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Additional Treatments to the Local tumour for metastatic prostate cancer: Assessment of Novel Treatment Algorithms, a multicentre, phase II randomised controlled trial (IP2-ATLANTA)

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-042953

Article Type: Protocol

Date Submitted by the 24-Jul-2020 Author:

Complete List of Authors: Connor, Martin; Imperial College London, Department of Surgery and Cancer; Imperial College Healthcare NHS Trust, Imperial Urology Shah, Taimur T; Imperial College London, Department of Surgery and Cancer Smigielska, Katarzyna; Imperial College London, Department of Surgery and Cancer; Imperial College London, Imperial College Clinical Trials Unit Day, Emily; Imperial College London, Imperial College Clinical Trials Unit Sukumar, Johanna; Imperial College London, Department of Surgery and Cancer; Imperial College London, Imperial College Clinical Trials Unit Fiorentino, Francesca; Imperial College London, Imperial College Clinical Trials Unit Sarwar, Naveed; Imperial College Healthcare NHS Trust, Department of Oncology http://bmjopen.bmj.com/ Gonzalez, Michael; Imperial College Healthcare NHS Trust, Department of Oncology Falconer, Alison; Imperial College Healthcare NHS Trust, Department of Oncology Klimowska-Nassar, Natalia; Imperial College London, Department of Surgery and Cancer; Imperial College London, Imperial College Clinical Trials Unit Evans , Martin; Imperial College London, Department of Surgery and

Cancer on October 1, 2021 by guest. Protected copyright. Naismith, Olivia; Royal Marsden NHS Foundation Trust, Radiotherapy Trials Quality Assurance (RTTQA) Thippu Jayaprakash, Kamalram; Addenbrooke's Hospital, Department of Oncology Price, Derek; Imperial College London, Department of Surgery and Cancer Gayadeen, Shiva; Imperial College Healthcare NHS Trust, Department of Oncology Basak, Dolan; Imperial College Healthcare NHS Trust, Department of Oncology Horan, Gail; Addenbrooke's Hospital, Department of Oncology McGrath, John; Royal Devon and Exeter NHS Foundation Trust, Urology Sheehan, Denise; Royal Devon and Exeter NHS Foundation Trust, Department of Oncology Kumar, Manal; Arrowe Park Hospital, Department of Urology Ibrahim , Azman; Clatterbridge Cancer Centre NHS Foundation Trust,

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 39 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 1 2 3 Department of Clinical Oncology 4 Brock, Cathryn; Chelsea and Westminster Hospital NHS Foundation 5 Trust, Department of Oncology 6 Pearson, Rachel; Newcastle Upon Tyne Hospitals NHS Foundation Trust, 7 Department of Oncology 8 Anyamene , Nicola; London North West University Healthcare NHS Trust, 9 Department of Oncology Heath , Catherine; University Hospital Southampton NHS Foundation 10 Trust, Department of Radiotherapy 11 Shergill, Iqbal; Wrexham Maelor Hospital, Department of Urology 12 Rai, Bhavan; Newcastle Upon Tyne Hospitals NHS Foundation Trust, 13 Department of Urology 14 Hellawell, Giles; London North West University Healthcare NHS Trust, 15 Department of Urology 16 Mccracken, Stuart; Sunderland Royal Hospital, Department of Urology For peerKhoubehi, Bijan; review Chelsea and Westminster only Healthcare NHS Trust, 17 Department of Urology 18 Mangar, Stephen; Imperial College Healthcare NHS Trust, Department of 19 Oncology 20 Khoo, Vincent; Royal Marsden NHS Foundation Trust, Department of 21 Oncology 22 Dudderidge, Tim; University Hospital Southampton NHS Foundation Trust, Department of Urology 23 Staffurth, John; Velindre Cancer Centre, Research; Cardiff University 24 School of Medicine, Division of Cancer and Genetics 25 Winkler, Mathias; Imperial College London, Department of Surgery and 26 Cancer; Imperial College Healthcare NHS Trust, Imperial Urology 27 Ahmed, Hashim; Imperial College London Division of Surgery, Imperial 28 College London 29 Prostate disease < UROLOGY, Radiation oncology < RADIOTHERAPY, 30 Keywords: RADIOTHERAPY, UROLOGY, Urological tumours < UROLOGY, 31 Genitourinary imaging < RADIOLOGY & IMAGING 32 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 on October 1, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 39

