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Abstract Background To speed up the evaluation of new therapies, the multi-arm, multi-stage trial design was suggested previously by the authors. Methods In this paper, we evaluate the performance of the two-stage, multi-arm design using four cancer trials conducted at the MRC CTU. The performance of the design at fictitious interim analyses is assessed using a conditional bootstrap approach. Results Two main aims are addressed: the error rate of correctly carrying on/stopping the trial at an interim analysis as well as quantifying the gains in terms of resources by employing this design. Furthermore, we make suggestions for the best timing of this interim analysis. Conclusion Multi-arm, multi-stage trials are an effective way of speeding up the therapy evaluation process. The design performs well in terms of the type I and II error rates.

Background and Objective: The use and duration of androgen deprivation therapy (ADT) with postoperative radiotherapy (RT) have been uncertain. RADICALS-HD compared adding no ("None"), 6-months ("Short"), or 24-mo ("Long") ADT to study efficacy in the long term., Methods: Participants with prostate cancer were indicated for postoperative RT and agreed randomisation between all durations. ADT was allocated for 0, 6, or 24 mo. The primary outcome measure (OM) was metastasis-free survival (MFS). The secondary OMs included freedom from distant metastasis, overall survival, and initiation of nonprotocol ADT. Sample size was determined by two-way comparisons. Analyses followed standard time-to-event approaches and intention-to-treat principles., Key Findings and Limitations: Between 2007 and 2015, 492 participants were randomised one of three groups: 166 None, 164 Short, and 162 Long. The median age at randomisation was 66 yr; Gleason scores at surgery were as follows: <7 = 64 (13%), 3+4 = 229 (47%), 4+3 = 127 (26%), and 8+ = 72 (15%); T3b was 112 (23%); and T4 was 5 (1%). The median follow-up was 9.0 yr and, with MFS events reported for 89 participants (32 None, 31 Short, and 26 Long), there was no evidence of difference in MFS overall (logrank p = 0.98), and, for Long versus None, hazard ratio = 0.948 (95% confidence interval 0.54-1.68). After 10 yr, 80% None, 77% Short, and 81% Long patients were alive without metastatic disease. The three-way randomisation was not powered to conventional levels for assessment, yet provides a fair comparison., Conclusions and Clinical Implications: Long-term outcomes after radical prostatectomy are usually favourable. In those indicated for postoperative RT and considered suitable for no, short-term, or long-term ADT, there was no evidence of improvement with addition of ADT. Future research should focus on patients at a higher risk of metastases in whom improvements are required more urgently., (Copyright © 2024. Published by Elsevier B.V.)

Background: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure., Patients and Methods: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT., Results: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017)., Conclusion: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy., Trial Identification: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Multi-arm multi-stage (MAMS) randomised trial designs have been proposed to evaluate multiple research questions in the confirmatory setting. In designs with several interventions, such as the 8-arm 3-stage ROSSINI-2 trial for preventing surgical wound infection, there are likely to be strict limits on the number of individuals that can be recruited or the funds available to support the protocol. These limitations may mean that not all research treatments can continue to accrue the required sample size for the definitive analysis of the primary outcome measure at the final stage. In these cases, an additional treatment selection rule can be applied at the early stages of the trial to restrict the maximum number of research arms that can progress to the subsequent stage(s). This article provides guidelines on how to implement treatment selection within the MAMS framework. It explores the impact of treatment selection rules, interim lack-of-benefit stopping boundaries and the timing of treatment selection on the operating characteristics of the MAMS selection design., Methods: We outline the steps to design a MAMS selection trial. Extensive simulation studies are used to explore the maximum/expected sample sizes, familywise type I error rate (FWER), and overall power of the design under both binding and non-binding interim stopping boundaries for lack-of-benefit., Results: Pre-specification of a treatment selection rule reduces the maximum sample size by approximately 25% in our simulations. The familywise type I error rate of a MAMS selection design is smaller than that of the standard MAMS design with similar design specifications without the additional treatment selection rule. In designs with strict selection rules - for example, when only one research arm is selected from 7 arms - the final stage significance levels can be relaxed for the primary analyses to ensure that the overall type I error for the trial is not underspent. When conducting treatment selection from several treatment arms, it is important to select a large enough subset of research arms (that is, more than one research arm) at early stages to maintain the overall power at the pre-specified level., Conclusions: Multi-arm multi-stage selection designs gain efficiency over the standard MAMS design by reducing the overall sample size. Diligent pre-specification of the treatment selection rule, final stage significance level and interim stopping boundaries for lack-of-benefit are key to controlling the operating characteristics of a MAMS selection design. We provide guidance on these design features to ensure control of the operating characteristics., (© 2024. The Author(s).)

