Adjuvant or salvage radiotherapy for the treatment of localised prostate cancer? A prospectively planned aggregate data meta-analysis

Abstract

Abstract Background Three randomised trials, RADICALS (ISRCTN40814031), GETUG-AFU 17 (NCT00667069) and RAVES (NCT00860652), have compared adjuvant radiotherapy (ART) with a policy of salvage radiotherapy for PSA failure (SRT) after radical prostatectomy for men with localised prostate cancer, but have limited power for long-term outcomes. Therefore, the ARTISTIC collaboration prospectively planned a series of meta-analyses for each outcome. Methods Using a framework for adaptive meta-analysis (FAME), we prospectively defined our methods, including a consistent definition of PSA-driven event-free survival (EFS), prior to knowledge of trial results (CRD42019132669). We anticipated 240 events across all trials by Autumn 2019, giving 90% power to detect a 5% absolute difference in 5-year EFS. This provided a firm basis for a meta-analysis at this time. Results Across the 3 trials, 1074 men were randomised to ART and 1077 to SRT. To date, 395 men (37%) had commenced SRT. Patient characteristics were balanced within trials and overall. Men had median age of 65 years and most (77%) had a Gleason sum score of 7. Median follow-up ranged from 47 to 61 months. In August 2019, RADICALS and GETUG-AFU 17 provided EFS results for the meta-analysis (interim for GETUG-AFU 17). RAVES currently could only supply freedom from biochemical failure results. However, as the vast majority of first events across all trials are biochemical failures, these results have been pooled in a preliminary meta-analysis of EFS. Based on 245 events, the meta-analysis shows no evidence that EFS is improved with ART compared to SRT (HR\xa0=\xa01.09, 95% CI\xa0=\xa00.86-1.39, p\xa0=\xa00.47). This translates to a potential absolute difference of 1% at 5 years in favour of SRT (95% CI: 2% in favour ART to 4% in favour of SRT). Conclusions This collaborative, prospective and early meta-analysis of all men from 3 randomised trials, suggests that SRT and ART offer similar outcomes for EFS. However, SRT spares many men from receiving RT, and associated side-effects. Final data from GETUG-AFU 17 and RAVES may help establish whether some subgroups of men might benefit from either treatment. Longer follow-up is needed for a meta-analysis of metastasis-free survival. Clinical trial identification ISRCTN40814031; NCT00667069; NCT00860652. Legal entity responsible for the study University College London. Funding UK Medical Research Council. Disclosure C. Parker: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research Funding, Speaker Fees and Advisory Board Honoraria: Bayer; Honoraria (self), Advisory / Consultancy, Advisory Board Honoraria: AAA; Honoraria (self), Speaker Bureau / Expert testimony, Speaker Fees: Janssen. M.K.B. Parmar: Research grant / Funding (institution), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Astellas; Research grant / Funding (institution), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Clovis Oncology; Research grant / Funding (institution), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Novartis; Research grant / Funding (institution), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Pfizer; Research grant / Funding (institution), Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Sanofi. P. Sargos: Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies, Board and Meeting support: Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies, Board and Meeting support: Takeda; Non-remunerated activity/ies, Board and Meeting support: Ferring; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies, Board and Meeting support: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses, Board and Meeting support: Recordati. M.R. Sydes: Research grant / Funding (institution), Non-remunerated activity/ies, Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Astellas; Research grant / Funding (institution), Non-remunerated activity/ies, Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Clovis Oncology; Research grant / Funding (institution), Non-remunerated activity/ies, Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Novartis; Non-remunerated activity/ies, Unrestricted grant to contribute to another comparison of STAMPEDE which supports the protocol overall, plus relevant drug and distribution.: Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Speaker fee for educational meeting sponsored by Eli Lilly, plus travel costs: Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies, Unrestricted grant which contributes which supports the protocol overall, plus abiraterone and distribution for two of the STAMPEDE comparisons. Plus travel and speaker fees for two educational events (statistics lectures).: Janssen; Research grant / Funding (institution), Non-remunerated activity/ies, Unrestricted grant which contributes which supports the protocol overall, plus abiraterone and distribution for two of the STAMPEDE comparisons; Travel and speaker fees for two educational events (statistics lectures): Sanofi. All other authors have declared no conflicts of interest.