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4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the terms applicable for US Federal Government officers or employees acting as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author Forunless you peer are acting as review an employee on behalf only of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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4 Additional Treatments to the Local tumour for metastatic BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 prostate cancer: Assessment of Novel Treatment 7 8 Algorithms, a multicentre, phase II randomised controlled 9 10 11 trial (IP2-ATLANTA) 12 13 14 Martin J. Connor [1,2,3], Taimur T Shah [1], Kasia Smigielska [1,4], Emily Day [1,4], 15 16 Johanna Sukumar [1, 4], Francesca Fiorentino [1,4], Naveed Sarwar [5], Michael 17 18 Gonzalez [5], AlisonFor Falconer peer [5], Natalia review Klimowska-Nassar only [1, 4], Martin Evans [1, 19 4], Olivia Frances Naismith [6], Kamalram Thippu Jayaprakash [7], Derek Price [1], 20 21 Shiva Gayadeen [5], Dolan Basak [5], Gail Horan [7], John McGrath [8], Denise 22 23 Sheehan [8], Manal Kumar [9], Azman Ibrahim [10], Cathryn Brock [11], Rachel A. 24 25 Pearson [12], Nicola Anyamene [13], Catherine Heath [14], Iqbal Shergill [15], Bhavan 26 Rai [12], Giles Hellawell [13], Stewart McCracken [16], Bijan Khoubehi [11], Stephen 27 28 Mangar [5], Vincent Khoo [17], Tim Dudderidge [14], John Nicholas Staffurth [18], 29 30 Mathias Winkler [1,2,3], Hashim U. Ahmed [1,2] 31 32 33 1. Division of Surgery, Imperial Prostate, Department of Surgery and Cancer, 34 35 Faculty of Medicine, Imperial College London, London, UB1 3HW 36 37 2. Imperial Urology, Imperial College Healthcare NHS Trust, London, W6 8RF 38 3. Department of Urology, West Middlesex University Hospital (WMUH), Chelsea http://bmjopen.bmj.com/ 39 40 & Westminster NHS Foundation Trust, Isleworth, Middlesex, TW7 6AF 41 42 4. Imperial Clinical Trials Unit (ICTU), School of Public Health, Faculty of Medicine, 43 44 Imperial College London, London, UB1 3HW 45 5. Department of Oncology, Imperial College Healthcare NHS Foundation Trust, 46 on October 1, 2021 by guest. Protected copyright. 47 Charing Cross Hospital, London, W6 8RF 48 49 6. Radiotherapy Trials Quality Assurance (RTTQA), Department of Physics, The 50 Royal Marsden NHS Foundation Trust, London, SW3 6JJf 51 52 7.Department of Oncology, Addenbrooke’s Hospital and The Queen Elizabeth 53 54 Hospital Kings Lynn NHS Foundation, Norfolk, PE30 4ET 55 56 8.Department of Urology & Oncology, Royal Devon & Exeter Hospital, Exeter EX2 57 5DW 58 59 60

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1 2 3 9.Department of Urology, Arrowe Park Hospital, Wirral University NHS Foundation 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 Trust, Merseyside, CH49 5PE 6 7 10.Department of Oncology, Clatterbridge Cancer Centre NHS Foundation Trust, 8 Wirral, CH63 4JY 9 10 11.Department of Urology & Oncology, Chelsea and Westminster Hospital, 11 12 Chelsea & Westminster NHS Foundation Trust, SW10 9NH. 13 14 12.Department of Urology & Oncology, Northern Centre for Cancer Care, 15 Newcastle upon Tyne Hospitals NHS Foundation Trust, NE7 7DN 16 17 13.Department of Urology & Oncology, Northwick Park Hospital, London 18 For peer review only 19 Northwest University Healthcare NHS Trust, Harrow, HA1 3UJ 20 21 14.Department of Urology & Oncology, University Hospital Southampton NHS 22 Foundation Trust, Southampton, SO16 6YD 23 24 15.Department of Urology, Wrexham Maelor Hospital, Wales, LL13 7TD 25 26 16.Department of Urology, Sunderland Royal Hospital, Sunderland, SR4 7TP 27 17.Department of Clinical Oncology, The Royal Marsden Hospital & Institute of 28 29 Cancer Research, London, SW3 6JJ, 30 31 18.School of Medicine, Cardiff University, Cardiff, Wales, CF10 3AT 32 33 34 Corresponding Author: 35 36 Mr. Martin J. Connor 37 38 Division of Surgery http://bmjopen.bmj.com/ 39 40 Imperial Prostate 41 Department of Surgery & Cancer 42 43 Imperial College London 44 45 Room 5L.28 on October 1, 2021 by guest. Protected copyright. 46 Charing Cross Lab Block 47 48 [email protected] 49 50 51 52 Keywords: prostate cancer, metastatic, radiotherapy, radical prostatectomy, 53 cytoreductive, SABR, stereotactic radiotherapy, high intensity focussed ultrasound, 54 55 cryotherapy, oligo-metastatic disease, metastasis directed therapy. 56 57 58 59 60

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1 2 3 Abstract 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 7 Introduction: Survival in men diagnosed with de novo synchronous metastatic 8 prostate cancer has increased following the use of upfront systemic treatment, using 9 10 chemotherapy and other novel androgen receptor targeted agents, in addition to 11 12 standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis- 13 14 directed interventions are hypothesised to confer additional survival benefit. In this 15 setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the 16 17 addition of sequential multi-modal local and metastasis-directed treatments compared 18 For peer review only 19 to standard care alone. 20 21 22 23 Methods: A phase II, prospective, multi-centre, three-arm randomised controlled trial 24 incorporating an embedded feasibility pilot. All men with new histologically diagnosed, 25 26 hormone-sensitive, metastatic prostate cancer, within four months of commencing 27 28 ADT and of performance status 0 to 2 are eligible. Patients will be randomised to: 29 30 Control (Standard of Care [SOC]) OR Intervention 1 (minimally invasive ablative 31 therapy to prostate +/- pelvic lymph node dissection [PLND]) OR Intervention 2 32 33 (cytoreductive radical prostatectomy +/- PLND OR prostate radiotherapy +/- pelvic 34 35 lymph node radiotherapy [PLNRT]). Metastatic burden will be pre-specified using the 36 37 CHAARTED definition. Men with low burden disease in intervention arms are eligible 38 for metastasis-directed therapy, in the form of stereotactic ablative body radiotherapy http://bmjopen.bmj.com/ 39 40 (SABR) or surgery. Standard systemic therapy will be administered in all arms With 41 42 ADT +/- upfront systemic chemotherapy or androgen receptor agents. Patients will be 43 followed-up for a minimum of two-years. Primary outcome: PFS. Secondary outcomes 44 45 include: predictive factors for PFS and overall survival; urinary, sexual and rectal side- 46 on October 1, 2021 by guest. Protected copyright. 47 effects. Embedded feasibility sample size is 80, with 918 patients required in the main 48 49 phase II component. 50 51 52 53 Ethics and dissemination: Approved by HRA Wales REC 5 (19/WA0005). Funded 54 by the Wellcome Trust (204998/Z/16/Z). 55 56 57 58 Registration details: NCT03763253; ISCRTN58401737 59 60