Background: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear., Methods: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047., Findings: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths., Interpretation: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population., Funding: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society., Competing Interests: Declaration of interests AN reports honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck. ADC reports research grants for the STAMPEDE trial from Janssen, Astellas, Novartis, Sanofi, and Clovis. ACT reports research grants to their institution from Elekta, Varian, and Accuracy; honoraria for talks from Elekta, Accuracy, and Janssen; travel assistance for radiotherapy conferences from Elekta; serving on the data safety board for two academic trials; and roles as the Chair of the MR-Linac Consortium and the genitourinary lead editor for the International Journal of Radiation Oncology, Biology, Physics. AC reports receiving grants or contracts from the National Institute for Health and Care Research, Manchester Biomedical Research Centre, Cancer Research UK, Medical Research Council (MRC) UK, Prostate Cancer UK, Bayer UK, and Elekta; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from the American Society for Radiation Oncology, the American Society of Clinical Oncology, Cancer Research UK, Roche, AstraZeneca, and Bristol Myers Squibb (BMS). CNC reports support for the present manuscript from the Canadian Cancer Trials Group; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer Corp, Knight Therapeutics, and AbbVie. CLG reports participating in the independent data monitoring and steering committee for the BARCODE study at the Institute of Cancer Research in London (principal investigator Prof Ros Eeles). CCP reports consulting fees from AAA, ITM Radiopharma, Myovant, and Clarity Pharmaceuticals to his institution; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen and Bayer to his institution. CM reports that they are employed by University College London (UCL) as Trial Manager for RADICALS. FS reports grants or contracts from Janssen, Bayer, Merck, Pfizer, Astellas, BMS, Novartis, Sanofi, and AstraZeneca to his institution; consulting fees from Janssen, Bayer, Astellas, BMS, Novartis, Sanofi, AstraZeneca, Merck, and Pfizer to him; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Bayer, Myovant, Astellas, BMS, Novartis, Sanofi, AstraZeneca, Merck, and Pfizer to him. LCB reports their previous Institute of Cancer role was funded in part by a Biomedical Research Centre grant which was paid to the institution; the role was not connected to the RADICALS trial. MRS reports research grants and biomarker testing costs, all to their institution and all active in the past 36 months but on research outside of this research, from Astellas, Clovis Oncology, Janssen, Novartis, and Sanofi-Aventis; consulting fees from Eli Lilly; speaker fees at a clinical trial statistics training meeting for clinicians (no discussion of particular drugs) from Lilly Oncology, Janssen, and Eisai; and is an independent member of many independent data monitoring committees but all for academic sponsors and unpaid. NWC reports honoraria for lectures, advisory boards, and symposia from AstraZeneca, Janssen, Bayer, and Pfizer; support for travel to and attendance at a European meeting from Bayer; participation on the independent data monitoring committee for the Probio trial (Karolinska), and the trial steering committee for the Capi 28 trial (AstraZeneca) and the STAMPEDE trial (MRC); and is the Joint National Clinical Lead for the National Prostate Cancer Audit. PWMC reports grants or contracts from the Canadian Association of Radiation Oncology ACURA program and the Canadian Institute of Health Research; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer and EMD Serono; and participation on a data safety monitoring board or advisory board from TerSera, AbbVie, Tolmar, and Knight Therapeutics. PMP reports participation on a data safety monitoring board or advisory board for AAA Nordic, MSD, and Pfizer Denmark. SCM reports honoraria from Janssen, Astellas, Knight Therapeutics, AMGEN Pharmaceutical, AstraZeneca, AbbVie, and Bayer; and support for attending meetings or travel from TerSera and Sanofi. VK reports a Cancer Research UK grant for the CORE trial to his institution; honoraria from Accuracy, Astellas, Bayer, and Boston Scientific; meeting attendance support from Accuray, Astellas, AstraZeneca, Bayer, BMS, Boston Scientific, Janssen, Merck Sharp & Dohme, and Norvatis; is an unpaid member of the independent data monitoring committee for the EPIC trial and the advisory board for Bayer and Janssen; and is the unpaid Chair of National Cancer Research Institute Penile subgroup of the Bladder and Renal Clinical Studies Group. WRC reports consulting fees from Bayer and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Bayer, Janssen, AAA Novartis, and Myriad Genetics; and support for attending meetings or travel from Janssen, AAA Novartis, and Bayer. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain., Methods: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047., Findings: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths., Interpretation: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy., Funding: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society., Competing Interests: Declaration of interests AN reports honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck. ADC reports research grants for the STAMPEDE trial from Janssen, Astellas, Novartis, Sanofi, and Clovis. CMH is an executive committee member for the British Uro-Oncology Group. CNC reports support for the present manuscript from the Canadian Cancer Trials Group; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer Corp, Knight Therapeutics, and AbbVie. CLG reports that they participate in the independent data monitoring and steering committee for the BARCODE study at the Institute of Cancer Research in London (principal investigator Ros Eeles). CB reports stock or stock options from GSK; and has been an employee at GSK since August, 2023. CCP reports consulting fees from AAA, ITM Radiopharma, Myovant, and Clarity Pharmaceuticals to his institution; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen and Bayer to his institution. FS reports grants or contracts from Janssen, Bayer, Merck, Pfizer, Astellas, Bristol Myers Squibb (BMS), Novartis, Sanofi, and AstraZeneca to his institution; consulting fees from Janssen, Bayer, Astellas, BMS, Novartis, Sanofi, AstraZeneca, Merck, and Pfizer to him; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Bayer, Myovant, Astellas, BMS, Novartis, Sanofi, AstraZeneca, Merck, and Pfizer to him. LCB reports that their previous Institute of Cancer role was funded in part by a Biomedical Research Centre grant which was paid to the institution; the role was not connected to the RADICALS trial. MRS reports research grants and biomarker testing costs, all to institution and all active in past 36 months but on research outside of this research, from Astellas, Clovis Oncology, Janssen, Novartis, and Sanofi-Aventis; consulting fees from Eli Lilly; speaker fees at a clinical trial statistics training meeting for clinicians (no discussion of particular drugs) from Lilly Oncology, Janssen, and Eisai; and is an independent member of many independent data monitoring committees but all for academic sponsors and unpaid. NDJ is a Senior Investigator for the National Institute for Health and Care Research. NWC reports honoraria for lectures, advisory boards, and symposia from AstraZeneca, Janssen, Bayer, and Pfizer; support for travel to and attendance at a European meeting from Bayer; participation on an independent data monitoring committee for the Probio trial (Karolinska), and the trial steering committee for the Capi 28 Trial (AstraZeneca) and the STAMPEDE Trial (Medical Research Council [MRC]); and is the Joint National Clinical Lead for National Prostate Cancer Audit. PW reports an educational event payment from Astellas; conference and travel cost support from AstraZeneca and Aventis; and participation on the advisory board for Ferring and Roche. PWMC reports grants or contracts from CARO-ACURA and the Canadian Institutes of Health Research; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer and EMD Serono; and participation on a data safety monitoring board or advisory board for TerSera, AbbVie, Tolmar, and Knight Therapeutics. PMP reports participation on a data safety monitoring board or advisory board for AAA Nordic, MSD, and Pfizer Denmark. SCM reports honoraria from Janssen, Astellas, Knight Therapeutics, Amgen Pharmaceutical, AstraZeneca, AbbVie, and Bayer; and support for attending meetings or travel from TerSera and Sanofi. WRC reports consulting fees from Bayer and Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Bayer, Janssen, AAA Novartis, and Myriad Genetics; and support for attending meetings or travel from Janssen, AAA Novartis, and Bayer. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: It is unclear how to disseminate the results of randomised controlled trials effectively to health professionals and policymakers to improve treatment, care or prevention through changing policy and practice. This systematic review examined the effectiveness of different methods of dissemination of clinical research results to professional audiences., Methods: We systematically reviewed the published and grey literature from 2000 to 2022 for studies assessing different approaches for disseminating clinical study results to professional audiences (health professionals, policymakers and guideline developers). Two reviewers assessed potentially relevant full texts for inclusion. We grouped studies by intervention type, synthesising findings using effect direction plots. Outcomes were grouped into out-takes (e.g. awareness, knowledge, understanding), outcomes (e.g. attitude changes) and impact (changes in policy/practice). The quality of evidence was assessed using GRADE., Results: Our search identified 13,264 unique records, of which 416 full texts were assessed for eligibility. Of 60 studies that were identified as eligible for inclusion, 20 evaluated the effectiveness of interventions to disseminate clinical research results (13 RCTs, 2 observational studies, 3 pre- and post-intervention surveys and 2 cross-sectional surveys). Studies were grouped by intervention: 7 studies that involved face-to-face meetings between the target audience and trained educators were classified as 'outreach interventions'; 5 studies that provided a summary format for systematic review findings (e.g. summary of findings tables) were grouped together. There was high certainty evidence of a small beneficial impact of outreach interventions on health and moderate certainty evidence of impact on practice (mostly prescribing). There was no evidence of impact on policy and very low certainty around benefits on outcomes and out-takes. We found no consistent benefits of summary formats for systematic review results on outcomes or out-takes (moderate quality evidence). Other interventions with less evidence are reported in the Additional Materials., Conclusions: Outreach interventions to disseminate clinical research results can lead to changes in practice and improvements in health. However, these interventions can be resource-intensive. Investment is vital to identify and implement effective and cost-effective ways to disseminate results, so that the potential benefits of trials to patients can be realised., Trial Registration: International Prospective Register of Systematic Reviews (PROSPERO), CRD42019137364., (© 2024. The Author(s).)

