3 were reported for 20 (2%) patients who received RT within 1 year after randomisation; 10 (2%) were planned for weekly and 10 (2%) for daily treatment; no grade 4 or 5 urinary-related events were reported. Bowel-related late AEs of grade 3 or 4 were reported for 26 (3%) patients, 15 (3%) planned for weekly and 11 (2%) daily treatment (, Table F in ). For 610 patients with data available at 2 years, grade 3 urinary AEs were reported for 3 (0.5%) and grade 3 bowel AEs for 6 (1%) (Table G in ). At 4 years, 2/467 (0.4%) patients had grade 3 or 4 bowel toxicity (Table H in ).

Over the entire reported follow-up period, at least 1 grade 3 to 5 AE was reported for 458 (44%) of SOC and 451 (45%) SOC+RT patients. Areas of focus for this long-term analysis were endocrine disorders: 160/1,052 (15%) SOC versus 155/992 (16%) SOC+RT; musculoskeletal disorders: 112/1,052 (11%) SOC, 104/992 (10%) SOC+RT; blood and bone marrow disorders: 56/1,052 (5%) SOC, 49/992 (5%) SOC+RT; cardiovascular disorders: 46/1,052 (4%) SOC, 56/992 (6%) SOC+RT; renal disorders: 50/1,052 (5%) SOC, 52/992 (5%) SOC+RT; general disorders: 57/1,052 (5%) SOC, 43/992 (4%) SOC+RT; gastrointestinal disorders: 47/1,052 (4%) SOC, 52/992 (5%) SOC+RT; lab abnormalities: 49/1,052 (5%) SOC, 48/992 (5%) SOC+RT (Table I in , ). At 2 years, of 715 patients with data available, a grade 3 to 5 AE was reported for 52/320 (16%) SOC and 54/395 (14%) SOC+RT (Table J in , ). At 4 years, based on 358 patients, this was 12/133 (9%) SOC versus 29/225 (13%) SOC+RT (Table K in ).

QoL

There was no evidence of a difference in QoL scores over time between the allocated treatment groups. Average Global QoL in the first 2 years after randomisation across all patients was 73.2% SOC and 72.4% SOC+RT; absolute difference −0.8% (95% CI −2.5% to 0.9%), p = 0.349 (partly conditional analysis) (, ). When including patients who had died prior to an assessment as having a Global QoL score of 0% at that assessment, average Global QoL was 60.3% SOC versus 61.6% SOC+RT; absolute difference 1.3% (95% CI -1.1% to 3.8%), p = 0.287 (composite outcome analysis) (, ).

Average QLQ-30 Summary Score in the first 2 years across all patients was 85.4% SOC and 84.2% SOC+RT; absolute difference −1.2% (95% CI −2.4% to 0.0%), p = 0.050 (partly conditional analysis) (, ). When assuming a value of 0% for assessments after a patient had died, average Summary Score was 70.6% SOC and 71.7% SOC+RT; absolute difference 1.2% (95% CI −1.3% to 3.6%), p = 0.365 (composite outcome analysis) (, ).

Cross-sectional analyses of both Global QoL and QLQ-30 Summary Score indicated evidence of poorer QoL at week 12 after randomisation for patients allocated to SOC+RT—Global QoL absolute difference −2.9% (95% CI −4.8% to −1.0%, p = 0.003); Summary Score absolute difference −2.0% (95% CI −3.2% to −0.8%, p = 0.001)—but not at other assessments ().

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.

SLEFS in all patients.

Adjusted HR = 1.00 (95% CI 0.90 to 1.13; p = 0.931). HR, hazard ratio; RT, radiotherapy to the prostate; SLE, symptomatic local event; SOC, standard of care.

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LIFS in all patients.

Adjusted HR = 0.94 (95% CI 0.83 to 1.06; p = 0.286). HR, hazard ratio; LI, local intervention; RT, radiotherapy to the prostate; SOC, standard of care.

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Model-estimated Global QoL (partly conditional analysis in all patients).

Difference in weighted average: −0.8% (95% CI −2.5% to 0.9%; p = 0.349). QoL, quality of life; RT, radiotherapy to the prostate; SOC, standard of care.

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Model-estimated Global QoL (composite outcome analysis in all patients).

Difference in weighted average: 1.3% (95% CI −1.1% to 3.8%; p = 0.287). QoL, quality of life; RT, radiotherapy to the prostate; SOC, standard of care.