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1 2 3 STRENGTHS AND LIMITATIONS OF THIS STUDY 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 7 1. IP2-ATLANTA addresses an important research gap in the role of local and 8 metastasis-directed therapy in men with newly-diagnosed metastatic prostate 9 10 cancer. 11 12 2. This is the first phase II trial to include cytoreductive minimally invasive ablative 13 14 therapy alongside cytoreductive radical prostatectomy and prostate 15 radiotherapy. 16 17 3. The IP2-ATLANTA study builds on the clinical benefits derived from metastasis- 18 For peer review only 19 directed therapy (stereotactic ablative body radiotherapy and/or surgery) in a 20 21 previously untreated cohort of men with advanced disease. 22 4. Due to invasive interventions, blinding is not possible in the IP2-ATLANTA 23 24 study. 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 INTRODUCTION 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 Overall, 47,000 men are diagnosed with prostate cancer each year in the United 6 7 Kingdom (UK) [1]. Approximately, 4,500 of these men this will be diagnosed with de 8 novo synchronous metastatic disease at presentation [1]. As with the United States, 9 10 where just under 8% present with metastatic disease and where the annual burden is 11 12 predicted to reach approximately 15,000 cases by 2025, so the prediction for the same 13 14 magnitude is likely for the UK [2]. 15 16 17 Traditionally, such men were managed with androgen deprivation therapy (ADT) 18 For peer review only 19 alone, via medical or surgical castration [2]. Unfortunately the median time to the 20 21 emergence of a castrate resistant state is in the order of 11 to 18 months, limiting 22 overall survival (OS) to 3.5 years [3, 4]. Promisingly, the reported OS in this group 23 24 has now risen to a median 4.8 years with the addition of upfront systemic agents, such 25 26 as Docetaxel, Enzalutamide, Abiraterone Acetate or Apalutamide [5-9]. 27 28 29 Moving beyond early systemic therapy escalation there has been an increased focus 30 31 on the role of local cytoreductive and metastasis-directed interventions (primarily 32 33 stereotactic ablative body radiotherapy [SABR]) to gain additional oncological benefit 34 [2]. This is in part based upon the emergence of the ‘oligo-metastatic state’, which may 35 36 exhibit different biological characteristics to poly-metastatic prostate cancer [10]. 37 38 http://bmjopen.bmj.com/ 39 40 Such men present with a clinically-defined favourable metastatic burden, and are 41 hypothesised to occupy an intermediate state between ‘locally advanced’ and ‘poly- 42 43 metastatic’ disease [10, 11]. It is postulated, but not proven, that men exhibiting such 44 45 disease patterns gain most benefit in progression-free survival (PFS) and OS resulting on October 1, 2021 by guest. Protected copyright. 46 from localised cancer control achieved via cytoreductive interventions [2, 10]. 47 48 49 50 PATHOBIOLOGICAL BASIS FOR LOCAL CYTOREDUCTIVE & METASTASIS 51 DIRECTED THERAPY 52 53 The pathobiological basis underpinning local cytoreductive and metastasis-directed 54 55 therapy in prostate cancer is not fully delineated. Indeed, numerous theories exist 56 57 surrounding the role of the primary tumour and its relationship with metastases [2]. 58 59 60

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1 2 3 Local prostate cytoreduction is thought to primarily impact on tumour-derived factors 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 such as cytokines, chemokines and microRNAs [12, 13]. In particular, prostate tumour 6 7 cell shedding and dissemination has been shown to occur earlier, with the detection 8 of circulating tumour cells (CTCs) in blood and disseminated tumour cells (DTCs) in 9 10 bone marrow of patients staged as non-metastatic on conventional imaging (i.e. bone 11 12 scintigraphy) [14-18]. 13 14 15 This has led to a comparison to the “self-seeding” hypothesis, as described in other 16 17 solid organ malignancies involving the breast and colon [19, 20]. It posits that the 18 For peer review only 19 return of CTCs or DTCs from distant secondary sites alters the primary tumour 20 21 microenvironment (TME), via release of matrix metalloproteinases (e.g. matrix 22 metalloproteinase-1) and cytokines (e.g. CXC-motif chemokine 1) [19, 20] . In addition, 23 24 the primary tumour cells may also secrete interleukins (e.g. IL-6) that attract further 25 26 CTCs and promote local tumour angiogenesis [20, 21]. 27 28 29 Such circulation may lead not only to “self-seeding” but also the remodelling of a “pre- 30 31 metastatic niche” at new distant sites [19, 22, 23]. Bone marrow-derived 32 33 haematopoietic cells localise to support pre-metastatic niche’s, promoting the local 34 environment for colonisation [14, 16]. Bone marrow-derived endothelial and 35 36 mesenchymal cells are implicated in the maturation of micro- to macro-metastasis [23]. 37 38 Pre-clinical models have reported these cells are mobilised largely as a results of http://bmjopen.bmj.com/ 39 40 secretion of vascular endothelial growth factor (VEGF) and placental growth factor 41 (PIGF) by the primary tumour [23-25]. 42 43 44 45 Furthermore, investigators utilising multifocal sequencing approaches have revealed on October 1, 2021 by guest. Protected copyright. 46 the present of primary-tumour-to-metastasis, but also surprisingly, metastasis-to- 47 48 metastasis transfer of clonal tumour cells [26]. This subsequently lead to the 49 50 exploration of metastasis-directed therapy [27, 28]. 51 52 53 Metastasis-directed therapy commonly takes the form of ionizing radiation (i.e. SABR). 54 55 Such interventions are hypothesised to have an effect on distant tumours via the 56 57 release of tumour antigens, damage-associated molecular patterns (DAMPs), and 58 local activation of immune cells (including cytotoxic T-cells) [29-32]. This has been 59 60 coined the ‘abscopal effect’ and is associated with the generation of a systemic anti-