Aims: Androgen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer., Materials and Methods: The PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE [NCT00268476] platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately., Results: Recruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of -3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3-13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80-1.53; P = 0.54). Oncological outcomes are awaited., Future: Efficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure - overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Emerging data indicate comparable disease control and toxicity of normal postoperative fractionation and moderate hypofractionation radiation therapy (RT) in prostate cancer. In RADICALS-RT, patients were planned for treatment with either 66 Gy in 33 fractions (f) over 6.5 weeks or 52.5 Gy in 20f over 4 weeks. This non-randomized, exploratory analysis explored the toxicity of these 2 schedules in patients who had adjuvant RT., Methods and Materials: Information on RT dose was collected in all patients. The Radiation Therapy Oncology Group toxicity score was recorded every 4 months for 2 years, every 6 months until 5 years, then annually until 15 years. Patient-reported data were collected at baseline and at 1, 5, and 10 years using standard measures, including the Vaizey fecal incontinence score (bowel) and the International Continence Society Male Short-Form questionnaire (urinary incontinence). The highest event grade was recorded within the first 2 years and beyond 2 years and compared between treatment groups using the χ² test., Results: Of 634 patients, 217 (34%) were planned for 52.5 Gy/20f and 417 (66%) for 66 Gy/33f. In the first 2 years, grade 1 to 2 cystitis was reported more frequently among the 66 Gy/33f group (52.5 Gy/20f: 20% vs 66 Gy/33f: 30%; P = .04). After 2 years, grade 1 to 2 cystitis was reported in 16% in the 66-Gy group and 9% in the 52.5-Gy group (P = .08). Other toxic effects were similar in the 2 groups, and very few patients had any grade 3 to 4 toxic effects. Patients reported slightly higher urinary and fecal incontinence scores at 1 year than at baseline, but no clinically meaningful differences were reported between the 52.5 Gy/20f and 66 Gy/33f groups. Patient-reported health was similar at baseline and at 1 year and similar between the 52.5 Gy/20f and 66 Gy/33f groups., Conclusions: Severe toxic effects were rare after prostate bed radiation therapy with either 52.5 Gy/20f or 66 Gy/33f. Only modest differences were recorded in toxic effects or in patient-reported outcomes between these 2 schedules., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background: In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy., Methods: UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50-74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032., Findings: 202 562 eligible women were recruited (50 625 multimodal screening; 50 623 ultrasound screening; 101 314 no screening). 259 (0·5%) of 50 625 participants in the multimodal screening group and 520 (0·5%) of 101 314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04-13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4-13·0; p=0·042) at 18 years (21% [95% CI 15·6-26·2] vs 14% [95% CI 10·5-17·4])., Interpretation: To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer., Funding: National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal., Competing Interests: Declaration of interests UM had stock ownership, awarded by University College London (UCL) until October, 2021, in Abcodia, which holds the licence for risk of ovarian cancer algorithm (ROCA). UM and MKBP have received grants and AG-M, AR, SA, and MB have been funded by grants from the Medical Research Council (MRC), Cancer Research UK, the National Institute for Health Research (NIHR), and The Eve Appeal. UM has also received grants from the Australian National Health and Medical Research Council (NHMRC) and salary support from University College London Hospitals Biomedical Research Centre. UM, AG-M, and SA report research collaboration contracts with Cambridge University, QIMR Berghofer Medical Research Institute, Intelligent Lab on Fiber, RNA Guardian, Micronoma, MercyBio Analytics, Imperial College London, University of Innsbruck, and Dana Farber USA. UM holds patent number EP10178345.4 for Breast Cancer Diagnostics. UM received an honorarium for a lecture from the New York Obstetrical Society (USA), and was reimbursed for travel by New York Obstetrical Society, US National Cancer Policy Forum, and Robinson College, Cambridge, UK. UM is a member of Tina's Wish Scientific Advisory Board (USA) and Research Advisory Panel, Yorkshire Cancer Research (UK). She has been a member of International Alliance for Cancer Early Detection (ACED); data monitoring committee for the mixed COVID-19 vaccines study in India; Good Clinical Practice Professional Certification Scheme steering committee, CDSA, India; Clinical and Public Health Fellowship Selection Committee, Wellcome Trust DBT India Alliance; Prevention Expert Review Panel, Population Research Committee, Cancer Research UK; and chair of the data monitoring committee for GEM3. AG-M is a member of ACED Gynaecological Cancer Working Group and is ACED codirector Research Domain Trials. MKBP was an Associate Member of the EME funding committee while the project was active. SA reports funding to UCL from Abcodia between 2011 and 2020. SJS codeveloped ROCA in 1995, which was patented by Massachusetts General Hospital, MA, USA, and Queen Mary University of