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Model-estimated QLQ-30 Summary Score (partly conditional analysis in all patients).

Difference in weighted average: −1.2% (95% CI −2.4% to 0.0%; p = 0.050). RT, radiotherapy to the prostate; SOC, standard of care.

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Model-estimated QLQ-30 Summary Score (composite outcome analysis in all patients).

Difference in weighted average: 1.2% (95% CI −1.3% to 3.6%; p = 0.365). RT, radiotherapy to the prostate; SOC, standard of care.

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Highest grade AE reported over entire time on trial (CTCAE v4.0, all patients).

AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; RT, radiotherapy to the prostate; SOC, standard of care.

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Highest grade AE reported at 2 years in patients prior to disease progression (CTCAE v4.0).

AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; RT, radiotherapy to the prostate; SOC, standard of care.

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Highest Grade AE reported at 4 years in patients prior to disease progression (CTCAE v4.0).

AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; RT, radiotherapy to the prostate; SOC, standard of care.

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Time to reported initiation of abiraterone or enzalutamide from randomisation.

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Time to reported initiation of abiraterone or enzalutamide from FFS event.

FFS, failure-free survival; RT, radiotherapy to the prostate; SOC, standard of care.

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Table A in S1 Text. Baseline characteristics for metastatic volume analyses.

ADT, androgen deprivation therapy; IQR, interquartile range; PSA, prostate specific antigen; RT, radiotherapy to the prostate; SOC, standard of care; WHO, World Health Organization. Table B in S1 Text. Eligibility status following participant audit. RT, radiotherapy to the prostate; SOC, standard of care. Table C in S1 Text. Sensitivity analyses on OS based on explicit eligibility. ITT, intention-to-treat; OS, overall survival; RT, radiotherapy to the prostate; SOC, standard of care. Table D in S1 Text. First local intervention event reported (patients with event reported). PCa, prostate cancer; RT, radiotherapy to the prostate; SOC, standard of care; TURP, transurethral resection of the prostate. Table E in S1 Text. Summary of analyses of time to local event outcomes. *Subdistribution HR for competing risks models. ^Cox model, adjusting for age, nodal involvement, WHO performance status, regular aspirin or NSAID use and planned SOC docetaxel at randomisation, stratified by randomisation time period. +Fine and Gray model with outcome excluding PCa death and death from any cause as competing risk. NSAID, nonsteroidal anti-inflammatory drug; PCa, prostate cancer; SOC, standard of care; WHO, World Health Organization. Table F in S1 Text. Grade 3 to 5 late RT toxicities reported over entire time on trial (RTOG). Note: Treatment arms correspond to safety population; patients with ≥1 Follow-Up CRF returned. RT, radiotherapy to the prostate; RTOG, Radiation Therapy Oncology Group; SOC, standard of care. Table G in S1 Text. Grade 3 to 5 late RT toxicities reported at 2 years (RTOG). Note: Treatment arms correspond to safety population; patients with ≥1 Follow-Up CRF returned and no reported progression at 2 years. RT, radiotherapy to the prostate; RTOG, Radiation Therapy Oncology Group; SOC, standard of care. Table H in S1 Text. Grade 3 to 5 late RT toxicities reported at 4 years (RTOG). Note: Treatment arms correspond to safety population; patients with ≥1 Follow-Up CRF returned and no reported progression at 4 years. RT, radiotherapy to the prostate; RTOG, Radiation Therapy Oncology Group; SOC, standard of care. Table I in S1 Text. Grade 3 to 5 AEs reported over entire time on trial, overall and for selected body systems (CTCAE). Note: Treatment arms correspond to safety population; patients with ≥1 Follow-Up/SAE CRF returned. AE, adverse event; RT, radiotherapy to the prostate; RTOG, Radiation Therapy Oncology Group; SOC, standard of care. Table J in S1 Text. Grade 3 to 5 AEs reported at 2 years, overall and for selected body systems (CTCAE). Note: Treatment arms correspond to safety population; patients with ≥1 Follow-Up/SAE CRF returned and no reported progression at 2 years. AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; RT, radiotherapy to the prostate; SOC, standard of care. Table K in S1 Text. Grade 3 to 5 AEs reported at 4 years, overall and for selected body systems (CTCAE). Note: Treatment arms correspond to safety population; patients with ≥1 Follow-Up/SAE CRF returned and no reported progression at 4 years. AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; RT, radiotherapy to the prostate; SOC, standard of care.