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1 2 3 tumour immune response. Evidence for such a response in prostate cancer remains 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 sparse [27, 33]. 6 7 8 However, the recent ORIOLE phase II randomised study evaluated metastasis- 9 10 directed SABR, versus observation alone, in 54 men with metachronous disease. At 11 12 6-months progression occurred in 7/36 (19%) men treated with SABR, compared to 13 14 11/18 (61%) in the observation arm. Interestingly, the study reported clusters of similar 15 expanded T-cell receptors in some men (n = 3) in the treatment arm alone [27]. 16 17 18 For peer review only 19 Immune-mediate responses may not be limited to cytotoxic radiotherapy, with 20 21 minimally invasive ablative therapy (MIAT), such as the ‘cryo-immunological response’ 22 induced by cryotherapy, also described [34]. Such ablation leads to tumour-associated 23 24 antigens (TAAs), this may result in an anti-tumour response (humoral or cellular) [35]. 25 26 Activation of TAA-specific T-cells may occur at time of tissue necrosis [34]. 27 28 29 Similar to the cytotoxic abscopal response, the clinical translation of such observed 30 31 responses is unclear [2]. Early local prostate cryotherapy case series reported 32 33 spontaneous distant regression of metastasis, although this has not been replicated 34 in the contemporary literature [34, 36]. Furthermore, clinical augmentation of prostate 35 36 cryotherapy by immune-checkpoint inhibitors (e.g. anti-programmed cell death-1 37 38 antibody, PD-1) also demonstrated pre-clinical promise, but proved disappointing http://bmjopen.bmj.com/ 39 40 when translated into early phase clinical studies [37, 38]. Generally considered a low- 41 immunogenic disease, it is likely that if any oncological benefit is to be derived, it will 42 43 be reported when immunotherapy is added to existing proven systemic agents [39]. 44 45 on October 1, 2021 by guest. Protected copyright. 46 When taken collectively, removal of the primary tumour and possibly its metastatic 47 48 sites, may lead to a disruption in these immune-mediated pathological relationships 49 50 and result in regression of metastases with a prolonged cancer-specific survival 51 52 (CSS). 53 54 55 CATEGORISING METASTATIC BURDEN 56 57 A key research barrier at present is that there is no universally accepted definition for 58 oligometastatic disease, which varies depending on the anatomical site (nodal, 59 60 burden, visceral), absolute number (1 to 7), temporal pattern (outside vertebral bodies

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1 2 3 or pelvis) and diagnostic imaging utilised (conventional or molecular) [11]. 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 Consequently there is also no accepted definition for ‘high’ versus ‘low’ volume 6 7 disease [10, 40, 41]. At present oncology trials exploring systemic therapy have 8 frequently adopted the use of the CHAARTED definition of metastatic disease burden. 9 10 High burden disease is defined as four or more bone metastases with one or more 11 12 metastasis located outside the vertebral bodies or pelvis, and/or visceral metastasis 13 14 present [9, 42]. 15 16 17 CYTOREDUCTIVE PROSTATE RADIOTHERAPY 18 For peer review only 19 Two randomised studies (STAMPEDE and HORRAD) have evaluated the role of 20 cytoreductive local prostate radiotherapy in this cohort [42, 43]. 21 22 23 24 The Systemic Therapy in Advancing Or Metastatic Prostate Cancer: Evaluation Of 25 26 Drug Efficacy (STAMPEDE) collaborators explored the role of local prostate 27 radiotherapy in 2,061 men with newly diagnosed metastatic prostate cancer receiving 28 29 ADT, with 18% also receiving Docetaxel. Although no OS advantage was 30 31 demonstrated (HR 0.92, [95% CI 0.80-1.06]; p=0.27) in all burden metastatic disease, 32 radiotherapy did improve failure-free survival (HR 0·76, [95% CI 0·68–0·84]; 33 34 p<0·0001) [42]. Nevertheless, in the pre-specified subgroup of men with the 35 36 CHAARTED definition of low burden disease, a significant OS was reported (3-year 37 38 OS 81% vs 73%, HR 0.68, [95% CI 0.52–0.90]; p=0.007). As with any sub-group http://bmjopen.bmj.com/ 39 analyses this data needs it be interpreted cautiously. Furthermore, radiotherapy 40 41 treatment (weekly or daily) had acceptable side-effects with only a 5% grade 3-4 42 43 adverse event rate [42]. 44 45 46 The HORRAD phase three trial randomised 432 men to ADT with or without local on October 1, 2021 by guest. Protected copyright. 47 48 prostate radiotherapy. In accordance with STAMPEDE, no significant difference in 49 50 OS was observed between the two groups (median 45 months in experimental arm 51 versus 43 months with ADT alone; HR 0.90, [95% CI 0.70–1.14]; p = 0.40), though 52 53 there was a non-significant trend towards improved overall survival in the 160 patients 54 55 with low volume metastatic disease treated with radiotherapy (HR 0.68, 95% CI 0.42- 56 57 1.10). This study however was criticised for its lack of pre-specified metastatic burden 58 (including no knowledge of visceral disease) and potential underpowered sample size 59 60 [44]. Both trials took place at a time when upfront systemic agents had not been fully

