Men with prostate cancer can be spared radiotherapy after surgery

Barcelona, Spain, 27 September 2019 – Men with prostate cancer can be spared radiotherapy after surgery, according to late breaking results of the RADICALS-RT trial presented at the ESMO Congress 2019 in Barcelona, Spain. (1,2) The study answers a longstanding question about whether the benefits of radiotherapy after surgery outweigh the side-effects.

RADICALS-RT is the largest ever trial of postoperative radiotherapy in prostate cancer. It found no difference in disease recurrence at five years between men who routinely had radiotherapy shortly after surgery and men who had radiotherapy later, if the cancer came back.

Study first author Prof Chris Parker, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK said: “The results suggest that radiotherapy is equally effective whether it is given to all men shortly after surgery or given later to those men with recurrent disease. There is a strong case now that observation should be the standard approach after surgery and radiotherapy should only be used if the cancer comes back.”

“The good news is that in future, many men will avoid the side-effects of radiotherapy,” added Parker. “These include urinary leakage and narrowing of the urethra, which can make urination difficult. Both are potential complications after surgery alone, but the risk is increased if radiotherapy is used as well.”

The findings were confirmed in a collaborative meta-analysis, also presented at the ESMO Congress 2019, combining results of RADICALS with two similar trials, RAVES and GETUG-AFU17. (3) Author of the analysis, Dr Claire Vale, MRC Clinical Trials Unit, University College London, UK, said: “Results of the ARTISTIC meta-analysis confirm those of RADICALS, and provide greater evidence to support the routine use of observation and early salvage radiotherapy.”

“The meta-analysis provides the best opportunity to assess whether adjuvant radiotherapy may still have a role in some groups of men, and to investigate longer term outcomes,” added Vale.

Commenting on the data, Dr Xavier Maldonado, Hospital Universitari Vall d’Hebron, Barcelona, said: “These are the first results to suggest that postoperative radiotherapy for prostate cancer could be omitted or delayed in some patients. This will shorten the duration of treatment for these patients and allow better use of resources since today’s radiotherapy is technically sophisticated and therefore expensive. However, strict follow-up will be needed to identify patients requiring salvage radiotherapy.”

Maldonado noted that longer follow-up is needed for the main endpoint of RADICALS-RT, which is freedom from distant metastases at ten years, and to comprehensively report on toxicities.

Regarding the need for future research, Maldonado said the focus should be pinpointing which patients still require adjuvant radiotherapy to avoid a very early local relapse and potential subsequent metastases. “We need to develop genomic classifiers to help decide the best management strategy for each patient – whether it should include surgery and/or radiotherapy, and at which time points,” he said.

Results of RADICALS-RT

RADICALS-RT (NCT00541047) enrolled 1,396 patients after surgery for prostate cancer from the UK, Denmark, Canada, and Ireland. Men were randomly allocated to postoperative radiotherapy or the standard approach of observation only, with radiotherapy kept as an option if the disease recurred.

At a median follow-up of five years, progression free survival was 85% in the radiotherapy group and 88% in the standard care group (hazard ratio [HR] 1.10; 95% confidence interval [CI] 0.81-1.49; p=0.56).

Self-reported urinary incontinence was worse at one year in 5.3% of patients receiving radiotherapy compared to 2.7% who had standard care (p=0.008). Radiation Therapy Oncology Group (RTOG) grade 3/4 urethral stricture was reported at any time in 8% versus 5% of the radiotherapy and standard care groups, respectively (p=0.03). Longer follow-up is needed to report on survival and on the primary outcome of freedom from distant metastases.

Results of the ARTISTIC meta-analysis

The ARTISTIC collaboration meta-analysis included three randomised trials comparing adjuvant radiotherapy with early salvage radiotherapy following prostatectomy for men with localised prostate cancer: RADICALS (ISRCTN40814031), GETUG-AFU 17 (NCT00667069), and RAVES (NCT00860652). The analysis was planned before the results of the trials were known.

The results are based on all 2,151 men included in the three trials, of whom 1,074 were randomised to adjuvant radiotherapy and 1,077 men were randomised to early salvage radiotherapy – of those, 395 men (37%) have commenced salvage treatment to date.

The analysis found no evidence that adjuvant radiotherapy improves event free survival compared to early salvage radiotherapy (HR 1.12; 95% CI 0.88-1.42; p=0.37). (4) Based on these results, the difference in five-year event free survival is likely only to be around 1%.