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Statistical analysis plan.

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CONSORT checklist.

CONSORT, Consolidated Standards of Reporting Trials.

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List of investigators, oversight committees, and contributors.

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6 Jan 2022

Dear Dr Sydes,

Thank you for submitting your manuscript entitled "Radiotherapy to the prostate for men with metastatic prostate cancer: long-term results from the STAMPEDE randomised controlled trial (NCT00268476)" for consideration by PLOS Medicine.

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Kind regards,

Callam Davidson

Associate Editor

PLOS Medicine

7 Feb 2022

Dear Dr. Sydes,

Thank you very much for submitting your manuscript "Radiotherapy to the prostate for men with metastatic prostate cancer: long-term results from the STAMPEDE randomised controlled trial (NCT00268476)" (PMEDICINE-D-22-00022R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Callam Davidson,

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

In the Data Availability Statement (in the submission form) please include an appropriate contact email address for inquiries (this cannot be a study author).

Please remove the trial registration number from your title.

In your abstract ‘Methods and Findings’ please make the following changes:

* Please indicate the dates during which study enrollment and follow up occurred.

* Please include the duration of follow-up.

* Please clearly define the study outcomes.

* Please state that the analysis was intention-to-treat.

* Please include the important variables adjusted for in the analysis.

* Please state that there was no blinding to treatment allocation.

* Please include the important stratification factors adjusted for in the analysis.

* Please include a brief summary of adverse events.

* Please include a single sentence summary of the study’s main limitations at the end of the section (beginning ‘The main limitations of the study were…’, or similar).

Please remove details of funding from the end of the abstract.

At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

Please update citations so that they are not superscript, are within square brackets, and precede punctuation.

Please provide the name of the relevant Institutional Review Board/s that provided ethics approval in the Methods.

Thank you for providing a CONSORT checklist. Please do the following:

* Update the checklist to use section names and paragraph numbers rather than page numbers (which change during the revision process).

* Cite the checklist in your methods (e.g. ‘This trial is reported per the Consolidated Standards of Reporting Trials (CONSORT; see S1 checklist)’ or similar).

Please report p values to 3 decimal places (p<0.001) (e.g. at lines 207 and 218, but please check throughout).

Please define abbreviations used in your Tables and Figures (in the legend or in the figure/table itself where appropriate).

Please provide the unadjusted comparisons as well as the adjusted comparisons in Table 2. Please also indicate factors adjusted for in the legend.

Line numbering appears to disappear after page 17, please correct this to be continuous throughout the document.

In your Discussion, please include a paragraph covering the strengths and limitations of the study.

Author contributions and Competing interests can be removed from the manuscript as this information is captured as part of the submission form.

Please remove any formatting from your references (e.g. bold/italics) and only use et al. after listing the first six authors.

Comments from the reviewers:

Reviewer #1: Parker et al present the updated results of the STAMPEDE trial, arm H. This trial randomized >2000 men with newly diagnosed metastatic prostate cancer in the UK and Switzerland to standard of care (lifelong androgen deprivation therapy) +/- radiation therapy (RT) to the prostate. After the start of enrollment, it was determined that results would be analyzed by the volume of metastatic disease. The authors had previously reported in 2018 that prostate RT improves survival in men with low-volume disease but not high-volume disease, with a significant interaction (Parker et al, Lancet 2018). In this updated analysis, they demonstrate that the survival benefit differences found previously persist with additional follow-up. Furthermore, they present data on local events in the forms of Local Intervention Free Survival and Symptomatic Local Event-Free Survival.

This is an important update of the STAMPEDE trial, arm H, which helped change the treatment paradigm for men with low-volume de novo metastatic prostate cancer. While the updated survival findings, which demonstrated the continued benefit of prostate RT in low-volume disease, are not surprising, the authors do provide additional results in terms of local event analyses, toxicity including from RT, and quality of life (QOL) metrics. The findings of this study are important for the general medical public given the prevalence of prostate cancer. The manuscript is generally well-written and presents appropriate analyses.

Major comments

- Local Intervention Free Survival (LIFS) was defined as "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" (lines 120-122). I am not confident that death from prostate cancer should be considered in the definition of LIFS, since death from prostate cancer is uncommonly a consequence of local progression but rather typically due to an increase in metastatic disease burden. Did the authors consider an analysis of LIFS using a definition which excludes death from prostate cancer, using death from any cause as a competing risk event? Similarly, did the authors consider an analysis of Symptomatic Local Event-Free Survival (SLEFS) using a definition that excludes death from prostate cancer, again using competing risks survival analysis? Understandably, the sample sizes for these analyses are likely to be small since it appears that the majority of patients did not have events besides death from prostate cancer be reported.