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1 2 3 introduced and thus the true “additive” effect of local prostate radiotherapy in a 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 contemporary cohort remains unclear [2]. 6 7 8 CYTOREDUCTIVE RADICAL PROSTATECTOMY 9 10 Historical data from the Southwest Oncology Group (SWOG) 8894 trial randomising 11 12 1,286 men with metastatic disease to bilateral orchidectomy with placebo or flutamide 13 14 demonstrated, that a subgroup of men who underwent previous radical prostatectomy 15 had a significantly reduced risk of death (HR 0.77, [95% CI 0.53–0.80]) [45]. Building 16 17 on this, numerous retrospective series and registry data (e.g. Surveillance, 18 For peer review only 19 Epidemiology, and End Results, SEER) have reported improved OS and CSS in men 20 who undergo cytoreductive radical prostatectomy with low-burden or predominantly 21 22 osseous disease [46-51]. 23 24 25 26 At present, prospective evidence is limited to a 61-patient case-control study 27 conducted by Heidenreich and colleagues [52]. Performed in men with <4 metastases 28 29 and no visceral or extensive lymph node metastases, with a serum PSA level <1.0 30 31 ng/ml after neoadjuvant ADT, cytoreductive radical prostatectomy (CRP) and 32 33 extended pelvic lymph node dissection (ePLND) led to a 12.1 month improvement in 34 PFS compared to the control arm ADT alone (38.6 months vs 26.5 months; p = 0.0032) 35 36 [52]. There were no reported Grade 4 or 5 Clavien-Dindo classification complications 37 38 within this study, confirming the surgical feasibility reported in previous retrospective http://bmjopen.bmj.com/ 39 studies [46, 47]. 40 41 42 43 Multiple confirmatory randomised (NCT01751438 [BST]; NCT03655886 [LoMP II]) 44 45 and single-arm studies (TRoMbone; NCT02716974; NCT03298087) are ongoing with, 46 or without, MDT in this cohort [48, 53-56]. on October 1, 2021 by guest. Protected copyright. 47 48 49 50 CYTOREDUCTIVE MINIMALLY INVASIVE ABLATIVE THERAPY (MIAT) 51 With regard to cytoreductive MIAT, a single retrospective study evaluating whole-gland 52 53 cryotherapy in 23 men with a favourable response to 6-months ADT (PSA <1.0 ng/ml), 54 55

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1 2 3 Furthermore, the NCT02489357 pilot study interrogated the ‘cryo-immunological 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 response’ with PD-1 blockade using the antibody (Pembrolizumab) in addition to 6 7 cytoreductive cryotherapy [38]. In total 12 men with oligometastatic disease initiated 8 8-months of ADT and Pembrolizumab, with subsequent whole-gland cryotherapy [38]. 9 10 Primary endpoint was PSA <0.6 ng/ml at 1 year, and this was met in 42% (n = 5). 11 12 Median PFS was 14 months and median systemic therapy-free survival was 17.5 13 14 months [38]. There were no grade 3 adverse events, with Grade 1 (non-pad, 15 occasional) urinary incontinence in 16.7% (n = 2) [38]. This profile is in keeping with 16 17 the favourable early functional outcomes from cryotherapy in patients with non- 18 For peer review only 19 metastatic disease [58]. With regard to safety there were no reported cases of rectal 20 21 injury or fistulae in either study [38, 57]. In both studies men did not receive prior 22 systemic therapy escalation and thus the ‘additive’ value of cytoreductive cryotherapy 23 24 in such a cohort remains unclear [38, 57]. 25 26 27 METASTASIS-DIRECTED THERAPY 28 29 In men with recurrent distant oligometastases, a number of early phase clinical trials 30 31 (STOMP,ORIOLE, POPSTAR) have demonstrated promise with metastases-directed 32 33 therapy (either SABR or metastatectomy), mainly with regards to improving ADT-free 34 and early PFS [27, 59, 60]. It is unclear the impact of such interventions on OS [27, 35 36 59, 60]. 37 38 http://bmjopen.bmj.com/ 39 In de novo oligometastatic disease, a single pilot study including 20 men underwent 40 41 sequential systemic therapy (ADT), surgery (cytoreductive radical prostatectomy + 42 43 PLND +/- RPLND), and consolidation SABR to visible bone metastasis [61]. A novel 44 45 endpoint of “undetectable PSA (