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Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO Congress 2019

Official Congress Hashtag: #ESMO19

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References

1 LBA49_PR ‘Timing of radiotherapy (RT) after radical prostatectomy (RP): first results from the RADICALS RT randomised controlled trial (RCT) [NCT00541047]’ will be presented by Chris Parker during the Proffered Paper session on Friday, 27 September, 14:00 to 15:30 (CEST) in Sevilla Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019

2 https://www.esmo.org/Conferences/ESMO-Congress-2019

3 LBA48_PR ‘Adjuvant or salvage radiotherapy for the treatment of localised prostate cancer? A prospectively planned aggregate data meta-analysis’ will be presented by Claire L. Vale during the Proffered Paper session on Friday, 27 September, 14:00 to 15:30 (CEST) in Sevilla Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019

4 The data in the press release are the final data reported at ESMO 2019 and are updated from the initial abstract.

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LBA49_PR – Timing of Radiotherapy (RT) After Radical Prostatectomy (RP): First Results from the RADICALS RT Randomised Controlled Trial (RCT) [NCT00541047]

C. Parker¹, N.W. Clarke², A. Cook³, H.G. Kynaston⁴, P. Meidahl Petersen⁵, W. Cross⁶, R. Persad⁷, C. Catton⁸, J. Logue⁹, H. Payne¹⁰, F. Saad¹¹, K. Brasso¹², H. Lindberg¹³, A. Zarkar¹⁴, R. Raman¹⁵, M.A. Roder⁵, C. Heath¹⁶, W.R. Parulekar¹⁷, M.K.B. Parmar¹⁸, M.R. Sydes¹⁹

1Department Of Urology, The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, Sutton, United Kingdom, 2The Departments Of Surgery And Urology, The Christie and Salford Royal Hospitals, Manchester, United Kingdom, 3Mrc Clinical Trials Unit At Ucl, Institute of Clinical Trials and Methodology, UCL, London, United Kingdom, 4Division Of Cancer And Genetics, Cardiff School of Medicine, Cardiff, United Kingdom, 5Oncology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark, 6Department Of Urology, St James University Hospital, Leeds, United Kingdom, 7Bristol Urological Institute, North Bristol Hospitals, Bristol, United Kingdom, 8Radiation Oncology, Princess Margaret Hospital/ University Health Network, Toronto, Canada, 9Oncology, The Christie Hospital, Manchester, United Kingdom, 10Oncology, University College London Hospitals, London, United Kingdom, 11Department D’urologie, Centre Hospitalier de l’Universite de Montreal, Universite de Montreal, Montreal, Canada, 12Clinical Medicine, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark, 13Oncology, Herlev Hospital, Herlev, Denmark, 14Oncology, University Hospital Birmingham, Birmingham, United Kingdom, 15Oncology, Kent Oncology Centre, Canterbury, United Kingdom, 16Clinical Oncology, University Hospital Southampton, Southampton, United Kingdom, 17Oncology, Canadian Cancer Trials Group, Kingston, Canada, 18Institute Of Clinical Trials & Methodology, MRC Clinical Trials Unit at UCL, London, United Kingdom, 19Mrc Clinical Trials Unit At Ucl, Institute of Clinical Trials and Methodology-UCL, London, United Kingdom

Background: The optimal timing of RT after RP for prostate cancer (PCa) is uncertain. RADICALS-RT compared the efficacy and safety of adjuvant RT (aRT) versus an observation policy with salvage RT for PSA failure (Obs+sRT).

Methods: Patients with post-op PSA less than or equal to 0.2ng/ml and greater than or equal to 1 risk factor (pT3/4, Gleason 7-10, positive margins or pre-op PSA greater than or equal to 10ng/ml) were randomised less than or equal to 22wk after surgery to aRT or Obs+sRT for PSA failure (PSA greater than 0.1ng/ml or 3 consecutive rises). Stratification factors were Gleason score, margin status, RT schedule (52.5Gy/20f, 66Gy/33f) and centre. The primary outcome measure (OM) was freedom-from-distant metastases (FFDM) with >1200 pts needed for 80% power to detect an improvement from 90% to 95% at 10yr with aRT. It is too early to present results on the primary OM, but we present secondary OMs: bPFS (any of PSA greater than or equal to 0.4ng/ml post-RT, PSA greater than or equal to 2.0ng/ml at any time, local/distant progression, deferred HT, PCa death), freedom-from-non-protocol hormone therapy (HT), safety (RTOG scale), and patient reported OMs (ICSmaleSF). Standard survival analysis methods were used.

Results: 1396 pts were randomised (697 aRT, 699 Obs+sRT) from Oct-2007 to Dec-2016 (82% UK, 13% Denmark, 4% Canada, 1% Ireland). Median follow-up is 5yr. 93% (649/697) aRT started RT within 5mo; 33% (228/699) Obs+sRT started RT by 8yr after randomisation; 26% (166/649) aRT and 31% (71/228) Obs+sRT reported HT with their RT. With 169 events, bPFS at 5yr was 85% v 88% for aRT and Obs+sRT, respectively: HR=1.10 (95%CI 0.81-1.49, p=0.56). Freedom-from-non-protocol HT at 5yr was 92% v 94% (HR=1.24, 95%CI 0.76-2.01, p=0.39). Self-reported urinary incontinence was worse at 1yr in 5.3% vs 2.7% (p=0.008), and RTOG Grade 3/4 urethral stricture was reported at any time in 8% vs 5% (p=0.03), for aRT & Obs+sRT, respectively.