- The authors found that when stratified by RT schedule, the hazard ratio (HR) for weekly RT was 1.00 and for daily RT was 0.83 (interaction p=0.088). They then looked at specifically at patients with low-volume status and found a HR of 0.67 for weekly RT and 0.62 for daily RT (interaction p=0.732), demonstrating that RT schedule does not appear to influence outcomes for low-volume patients. As additional exploratory analysis, it may be informative to see a similar analysis of HRs by fractionation schedule for high-volume patients.

- One possible confounder in this study is the receipt of additional therapies not reported here, namely novel androgen receptor signaling inhibitors (ARSI). It is possible that patients in one group were more likely to have received ARSIs which can influence multiple outcomes, including survival, local events, toxicities, and quality of life metrics. Are the authors able to provide data on use of these novel therapies and if not, they should discuss this as a limitation of the study.

Minor comments

- Line 155: There is an extra period after "criteria."

- In Figure 1, it is unclear to me how the n's in the Long-term analysis row were derived from the Follow-up row, e.g. for the first column, 333+74+609=1016, yet the diagram states that n=1029 were analyzed for efficacy. Can the authors clarify this?

- It might be helpful to relabel metastatic disease burden as "low" and "high" in Table 1 to be uniform in the terminology.

- The legend descriptions for Figures 2A and 2B appear flipped (lines 210-218). There is no legend for Figure 2C.

- The authors state that they performed "cause-specific and competing-risk analyses." They should clarify whether this was done using Cox proportional hazard regression vs Fine-Gray regression and define what the competing risks were. Additionally, for prostate cancer-specific mortality, SLEFS, and LIFS, it would be helpful to see interaction p-values as well.

- The authors should clarify the percentage of patients who received 3D conformal RT (3D RT) vs intensity-modulated RT (IMRT). My sense is that the majority of patients likely received 3D RT which, in combination with the generous margins used (8mm posterior and 10mm elsewhere), is expected to increase the level of toxicity from RT compared to more modern, albeit expensive, techniques (i.e. image-guided IMRT with tighter margins, usually around 5mm if not less) used in many other parts of the world. This complicates the interpretation of toxicity and quality of life data presented here and hence should be discussed as a limitation.

Reviewer #2: This paper reports on the long term overall survival, quality of life and local events in patients with primary metastatic prostate cancer, randomised between with radiotherapy to the prostate or standard of care in the SRAMPEDE trial. This is an essential trial since it altered the guidelines into advising radiotherapy to the prostate in patients with low volume metastatic disease. The presented update on the survival data that confirms previous findings is very important. Also reporting on local problems and quality of life is useful, as local radiotherapy of the prostate is known to have a substantial impact on patients' health-related-quality-of-life potentially. The manuscript is well written and has a clear message.

There are a few issues in this report that should be addressed.

1) In the introduction, the authors write that they report on data on freedom from local interventions and mention urinary catheter, ureteric stents, nephrostomies, colostomy. Why did the authors eventually include death in their analysis on symptomatic local event? This is already addressed in their survival analysis. It there a difference in time to local event or proportion of local events when death is not included in this analysis?

2) Table 3 misses in the manuscript.

3) In the introduction, the authors write that the first report on quality of life of this trial. The HORRAD group also published results on the effect on HrQoL of radiotherapy in patients with metastastic prostate cancer. It would be helpful to compare the results of both similar trials in the discussion.

4) In analysing QoL questionnaires, only the global QoL scores were presented. Were there any differences in the different domains of the questionnaires between the two groups?

5) For time-to-event variables, report the number of events but not the proportion. Avoid reporting the percentage of deaths in reporting on survival. Although it is important to report the number of events, patients entered the study at different times and were followed for different periods; hence, the reported proportion is meaningless.

Reviewer #3: This is a useful and well-conducted RCT on the long-term results of radiotherapy on the prostate for men with metastatic prostate cancer. The study design, statistical methods and analyses, and presentation (tables and figures) and interpretation of the results are mostly adequate and of a good standard. However, there are still a few issues needing attention.