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1 2 3 IP2-ATLANTA STUDY HYPOTHESIS 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 We hypothesise that men with metastatic disease who undergo treatment of the local 6 7 tumour in the form of either radical therapy (prostatectomy or external beam 8 radiotherapy), or minimally invasive ablative therapy, combined with metastases- 9 10 directed therapy, will improve progression-free survival in comparison patients who 11 12 receive standard of treatment alone. 13 14 15 PATIENT AND PUBLIC INVOLVEMENT 16 17 A patient-involvement focus group was held with six patients who had advanced or 18 For peer review only 19 metastatic prostate cancer, to determine initial patient acceptability and gauge 20 21 important opinions on the proposed amendment and study design. Four patients had 22 previously received radiotherapy as either their primary or secondary treatment. 23 24 Comments from the group discussion were recorded along with anonymous 25 26 questionnaires, which the patients returned, by post after the meeting. Two patient 27 and public involvement (PPI) representatives were present during the HRA REC 28 29 assessment. They will continue to be involved throughout the duration of the trial with 30 31 the Trial Management Group and other patients not involved in the direct management 32 33 of the study will be on the independent Trials Steering Committee. 34 35 36 METHODS AND ANALYSIS 37 38 http://bmjopen.bmj.com/ 39 40 STUDY DESIGN 41 IP2-ATLANTA is an unblinded, randomised, multicentre, interventional three-arm 42 43 study with an active comparator arm incorporating standard of care (SOC) (Figure 1). 44 45 Study participants will be randomised to: Control arm (standard of care); Intervention on October 1, 2021 by guest. Protected copyright. 46 arm 1 (MIAT +/- pelvic lymph node dissection [PLND]) or Intervention arm 2 (prostate 47 48 external beam radiotherapy [EBRT] +/- PLNRT OR cytoreductive radical 49 50 prostatectomy [CRP] +/- PLND). Systemic therapy in all arms includes ADT +/- 51 52 Docetaxel, Abiraterone Acetate, Enzalutamide, Apalutamide, as appropriate. Men with 53 low-burden disease in intervention arms are eligible for metastases-directed therapy 54 55 in the form of SABR or surgery (Figure 1). 56 57 58 59 60

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1 2 3 STUDY POPULATION 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 Men who are willing to undergo local therapy to the prostate and selective metastases- 6 7 directed therapy for newly diagnosed metastatic prostate cancer in addition to 8 standard care systemic treatment upfront. 9 10 11 12 ELIGIBILITY 13 14 15 INCLUSION CRITERIA 16 17 1. Diagnosed with prostate cancer within 6 months of screening visit 18 2. Metastatic diseaseFor (Any peer T, Any N,review M1+) of any grade,only stage or Prostate Specific 19 20 Antigen (PSA) level. 21 22 3. Fit to undergo standard of care systemic treatment for metastatic disease and both 23 minimally invasive therapy and prostate EBRT/cytoreductive radical 24 25 prostatectomy. 26 27 4. Performance status 0-2. 28 29 5. Histologically-proven local tumour. 30 31 32 EXCLUSION CRITERIA 33 34 1. Patient did not undergo and/or is unable to undergo standard of care baseline 35 imaging tests for confirmation of metastatic status (CT abdomen/pelvis AND chest 36 37 X-ray (or CT chest) AND radioisotope bone scan (or whole body imaging such as 38 http://bmjopen.bmj.com/ 39 MRI or PET imaging as alternative to all preceding scans mentioned here) AND 40 41 prostate MRI. 42 2. Prior exposure to long-term androgen deprivation therapy or hormonal therapy for 43 44 the treatment of prostate cancer unless started within 4 months of screening visit. 45 46 3. Prior chemotherapy or local or systemic therapy for treatment of prostate cancer on October 1, 2021 by guest. Protected copyright. 47 48 (apart from ADT or hormonal therapy as outlined above). 49 50 51 IDENTIFICATION OF PATIENTS & CONSENT 52 53 All men diagnosed with prostate cancer who go to a multidisciplinary team meeting or 54 a tumour board as well as any man meeting the eligibility criteria prior to tumour board 55 56 discussion will be identified for screening. Members of the tumour board will identify 57 58 patients suitable for IP2-ATLANTA. The treating clinicians will mention the study and 59 60 then the local research nurses/fellows, clinical trial coordinators, clinical trial

