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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.)

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.

Importance: Prostate radiotherapy (RT) improves survival in men with low-burden metastatic prostate cancer. However, owing to the dichotomized nature of metastatic burden criteria, it is not clear how this benefit varies with bone metastasis counts and metastatic site., Objective: To evaluate the association of bone metastasis count and location with survival benefit from prostate RT., Design, Setting, and Participants: This exploratory analysis of treatment outcomes based on metastatic site and extent as determined by conventional imaging (computed tomography/magnetic resonance imaging and bone scan) evaluated patients with newly diagnosed metastatic prostate cancer randomized within the STAMPEDE trial's metastasis M1 RT comparison. The association of baseline bone metastasis counts with overall survival (OS) and failure-free survival (FFS) was assessed using a multivariable fractional polynomial interaction procedure. Further analysis was conducted in subgroups., Interventions: Patients were randomized to receive either standard of care (androgen deprivation therapy with or without docetaxel) or standard of care and prostate RT., Main Outcomes and Measures: The primary outcomes were OS and FFS., Results: A total of 1939 of 2061 men were included (median [interquartile range] age, 68 [63-73] years); 1732 (89%) had bone metastases. Bone metastasis counts were associated with OS and FFS benefit from prostate RT. Survival benefit decreased continuously as the number of bone metastases increased, with benefit most pronounced up to 3 bone metastases. A plot of estimated treatment effect indicated that the upper 95% CI crossed the line of equivalence (hazard ratio [HR], 1) above 3 bone metastases without a detectable change point. Further analysis based on subgroups showed that the magnitude of benefit from the addition of prostate RT was greater in patients with low metastatic burden with only nonregional lymph nodes (M1a) or 3 or fewer bone metastases without visceral metastasis (HR for OS, 0.62; 95% CI, 0.46-0.83; HR for FFS, 0.57; 95% CI, 0.47-0.70) than among patients with 4 or more bone metastases or any visceral/other metastasis (HR for OS, 1.08; 95% CI, 0.91-1.28; interaction P = .003; HR for FFS, 0.87; 95% CI, 0.76-0.99; interaction P = .002)., Conclusions and Relevance: In this exploratory analysis of a randomized clinical trial, bone metastasis count and metastasis location based on conventional imaging were associated with OS and FFS benefit from prostate RT in M1 disease., Trial Registration: ClinicalTrials.gov Identifier: NCT00268476; ISRCTN.com Identifier: ISRCTN78818544.

Background: Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy., Methods: We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476., Findings: Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63-73) and median amount of prostate-specific antigen of 97 ng/mL (33-315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68-0·84; p<0·0001) but not overall survival (0·92, 0·80-1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3-4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy)., Interpretation: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer., Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis., (Copyright © 2018 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.)