1) For the subgroup analyses on low and high burden groups, there are 6% missing data (without disease burden classification). But I haven't seen any sensitivity analysis on the missing data. What is the impact of missing data on the analysis results? Any potential bias? At least we'd like to see the patterns and characteristics of the patients without burden classification as compared to those with burden classification. May need to address the issue as a limitation in the discussion if missing is not at random.

2) In the analysis of the high-burden metastatic disease group (figue 2B), significant interaction was found. However, it is not clear whether the interaction term was dealt with in the analysis, and if yes, how it was dealt with. This question also applies to a few other analyses involving significant interations terms.

3) Sample size calculation was never mentioned in the paper. I am aware this is a follow-up on the previous published paper but at least authors can mention the sample size and direct readers to previous papers or protocol.

4) In statistical analysis section on page 11, it says "The proportional hazards assumption was tested", but with what method?

Any attachments provided with reviews can be seen via the following link:

[LINK]

4 Mar 2022

Submitted filename: Response-to-reviewers_2022-02-28_v1.pdf

Click here for additional data file.

1 Apr 2022

Dear Dr. Sydes,

Thank you very much for re-submitting your manuscript "Radiotherapy to the prostate for men with metastatic prostate cancer: long-term results from the STAMPEDE randomised controlled trial (NCT00268476)" (PMEDICINE-D-22-00022R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and it was also seen again by three reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We hope to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Apr 08 2022 11:59PM.

Sincerely,

Callam Davidson,

Associate Editor

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

Please update your title to include the setting (‘Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: long-term results from the STAMPEDE randomised controlled trial’).

As your author list runs to >30 authors, please consider grouping authors under a collaborative group such that the named author list is ≤30 authors.

Data Availability Statement: Thank you for providing a contact email address (mrcctu.datareleaserequest@ucl.ac.uk). Please ensure this is included in your Data Availability Statement (via the submission form), as the current version recommends contacting the trial team (PLOS does not permit listing study authors as the point of contact for data requests).

In your abstract ‘Methods and Findings’ please make the following changes:

* Please include the setting.

* Please include the length of follow up

* Per our in-house style, please include a single sentence summary of the study’s main limitations at the end of the section (beginning ‘The main limitations of the study were…’, or similar). See previous PLOS Medicine papers for examples.

Please ensure the Abstract and Title are both updated in the submission form as well as the main paper (currently the two versions differ).

Please report p values to 3 decimal places throughout the document (P<0.001 should be the minimum value reported). Example at line 27 and in Figure 2A, but please check throughout.

There is no need to include the original p values as footnotes.

Line 35: Please update to ‘indicating that it should be recommended as a standard of care’ (applies also to concluding paragraph).

Citations throughout should precede punctuation throughout.

Your Author Summary should follow the format here: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

Please update your CONSORT checklist to use section names and paragraph numbers rather than page numbers (which change during the revision process).

The name of the CONSORT checklist file also seems like it does not match the manuscript (‘The Impact of a Community-Oriented Problem-Based Learning Curriculum Reform on the Quality of Primary Care Delivered by Graduates’). Please check.

Thank you for presenting your unadjusted comparisons in Table 2. A line can be added to the Methods section noting that these comparisons were presented in response to a request from the handling editor and thus represents a change from the SAP.

The Financial Disclosure can be removed from the main text, the relevant information should instead be captured in the submission form (answers will then be published as metadata).

Please remove the abbreviations list from the main text and instead define abbreviations on first use/in table and figure legends.

Line 88: Please update the citations here to [2, 3].

When presenting hazard ratios in the Results, please consistently indicate whether these are adjusted or unadjusted ratios (e.g., Section 3.3, paragraph 1 and paragraph 2, HRs are reported differently despite both representing adjusted HRs).

Apologies if I missed it but I couldn’t find an in-text reference for Figure S5?

Comments from Reviewers:

Reviewer #1: I would like to thank the authors for appropriately addressing the comments which I previously raised. I do not have any additional major comments. The authors should be congratulated on this important contribution.

Of note, Table S5 appears to be currently formatted in such a way that the right portion of the table is cut off and not visible in either the PDF or the Word document. I would recommend that the orientation of this page be changed to landscape to allow for the entire table to be viewed.

Reviewer #2: The authors made several improvements to the document based on the reviewers comments, I have no further issues to raise.

Reviewer #3: Thanks authors for their effort to improve the manuscript. I am satisfied with the response and revision. No further issues needing attention.