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1 2 3 practitioners or the treating clinicians will then approach the patient if they are 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 interested. A Patient Information Sheet (PIS) will be given, or if agreed, emailed or 6 7 posted out to the patient. Those patients already aware of the diagnosis can be 8 approached by telephone to enquire as to their interest in the study so that a PIS can 9 10 be then be sent out by email or post prior to a clinical visit. Patients will be given as 11 12 much time as they need to read the PIS before consenting to participate (with a 13 14 minimum of 24 hours). 15 16 17 18 For peer review only 19 RANDOMISATION 20 21 Stratified randomisation will take into account the following variables to create 16 22 strata in total: 23 24 - Intent to treat pelvic lymph nodes?: yes versus no 25 26 - Metastatic burden: low versus high (CHAARTED definition) [9]. 27 - Intent to use systemic agent (i.e. Docetaxel, Abiraterone Acetate, Enzalutamide, 28 29 Apalutamide)?: yes versus no 30 31 - Intent to use metastases directed therapy?: yes versus no 32 33 34 TRIAL TREATMENT 35 36 37 38 CONTROL ARM (STANDARD OF CARE) http://bmjopen.bmj.com/ 39 40 SOC treatment as determined by the treating physician: ADT with or without 41 Docetaxel or other systemic standard of care treatment, including but not limited to, 42 43 Abiraterone Acetate or Enzalutamide. Radiotherapy to the prostate only in this arm 44 45 is defined as for ‘symptom control’ in high volume (>/=4) metastases or to mirror on October 1, 2021 by guest. Protected copyright. 46 current accepted local radiotherapy dose regimens, external beam prostate 47 48 radiotherapy using a dose of 36Gy/6Fr OR 55Gy/20Fr OR 60Gy/20Fr over 27 days 49 50 as defined in Local Radiotherapy Standard Operating Procedure (SOP), for men with 51 52 low volume metastases (<4 metastases). MDT will not be permitted in the control 53 arm. Palliative radiotherapy for symptom control or for prevention of fracture will be 54 55 permitted as local clinical practice. 56 57 58 ADT, but not Docetaxel, may be initiated prior to recruitment. The decision as to 59 60 which SOC systemic therapy regimen will be decided by the treating clinician and/or

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1 2 3 clinical team, to be declared upfront prior to randomisation. If radiotherapy is planned 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 for local disease in men randomised to the SOC arm with low volume metastases, 6 7 then this will be declared prior to randomisation by the treating physician. The use of 8 PLNRT will not be permitted in the control arm. 9 10 11 INTERVENTION ARMS 12 13 Whilst discussing the intervention arms we should also consider the impact that SOC 14 15 treatment may have on down-staging the local tumour. As the SOC treatment would 16 17 be administered prior to any local MIAT or CRP/EBRT in the intervention arms 1 and 18 2, an attempt at reclassifyingFor peer the residual review disease with only a prostate MRI and biopsies 19 20 would be pragmatic. This is to prevent patients from developing adverse events from 21 22 unnecessary local treatment when they have no evidence of residual disease. Patients 23 with positive post-SOC biopsies would then receive the local treatment as outlined 24 25 below. Randomisation would occur at enrolment with planned intention to treat (ITT) 26 27 and per-protocol analyses. 28 29 30 Biopsies at 6-9 months from initiation of SOC therapy are part of the protocol during 31 32 the embedded feasibility pilot. As we currently do not know the significance of residual 33 34 disease after SOC therapy, even if determined to be low-volume and low-grade, all 35 patients with positive biopsies will be offered local treatment as per randomisation. 36 37 The pilot stage would obtain a point estimate of the magnitude of this response and 38 http://bmjopen.bmj.com/ 39 also patient acceptability of a post-systemic therapy prostate biopsy. Taken 40 41 collectively this will assist in informing the study investigators of their ongoing utility in 42 the main phase II component, where they are not presently mandated. 43 44 45 46 INTERVENTION ARM 1: MIAT on October 1, 2021 by guest. Protected copyright. 47 48 MIAT to the prostate with or without PLND in addition to SOC systemic treatment. 49 The exact treatment protocol and modality used (cryotherapy or high-intensity 50 51 focused ultrasound [HIFU]) will be set within the trial MIAT SOP. For those patients 52 53 who are undergoing MIAT no local prostate radiotherapy will be given as part of the 54 intervention. Radiotherapy can be administered for palliative reasons. Cases may be 55 56 referred for multidisciplinary discussion to the ATLANTA MIAT Quality Assurance 57 58 Board. 59 60

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1 2 3 INTERVENTION ARM 2: RADICAL THERAPY 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 In addition to SOC systemic treatment, radical therapy involves either: i) cytoreductive 6 7 radical prostatectomy, with or without PLND, or ii) prostate EBRT, with or without 8 simultaneous PLNRT. The actual modality will be based on physician and patient 9 10 preference as well as patient co-morbidities and performance status. 11 12 The surgical technique is at the discretion and expertise of the surgical team but will 13 14 reflect current UK surgical practice, laid down in the cytoreductive radical 15 prostatectomy SOP. Trial surgeons must meet minimum case volume and optimal 16 17 complication outcomes prior to operating in this trial. Further, they must receive peer- 18 For peer review only 19 approval from the IP2-ATLANTA Surgeons Quality Assurance Board. For patients who 20 21 are undergoing prostatectomy no local prostate radiotherapy will be given as part of 22 the intervention. Radiotherapy can be given subsequently for palliative reasons. 23 24 25 26 Two local prostate radiotherapy dose and fractionation options are available: 27 28 29 . 60Gy in 20 fractions. Treating the prostate to 60Gy and the seminal vesicles 30 31 to 47Gy using a simultaneous integrated boost administered over 27 days. If 32 33 the pelvic lymph nodes are to be treated then this will be done simultaneously 34 to a dose of 47Gy in 20 fractions (if treated). 35 36 . 74-78Gy in 37-39 fractions. Treat the prostate to 74-78Gy and the seminal 37 38 vesicles to 60Gy, using as simultaneous integrated boost. If the pelvic lymph http://bmjopen.bmj.com/ 39 40 nodes are to be treated then this will done simultaneously to a dose of 55Gy in 41 37-39 fractions (in accordance to same fractions employed for treating the 42 43 prostate and seminal vesicles). 44 45 on October 1, 2021 by guest. Protected copyright. 46 The principles of pelvic nodal treatment within the study will follow those of the 47 48 PIVOTALboost study (nodal arm-B), with variation to allow both dose and fractionation 49 50 regimes [62]. Quality assurance for radiotherapy will be completed by the UK national 51 52 Radiotherapy Trials Quality Assurance (RTTQA) team. 53 54 55 METASTASES-DIRECTED THERAPY: INTERVENTION ARMS 1 & 2 56 57 In men with low-burden disease in both intervention arms 1 and 2, MDT, may be used 58 but intent-to-use MDT is to be declared prior to randomisation. In the case of a 59 60 metastatic recurrence after MDT, a re-treatment with MDT would be allowed if there