London, London, UK, and is owned by these universities (the patent has expired). Massachusetts General Hospital and Queen Mary University of London granted a licence for the ROCA to Abcodia in 2014. SJS reports stock options from SISCAPA Assay Technologies for participation on a board and from the US National Cancer Institute, NIHR, and Mercy Bioanalytics. SJS participated in the independent data monitoring committee for GRAIL, and served on the clinical advisory board for Guardant Health (for which he was paid consulting fees), and on the Scientific Advisory Board for LUNGevity. SJS also has a collaboration agreement with Freenome. IJJ reports grants from Eve Appeal Charity, MRC, Cancer Research UK, and NIHR during the conduct of the study. IJJ coinvented the ROCA in 1995. Massachusetts General Hospital and Queen Mary University of London granted a licence for the ROCA to Abcodia in 2014. IJJ is non-executive director, shareholder, and consultant to Abcodia and has rights to royalties from sales of the ROCA. IJJ founded (in 1985), was a trustee of (2012–14), and is now an Emeritus trustee (2015–present) of The Eve Appeal, one of the funding agencies for UKCTOCS. LF reports MRC funding for the psychosocial group of the UKCTOCS study 2001–13, paid to University of Sussex. NS received honoraria from AstraZeneca–MSD and GSK for participation in advisory boards. AJM was a member of NIHR Health Technology Assessment and Efficacy and Mechanism Evaluation editoral board (2012–22). RM reports funding from The Eve Appeal, Rosetrees Trust, Barts Charity, Yorkshire Cancer Research, Ovacure, British Gynaecological Cancer Society, AstraZeneca, and GSK. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours., Methods: The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591., Findings: We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55-85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9-11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (p interaction =0·0019), higher volume of metastases (p interaction =0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (p interaction =0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (-1%, 95% CI -15 to 12, for progression-free survival; 0%, -10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival)., Interpretation: The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes., Funding: UK Medical Research Council and Prostate Cancer UK., Competing Interests: Declaration of interests BT declares consulting fees from Amgen, Astellas, Bayer, Ferring, Novartis, and Janssen; payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Amgen, Astellas, Bayer, Ferring, Novartis, Janssen, and Myovant during the past 36 months. CJS declares grants or contracts from Bayer, Sanofi, Astellas/Pfizer, Dendreon, and Janssen, and personal consulting fees from Bayer, Astellas, Janssen, CellCentric, PointBiopharma, Pfizer, Novartis, Genentech/Roche, Bristol Myers Squibb (BMS), Lilly, Henguiu, and AstraZeneca during the past 36 months. GG declares institutional grants from BMS; institutional payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Janssen, Amgen, BMS, IPSEN, AAA, Curium, AstraZeneca, Bayer, Pfizer/Merck, and Astellas; personal payment for expert testimony from BMS, Bayer, and Pfizer/Merck; and institutional support for attending meetings or travel from Janssen, BMS, AstraZeneca, Bayer, and Pfizer/Merck during the past 36 months. GL declares payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Sanofi-Genzyme; participation on a data safety monitoring board or advisory board from Janssen; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, from ECOG-ACRIN (Prostate Cancer Subcommittee Chair) during the past 36 months. MRS declares grants or contracts from Astellas, Clovis Oncology, Janssen, Pfizer, Novartis, and Sanofi-Aventis (all on research that is independent of this manuscript); consulting fees from Eli Lilly; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Lilly Oncology and Janssen (speaker fees not relating to any particular medicinal product) during the past 36 months. KF declares institutional honoraria for participation on advisory boards and in talks for Amgen, Astellas, AstraZeneca, Bayer, Clovis, Daiichi Sankyo, Janssen, MSD, Novartis/AAA, Pfizer, and Sanofi, and personal honoraria for participation in advisory boards with Arvinas, CureVac and Orion during the past 36 months. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival., Methods: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0-2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m 2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544)., Findings: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86-107) in the abiraterone trial and 72 months (61-74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8-86·9) in the abiraterone group versus 45·7 months (41·6-52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53-0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9-81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3-59·0) in the standard of care group (HR 0·65 [0·55-0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83-1·32]; p interaction =0·71) or between-trial heterogeneity (I 2 p=0·70). In the first 5 years of treatment, grade 3-5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial)., Interpretation: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years., Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas., Competing Interests: Declaration of interests GA reports personal fees, grants, and travel support from Janssen and Astellas; personal fees or travel support from Pfizer, Ipsen, Novartis (Advanced Accelerator Applications), Abbott Laboratories, Ferring, ESSA Pharmaceuticals, Bayer Healthcare Pharmaceuticals, BeiGene, Takeda, AstraZeneca, and Sanofi Aventis; grant support from AstraZeneca, Innocrin Pharma, and Arno Therapeutics; receives a share of the royalty income from The Institute of Cancer Research Rewards to Discoverers Scheme for abiraterone; and holds a patent on plasma methylation signatures as biomarkers for prostate cancer (GB1915469.9). LM, AC, CB, CG, HR, CLA, CM, NP, CP, CD-M, DG, MRS, LCB, REL, and MKBP report research grants for the STAMPEDE trial from Janssen, Astellas, Novartis, Sanofi, and Clovis. NWC reports personal fees from Janssen and Astellas. AS reports grants or contracts with the National Institute for Health Research, John Black Charitable Foundation, and Prostate Cancer Foundation. RJJ reports research grants from Astellas, Clovis, Exelixis, Bayer, and Roche; and advisory board participation and speaker's honoraria from Janssen, Astellas, Bayer, Novartis, Pfizer, Merck Serono, MSD, Roche, Ipsen, and Bristol Myers Squibb. CCP reports consulting fees from Advanced Accelerator Applications, ITM Radiopharma, Myovant, and Clarity Pharmaceuticals; and speaker's honoraria from Janssen and Bayer. SG reports consulting fees from Tolremo; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, educational events, and honoraria from Silvio Grasso Consulting, WebMD (Medscape), European Society of Medical Oncology, Orikata, Swiss Group for Clinical Cancer Research, Beijing United Family Hospital and Clinics, Deutchland European School of Oncology, Swiss Academy of Multidisciplinary Oncology, PeerVoice, and Radiotelevisione Svizzera Italiana; travel support from Proteomedix and AstraZeneca; a patent for biomarker discovery (WO 2009138392 A1); advisory board participation for Janssen, MSD, Bayer, Roche, Astellas, Pfizer, Telixpharma, Bristol Myers Squibb, Advanced Accelerator Applications, Orion, Novartis, Modra Pharmaceuticals, AstraZeneca, Myriad Genetic, and Amgen; and a scientific committee role for Pfizer. CG reports institution funding from Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi Genzyme; and charitable funding from Cancer Research UK and Medical Research Council. SC reports consulting fees from Telix, Novartis (Advanced Accelerator Applications), Huma, Remedy Bio, and Curesponse; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bayer, Janssen, Astellas, Amgen, and Advanced Accelerator Applications; participation on a data safety monitoring board or advisory board for Amgen, Janssen, and Bayer; and stocks in Huma and Remedy Bio. JMO reports a grant from Prostate Cancer UK. AB reports speaker's fees from Janssen, Astellas, Bristol Myers Squibb, Roche, MSD, and Bayer; support for attending meetings and travel from Janssen and Bayer; and participation on a data safety monitoring board or advisory board for Janssen, Bristol Myers Squibb, and AstraZeneca. NS reports support for travel expenses from Janssen-Cilag. JT reports support from Janssen and Astellas for conference attendance; and participation in advisory boards for Janssen and Astellas. PD reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Pfizer, Bristol Myers Squibb, Ipsen, EUSA Pharma, and EISAI; support for attending meetings or travel from Janssen and Ipsen; and participation on a data safety monitoring board or advisory board for Pfizer and EUSA Pharma. OP reports support for educational meetings and conference attendance from Janssen and Astellas. AR reports sponsorships for attending a conference from Janssen. AHM reports sponsorship to attend an educational meeting from Astellas. RC reports consulting fees from Astellas, Bayer, Novartis, Janssen, Sanofi, Pfizer, MSD, Bristol Myers Squibb, Roche, Debiopharm, AstraZeneca, Ipsen, and Merck; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Astellas, Janssen, Roche, and Merck; and participation as a board member for the Swiss Group for Clinical Cancer Research. DPD reports consulting fees and participation on an advisory board for Janssen; and a patent for a localisation and stabilisation device (EP1933709B1). MRS reports speaker fees from Eisai and being a non-paid member of independent data monitoring committees for academic sponsors. NDJ reports research grants for the STAMPEDE trial from Janssen, Astellas, Novartis, Sanofi, Clovis, and Cancer Research UK; and consulting and lecture fees from Astellas and Janssen. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Increasing evidence suggests that some immunotherapy dosing regimens for patients with advanced cancer could result in overtreatment. Given the high costs of these agents, and important implications for quality of life and toxicity, new approaches are needed to identify and reduce unnecessary treatment. Conventional two-arm non-inferiority designs are inefficient in this context because they require large numbers of patients to explore a single alternative to the standard of care. Here, we discuss the potential problem of overtreatment with anti-PD-1 directed agents in general and introduce REFINE-Lung (NCT05085028), a UK multicentre phase 3 study of reduced frequency pembrolizumab in advanced non-small-cell lung cancer. REFINE-Lung uses a novel multi-arm multi-stage response over continuous interventions (MAMS-ROCI) design to determine the optimal dose frequency of pembrolizumab. Along with a similarly designed basket study of patients with renal cancer and melanoma, REFINE-Lung and the MAMS-ROCI design could contribute to practice-changing advances in patient care and form a template for future