Any attachments provided with reviews can be seen via the following link:

[LINK]

13 Apr 2022

Submitted filename: Responses_2022-04-11_v1.pdf

Click here for additional data file.

22 Apr 2022

Dear Dr Sydes,

On behalf of my colleagues and the Academic Editor, Dr Brenton, I am pleased to inform you that we have agreed to publish your manuscript "Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: long-term results from the STAMPEDE randomised controlled trial" (PMEDICINE-D-22-00022R3) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

Prior to final acceptance, please make the following changes:

Early in the "Methods and findings" subsection of the abstract, please add a sentence, say, to quote the demographic characteristics of study participants.

There appears to have been a small misunderstanding on one editorial point: Please add a new final sentence to the "Methods and findings" subsection of the abstract, which should begin "Study limitations include ..." or similar and should quote 2-3 of the study's main limitations.

Please adapt the "Author Summary" so that each of the three subsections consists of no more than 3-4 points. To achieve this, some points can be removed (e.g., "Prostate cancer is the most common cancer ..." and "The dataset was frozen in 2021 ...") and in some cases shorter points could be combined.

We suggest adapting "CONSORT diagram" to "Participant flowchart" throughout.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process.

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Richard Turner PhD, for Callam Davidson

Senior Editor, PLOS Medicine

rturner@plos.org

Table 1

Baseline characteristics of all patients in the comparison.

Characteristic		SOC (n = 1,029)	SOC+RT (n = 1,032)
Age at randomisation (years)	Median (IQR)	68 (63 to 73)	68 (63 to 73)
	Range	37 to 86	45 to 87
WHO performance status	0	732 (71%)	734 (71%)
	1 to 2	297 (29%)	298 (29%)
Pain from prostate cancer	Absent	826 (81%)	855 (83%)
	Present	198 (19%)	172 (17%)
	Missing	5	5
Previous notable health issues	Myocardial infarction	67 (7%)	58 (6%)
	Cerebrovascular disease	29 (3%)	32 (3%)
	Congestive heart failure	5 (<1%)	8 (1%)
	Angina	46 (4%)	52 (5%)
	Hypertension	408 (40%)	444 (43%)
T-category at randomisation	T0	0 (0%)	1 (<1%)
	T1	12 (1%)	12 (1%)
	T2	84 (9%)	89 (9%)
	T3	585 (62%)	603 (63%)
	T4	260 (28%)	247 (26%)
	TX	88	80
N-category at randomisation	N0	345 (36%)	344 (36%)
	N+	620 (64%)	620 (64%)
	NX	64	68
Metastatic burden	Low metastatic burden*	409 (42%)	410 (43%)
	High metastatic burden	567 (58%)	553 (57%)
	Not classified	53	69
Sites of metastases	Bone	919 (89%)	917 (89%)
	Liver	23 (2%)	19 (2%)
	Lung	42 (4%)	48 (5%)
	Distant lymph nodes	295 (29%)	304 (29%)
	Other	35 (3%)	32 (3%)
Gleason sum score	< = 7	173 (17%)	175 (18%)
	8 to 10	826 (83%)	820 (82%)
	Unknown	30	37
PSA pre-ADT (ng/ml)	Median (IQR)	98 (30 to 316)	97 (33 to 313)
	Range	1 to 20,590	1 to 11,156
Time from diagnosis (days)	Median (IQR)	73 (55 to 94)	73 (55 to 93)
	Missing	1	2
Days from starting hormones	Median (IQR)	53 (35 to 70)	55 (34 to 70)
	Range	-3 to 84	0 to 86
	Missing	17	13
Planned for SOC docetaxel	No	845 (82%)	849 (82%)
	Yes	184 (18%)	183 (18%)
Nominated RT schedule	36 Gy/6 f over 6 weeks	482 (47%)	498 (48%)
	55 Gy/20 f over 4 weeks	547 (53%)	534 (52%)

*Note: One patient classified with low-burden disease was subsequently restaged as nonmetastatic by the randomising site. They remain in the low metastatic burden subgroup for this analysis.

ADT, androgen deprivation therapy; IQR, interquartile range; PSA, prostate specific antigen; RT, radiotherapy to the prostate; SOC, standard of care; WHO, World Health Organization.

Table 2

Summary of estimated treatment effect for main outcome measures: all patients and metastatic burden subgroups.