Conclusions: First results from RADICALS-RT do not show a benefit for aRT after RP in this patient group. Further follow-up is needed to report on long-term OMs, including FFDM. Adjuvant RT after RP increases risk of urinary morbidity. An observation policy with sRT for PSA failure should be the current standard after RP.

Clinical trial identification: RADICALS MRC Clinical Trials Unit at UCL Protocol v6.0 (14th Dec 2018) ISRCTN 40814031

Legal entity responsible for the study: University College London

Funding: Cancer Research UK; MRC Clinical Trials Unit at UCL; Canadian Cancer Trials Group

Disclosure: C. Parker: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research Funding, Speaker Fees and Advisory Board Honoraria: Bayer; Advisory / Consultancy, Advisory Board Honoraria: AAA; Speaker Bureau / Expert testimony, Speaker Fees: Janssen.

N.W. Clarke: Advisory / Consultancy, Consultation and advisory fees: Janssen.

C. Catton: Advisory / Consultancy, Consulting fees: Bayer; Advisory / Consultancy, Research grant / Funding (self), Consulting fees and research support: Abbvie; Advisory / Consultancy, Consulting fees: Sanofi; Research grant / Funding (institution), Peer reviewed trial funding: Canadian Cancer Trials Group.

H. Payne: Advisory / Consultancy, Speaker Bureau / Expert testimony, Paid lectures and advisory boards : Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Paid lectures and advisory boards: Astellas; Advisory / Consultancy, Paid advisory boards: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Paid lectures and advisory boards: Ferring; Advisory / Consultancy, Paid advisory boards: Ipsen.

F. Saad: Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Astellas; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Amgen; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Janssen; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bayer; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Sanofi; Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca.

H. Lindberg: Research grant / Funding (self), Non-remunerated activity/ies: Astellas Pharma; Research grant / Funding (self), Non-remunerated activity/ies: Bayer; Research grant / Funding (self), Non-remunerated activity/ies: Janssen; Research grant / Funding (self), Non-remunerated activity/ies: Sanofi Aventis; Research grant / Funding (self): Roche.

A. Zarkar: Travel / Accommodation / Expenses, Support for attendance of a conference: Bayer; Speaker Bureau / Expert testimony, Educational meeting presentation: Pfizer; Speaker Bureau / Expert testimony, Chairing an educational meeting presentation: Janssen; Speaker Bureau / Expert testimony, Educational meeting presentation: Astellas; Research grant / Funding (self), IST: Sanofi.

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.

M.R. Sydes: 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; Speaker Bureau / Expert testimony, Speaker Fees: Janssen.

LBA48_PR – Adjuvant or salvage radiotherapy for the treatment of localised prostate cancer? A prospectively planned aggregate data meta-analysis

C.L. Vale1, M. Brihoum2, S. Chabaud3, A. Cook1, D. Fisher1, S. Forcat1, C. Fraser-Browne4, A. Herschtal5, A. Kneebone6, S. Nenan7, C. Parker8, M.K.B. Parmar9, M. Pearse10, P. Richaud11, E. Rogozinska1, P. Sargos11, M.R. Sydes9, J.F. Tierney1

1Mrc Clinical Trials Unit At Ucl, Institute of Clinical Trials and Methodology, UCL, London, United Kingdom, 2Direction De La Recherche Et Du Developpement, Unicancer, Paris, France, 3Biostatistics, Centre Leon Berard, Lyon, France, 4Cancer And Blood Research, Auckland City Hospital, Auckland, New Zealand, 5Department Of Biostatistics And Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Australia, 6Department Of Radiation Oncology, Northern Sydney Cancer Centre, Sydney, Australia, 7Getug – Gerico – Supportive Care Group, Unicancer, Paris, France, 8Department Of Urology, The Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Sutton, United Kingdom, 9Institute Of Clinical Trials & Methodology, MRC Clinical Trials Unit at UCL, London, United Kingdom, 10Department Of Radiation Oncology, Auckland City Hospital, Auckland, New Zealand, 11Radiation Therapy Unit, Institute Bergonie, Bordeaux, France

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=1.09, 95% CI=0.86-1.39, p=0.47). 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: RADICALS: ISRCTN40814031 GETUG-17: NCT00667069 RAVES: 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. Plus travel and speaker fees for two educational events (statistics lectures).: Sanofi.