immunotherapy optimisation studies across cancer types and indications. This new trial design is applicable to many new or existing agents for which optimisation of dose, frequency, or duration of therapy is desirable., Competing Interests: Declaration of interests EG has received consultancy fees from Achilles Therapeutics. CO has received consultancy fees from Sebastian Bio, speaker fees from Bristol Myers Squibb; is on the scientific advisory board of Neuvogen and Sebastian Bio; has received research funding from Merck Sharpe and Dohme and Verastem; and has received institutional research funding from Delcath Systems, Merck Sharpe and Dohme, PsiOxus, Touchlight Genetics, Transgene, and Verastem. FB has received research funding from Merck and Roche. JS has stock ownership in Epsilogen; has received assistance in attendance of scientific meetings from Amgen, Bristol Myers Squibb, and Janssen; and has received institutional reimbursement for advisory roles from 4D Pharma, Apobec, Avacta, AstraZeneca, Bristol Myers Squibb, and Roche. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We describe the command artbin, which offers various new facilities for the calculation of sample size for binary outcome variables that are not otherwise available in Stata. While artbin has been available since 2004, it has not been previously described in the Stata Journal . artbin has been recently updated to include new options for different statistical tests, methods and study designs, improved syntax, and better handling of noninferiority trials. In this article, we describe the updated version of artbin and detail the various formulas used within artbin in different settings.

We describe a new command, artcat, that calculates sample size or power for a randomized controlled trial or similar experiment with an ordered categorical outcome, where analysis is by the proportional-odds model. artcat implements the method of Whitehead (1993, Statistics in Medicine 12: 2257-2271). We also propose and implement a new method that 1) allows the user to specify a treatment effect that does not obey the proportional-odds assumption, 2) offers greater accuracy for large treatment effects, and 3) allows for noninferiority trials. We illustrate the command and explore the value of an ordered categorical outcome over a binary outcome in various settings. We show by simulation that the methods perform well and that the new method is more accurate than Whitehead's method.

Background: MND-SMART is a platform, multi-arm, multi-stage, multi-centre, randomised controlled trial recruiting people with motor neuron disease. Initially, the treatments memantine and trazodone will each be compared against placebo, but other investigational treatments will be introduced into the trial later. The co-primary outcomes are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALS-FRS-R) functional outcome, which is assessed longitudinally, and overall survival., Methods: Initially in MND-SMART, participants are randomised 1:1:1 via a minimisation algorithm to receive placebo or one of the two investigational treatments with up to 531 to be randomised in total. The comparisons between each research arm and placebo will be conducted in four stages, with the opportunity to cease further randomisations to poorly performing research arms at the end of stages 1 or 2. The final ALS-FRS-R analysis will be at the end of stage 3 and final survival analysis at the end of stage 4. The estimands for the co-primary outcomes are described in detail. The primary analysis of ALS-FRS-R at the end of stages 1 to 3 will involve fitting a normal linear mixed model to the data to calculate a mean difference in rate of ALS-FRS-R change between each research treatment and placebo. The pairwise type 1 error rate will be controlled, because each treatment comparison will generate its own distinct and separate interpretation. This publication is based on a formal statistical analysis plan document that was finalised and signed on 18 May 2022., Discussion: In developing the statistical analysis plan, we had to carefully consider several issues such as multiple testing, estimand specification, interim analyses, and statistical analysis of the repeated measurements of ALS-FRS-R. This analysis plan attempts to balance multiple factors, including minimisation of bias, maximising power and precision, and deriving clinically interpretable summaries of treatment effects., Trial Registration: EudraCT Number, 2019-000099-41. Registered 2 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=mnd-smart ClinicalTrials.gov, NCT04302870 . Registered 10 March 2020., (© 2023. The Author(s).)

Background: Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations., Methods: Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a 1-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols., Results: We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement., Discussion: Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently., (© 2022. The Author(s).)

Background: Genomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown., Methods: We performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression., Results: The burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10 -6 ). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov-Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037)., Conclusions: Copy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes., Trial Registration: ClinicalTrials.gov NCT00268476 , registered on December 22, 2005. EudraCT  2004-000193-31 , registered on October 4, 2004., (© 2022. The Author(s).)