Outcome measure	Patient group	Adjusted HR~	Unadjusted HR^	Event free at 5 years+		RMST+
				SOC	SOC+RT		SOC	SOC+RT	Difference
OS	All patients	0.90 (0.81 to 1.01)	0.90 (0.81 to 1.01)	42%	45%		52.9	55.5	2.5 (−0.2 to 5.2)
	Low metastatic burden	0.64 (0.52 to 0.79)	0.66 (0.54 to 0.82)	53%	65%		60.6	69.0	8.4 (4.5 to 12.2)
	High metastatic burden	1.11 (0.96 to 1.28)	1.08 (0.94 to 1.25)	35%	30%		47.7	45.5	−2.2 (−5.7 to 1.2)
	Weekly RT (36 Gy/6 f)	1.00 (0.85 to 1.18)	1.01 (0.86 to 1.19)	44%	42%		53.9	53.6	−0.3 (−3.4 to 2.8)
	(Low metastatic burden)	0.67 (0.49 to 0.93)	0.71 (0.52 to 0.97)	54%	64%		61.3	68.2	6.9 (0.6 to 13.2)
	(High metastatic burden)	1.22 (0.99 to 1.50)	1.19 (0.97 to 1.46)	37%	29%		48.9	44.5	−4.3 (−9.6 to 0.9)
	Daily RT (55 Gy/20 f)	0.83 (0.71 to 0.97)	0.81 (0.69 to 0.95)	41%	47%		52.2	57.2	5.0 (1.1 to 8.9)
	(Low metastatic burden)	0.62 (0.47 to 0.83)	0.63 (0.48 to 0.84)	52%	66%		59.9	69.5	9.6 (4.0 to 15.2)
	(High metastatic burden)	1.02 (0.83 to 1.25)	0.99 (0.81 to 1.21)	33%	32%		46.8	46.6	−0.2 (−4.5 to 4.0)
Prostate cancer–specific survival *	All patients	0.92 (0.81 to 1.04)	0.92 (0.81 to 1.04)	49%	51%		57.6	59.5	1.9 (−1.1 to 5.0)
	Low metastatic burden	0.62 (0.49 to 0.79)	0.64 (0.50 to 0.81)	62%	72%		65.7	73.7	8.0 (4.0 to 12.0)
	High metastatic burden	1.12 (0.96 to 1.31)	1.10 (0.94 to 1.28)	41%	35%		51.8	49.0	−2.8 (−6.6 to 1.0)
SLEFS #	All patients	1.00 (0.90 to 1.13)	1.00 (0.90 to 1.12)	39%	40%		49.2	48.9	−0.3 (−3.5 to 2.8)
	Low metastatic burden	0.72 (0.59 to 0.88)	0.73 (0.60 to 0.90)	46%	58%		54.5	61.8	7.2 (2.5 to 11.9)
	High metastatic burden	1.23 (1.06 to 1.42)	1.21 (1.05 to 1.40)	33%	26%		45.1	39.4	−5.8 (−9.7 to −1.9)
LIFS #	All patients	0.94 (0.83 to 1.06)	0.93 (0.83 to 1.05)	44%	47%		53.5	55.1	1.6 (−1.5 to 4.7)
	Low metastatic burden	0.62 (0.49 to 0.77)	0.63 (0.50 to 0.78)	54%	67%		59.7	69.1	9.5 (5.2 to 13.8)
	High metastatic burden	1.18 (1.01 to 1.37)	1.16 (1.00 to 1.34)	38%	32%		49.0	44.7	−4.4 (−8.4 to −0.4)

Note: HR and RMST difference are for SOC+RT relative to SOC.

*Cause-specific treatment × metastatic burden interaction test p < 0.001 [p = 0.0000977]. Competing risks analysis: overall adjusted sub-HR = 0.93 (95% CI 0.82 to 1.05; p = 0.260); low-burden adjusted sub-HR = 0.66 (95% CI 0.52 to 0.83; p = 0.001); high-burden adjusted sub-HR = 1.11 (95% CI 0.95 to 1.29; p = 0.189); treatment × metastatic burden interaction test p < 0.001 [p = 0.000350].

#SLEFS: treatment × metastatic burden interaction test p < 0.001 [p = 0.0000314]. LIFS interaction p < 0.001 [p = 2.53 × 10−6].

~Estimates from Cox models adjusting for age, nodal involvement, WHO performance status, regular aspirin or NSAID use, and planned SOC docetaxel at randomisation, stratified by randomisation time period.

^Estimates from unadjusted, unstratified Cox models.

