Abstract 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≤0.2ng/ml and ≥1 risk factor (pT3/4, Gleason 7-10, positive margins or pre-op PSA≥10ng/ml) were randomised ≤22wk after surgery to aRT or Obs+sRT for PSA failure (PSA≥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≥0.4ng/ml post-RT, PSA≥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 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. All other authors have declared no conflicts of interest.