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10 -9 ) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2-3 months. Recent improved mechanistic understanding of MND heralds a new translational era with many potential targets being identified that are ripe for clinical trials. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART) aims to evaluate the efficacy of drugs efficiently and definitively in a multi-arm, multi-stage, adaptive trial. The first two drugs selected for evaluation in MND-SMART are trazodone and memantine., Methods and Analysis: Initially, up to 531 participants (177/arm) will be randomised 1:1:1 to oral liquid trazodone, memantine and placebo. The coprimary outcome measures are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) and survival. Comparisons will be conducted in four stages. The decision to continue randomising to arms after each stage will be made by the Trial Steering Committee who receive recommendations from the Independent Data Monitoring Committee. The primary analysis of ALSFRS-R will be conducted when 150 participants/arm, excluding long survivors, have completed 18 months of treatment; if positive the survival effect will be inferentially analysed when 113 deaths have been observed in the placebo group. The trial design ensures that other promising drugs can be added for evaluation in planned trial adaptations. Using this novel trial design reduces time, cost and number of participants required to definitively (phase III) evaluate drugs and reduces exposure of participants to potentially ineffective treatments., Ethics and Dissemination: MND-SMART was approved by the West of Scotland Research Ethics Committee on 2 October 2019. (REC reference: 19/WS/0123) Results of the study will be submitted for publication in a peer-reviewed journal and a summary provided to participants., Trial Registration Numbers: European Clinical Trials Registry (2019-000099-41); NCT04302870., Competing Interests: Competing interests: CJW is a member of the independent data monitoring committee for a trial of masitinib in ALS, for which his institution receives funding from AB Science. In the last 3 years, JC has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society. A local principal investigator for commercial trials funded by: Actelion, Novartis and Roche; and has taken part in advisory boards/consultancy for Azadyne, Janssen, Merck, NervGen, Novartis and Roche., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival., Methods: Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression)., Results: Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity., Conclusions: There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases., (© The Author(s) 2022. Published by Oxford University Press.)

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., 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.

Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011-2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE's £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP's indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup., Competing Interests: Besides the funding declared above, • CDB reports grants from Novartis, Sanofi-Aventis, Pfizer, Janssen Pharma, Cancer Research UK, and Medical Research Council. • DD reports personal fees from The Institute of Cancer Research, grants from Cancer Research UK Program Grant and personal fees from Janssen. In addition, DD has a patent EP1933709B1 issued. • GA reports receiving commercial research grants from Janssen and AstraZeneca; has received honoraria and/or travel support from the speakers’ bureaus of Janssen, Astellas, Pfizer, Ferring, Sanofi-Aventis and Roche/Ventana; and has served as a consultant for/advisory board member of Janssen, Bayer, Astellas, Pfizer, Novartis, AstraZeneca, Orion, and Essa. GA has an ownership interest (including patents) in The Institute of Cancer Research Rewards to Discoverers for abiraterone acetate. • RJJ reports grants and personal fees from Astellas, AstraZeneca, Exelixis, and Roche; grants, personal fees and non-financial support from Bayer; personal fees and non-financial support from Bristol Myers Squibb, Janssen, Ipsen, and MSD; and personal fees from Merck Serono, Novartis, Pfizer, Sanofi Genzyme, and EUSA. • WC reports grants from Myriad Genetics. • CP reports personal fees from Bayer, Clarity, ITM (Isotopen Technologien Muenchen AG), Janssen, and Myovant. • SG reports personal fees from Sanofi, Orion, Roche, Janssen Cilag, and Amgen; other benefits from Menarini Silicon Biosystems, Bayer, AAA International, ProteoMediX, Toledo, and MSD; personal fees and other benefits from Astellas Pharma; and grants from Astellas Pharma. • ZM reports involvement in consultancy and advisory boards at Janssen and Sanofi, in advisory boards at Astellas, and sponsorship to attend medical conferences from Astellas, Bayer and Janssen. • NWC reports receiving research grants AstraZeneca and Janssen; honoraria and/or travel support from the speakers’ bureaus of Janssen, Astellas, Ferring, Sanofi-Aventis and has served as a consultant for/advisory board member of Janssen, Bayer, Astellas, Ferring, and AstraZeneca. • MKBP reports unrestricted grant funding to contribute to STAMPEDE overall from Astellas, Clovis Oncology, Novartis, Pfizer and Sanofi. • MRS reports grants from Clovis, grants and non-financial support from Astellas, Janssen, Novartis, Pfizer, and Sanofi to support the running of STAMPEDE; and personal fees from Lilly Oncology and Janssen for educational events unconnected to the submitted work or the underpinning trial. • NDJ reports grants and personal fees from Janssen, Astellas, and Sanofi, and personal fees from AstraZeneca, during the conduct of the study. • CSC, RMH, AG, FCI, DM, HLR, JMR, RM, JFL and JW have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.