+Survival probabilities and RMST estimates are taken from FPMs with t-star = 91 months.

HR, hazard ratio; LIFS, local intervention–free survival; NSAID, nonsteroidal anti-inflammatory drug; RMST, restricted mean event-free (“survival”) time; RT, radiotherapy to the prostate; SLEFS, symptomatic local event–free survival; SOC, standard of care; WHO, World Health Organization.

Table 3

First symptomatic local event reported (patients with event reported).

Type of event	SOC (n = 608)	SOC+RT (n = 601)
Urinary tract infection	57 (9%)	80 (13%)
Urinary catheter	52 (9%)	44 (7%)
Acute kidney injury	33 (5%)	34 (6%)
TURP	24 (4%)	24 (4%)
Urinary tract obstruction	15 (2%)	15 (3%)
Ureteric stent	19 (3%)	8 (1%)
Nephrostomy	5 (1%)	2 (<1%)
Colostomy	3 (<1%)	3 (1%)
Surgery for bowel obstruction	0 (0%)	2 (<1%)
PCa death	400 (66%)	389 (65%)

PCa, prostate cancer; RT, radiotherapy to the prostate; SOC, standard of care; TURP, transurethral resection of the prostate.

Table 4

Patients with grade 3/4 worst late RT toxicity score reported over entire time on trial.

Toxicity area	SOC+RT
	Weekly,36 Gy/6 f(n = 473)	Daily,55 Gy/20 f(n = 517)
Urinary	10 (2%)	10 (2%)
Hematuria	4 (1%)	4 (1%)
Urethral stricture	3 (1%)	4 (1%)
Cystitis	3 (1%)	4 (1%)
Bowel	15 (3%)	11 (2%)
Proctitis	9 (2%)	5 (1%)
Diarrhea	6 (1%)	6 (1%)
Rectal–anal stricture	0 (0%)	0 (0%)
Rectal ulcer	0 (0%)	1 (<1%)
Bowel obstruction	1 (<1%)	1 (<1%)

Note: SOC+RT in safety population (RTOG scale; patients with RT started within 1 year of randomisation). There were no reported grade 5 late RT toxicity events.

RT, radiotherapy to the prostate; SOC, standard of care.

Table 5

Summary of QoL analyses.

Outcome measure	Analysis	Average over first 2 years on trial		Difference (95% CI)
		SOC	SOC+RT
Global QoL (%)	Partly conditional	73.2%	72.4%	−0.8% (−2.5% to 0.9%)
	Composite outcome	60.3%	61.6%	1.3% (−1.1% to 3.8%)
	Cross-sectional: 12 weeks	n/a	n/a	−2.9% (−4.8% to −1.0%)
	Cross-sectional: 24 weeks	n/a	n/a	−0.9% (−3.1% to 1.3%)
	Cross-sectional: 60 weeks	n/a	n/a	−1.4% (−4.1% to 1.3%)
	Cross-sectional: 104 weeks	n/a	n/a	1.8% (−2.4% to 6.0%)
QLQ-30 Summary Score (%)	Partly conditional	85.4%	84.2%	−1.2% (−2.4% to 0.0%)
	Composite outcome	70.6%	71.7%	1.2% (−1.3% to 3.6%)
	Cross-sectional: 12 weeks	n/a	n/a	−2.0% (−3.2% to −0.8%)
	Cross-sectional: 24 weeks	n/a	n/a	−1.0% (−2.3% to 0.4%)
	Cross-sectional: 60 weeks	n/a	n/a	−1.0% (−2.8% to 0.7%)
	Cross-sectional: 104 weeks	n/a	n/a	0.9% (−1.8% to 3.6%)

Note: Partly conditional estimates are based on observed and multiply imputed data from patients alive at scheduled assessments within the first 2 years since randomisation. Composite outcome estimates are based on observed data and implied imputation of missing data from scheduled assessments when a patient was alive, and the assumption of a patient’s Global QoL/QLQ-30 Summary Score being 0% at all scheduled assessments after they have died. Cross-sectional analyses estimate the difference in average Global Qol/QLQ-30 Summary Score between SOC+RT and SOC treatment groups at the specified scheduled assessment, controlling for response at baseline, in complete cases only (i.e., in patients with outcome data provided at baseline and who have survived and for who outcome data is available at the specified scheduled assessment).

QoL, quality of life; RT, radiotherapy to the prostate; SOC, standard of care.