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1 2 3 were new metastatic areas/locations. The imaging reporting of metastases as well as 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 doses and protocol for MDT will be defined and determined by the Imaging Reporting 6 7 SOP and Metastases-Directed Therapy SOP. 8 9 10 SABR should not be delivered whilst concurrent chemotherapy is being delivered. 11 12 Concurrent hormonal therapy is acceptable. SABR delivered to metastases must be 13 14 completed within 3 months of: prostate radiotherapy +/- PLNRT OR cytoreductive 15 radical prostatectomy +/- PLND OR MIAT +/- PLND. Constraints on the dose and 16 17 fractionations by anatomical site mirror all those defined in the SABR UK consortium 18 For peer review only 19 guidelines v.6.1 guidelines (2019) or, if absent, in CORE Trial Radiotherapy, Planning 20 21 & Delivery guidelines v.2.0 (2018) [63, 64]. Quality assurance for SABR will be 22 completed by the RTTQA body. 23 24 25 26 STUDY ENDPOINTS & OUTCOME MEASURES 27 Primary and secondary endpoints for the study are presented in Table 1. Study 28 29 outcome measures are presented in Table 2. 30 31 32 FOLLOW-UP 33 34 35 Follow-up will consist of 12-weekly serum PSA tests in the first year and 2-weekly 36 37 thereafter, until mortality or 4 years after initial randomisation, whichever is first (Table 38 3.). PROMS will be collected every 6-months in the first year and annually thereafter, http://bmjopen.bmj.com/ 39 40 until mortality or 4 years after initial randomisation, whichever is first. Minimum follow- 41 42 up for each patient will be 2 years. However, yearly follow-up will continue long term 43 44 alongside linkage to national database. 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 PATIENT REPORTED OUTCOME MEASURES 49 50 The European Organisation for the Research and Treatment of Cancer (EORTC), 51 52 Core Quality of Life Questionnaire-C30 (QLQ-C30), with prostate-specific, fatigue, 53 54 elderly, general and bone metastases modules, International Prostatic Symptoms 55 56 Score (IPSS), The Expanded Prostate Cancer Index Composite Bowel and Bladder 57 (EPIC) and International Index of Erectile Function 5 (IIEF15) will be used. The 58 59 EuroQol (EQ-5D-5L) will be used in the study as a generic measure of health-related 60

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1 2 3 quality-of-life which can be linked to public preferences. These data will be used to 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 calculate quality-adjusted life-years as part of a future health economic evaluation. 6 7 Patients agreeing to return questionnaires on quality-of-life will continue to complete 8 quality of life data for 4 years after enrolment. 9 10 STUDY VISITS 11 12 13 Follow up visits for the administration of SOC therapy and clinical review will occur in 14 15 accordance with the local hospitals follow-up protocols. In the intervention arms, of the 16 17 embedded feasibility pilot only, a prostate MRI, systematic and targeted transrectal or 18 transperineal biopsyFor will be peer performed review at 6-9 months followingonly the initiation of the SOC 19 20 therapy. In the main phase II component, these procedures can be carried out by local 21 22 centres at the discretion of local clinicians and when they are, data should be collected 23 on their outcomes. 24 25 26 27 For those randomised to MIAT or CRP/EBRT, a date for treatment(s) will be booked 28 29 in accordance with the local hospital waiting lists. Removal of the urethral catheter 30 after MIAT or CRP will occur after a minimum period of 7-days during a hospital visit 31 32 or can be removed either at the GP surgery or at a local hospital to the patient. 33 34 35 Further clinical reviews will occur as SOC visits at 12, 26, 28, 32, 34 and 52 weeks in 36 37 the 1st year and 24-weekly intervals thereafter until mortality or 2 years after 38 http://bmjopen.bmj.com/ 39 enrolment, whichever is first. 40 41 42 Collection of partial postcodes 43 44 In order to get an area-based estimate of deprivation, the participants’ partial 45 46 postcodes will be converted into an Index of Multiple Deprivation (IMD) score. The IMD on October 1, 2021 by guest. Protected copyright. 47 48 is the established index of deprivation for England and Wales and has been adopted 49 widely in studies across local and national government. IMD is based on detailed ward- 50 51 level index based on several separate domains. Similarly, Scottish Index of Multiple 52 53 Deprivation (SIMD) will be collected for participants in Scotland. Additionally, partial 54 postcodes will be collected only from the participants who provide optional consent. 55 56 Data will be stored in the secure and password protected InForm Database. 57 58 59 60

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1 2 3 Further Follow-up Imaging 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 Follow-up imaging to determine response from treatment on primary and metastatic 6 7 disease will not be protocolled but we recommend imaging to take place when there 8 is suspicion of progression, such as patients with a rising PSA (i.e. biochemical 9 10 failure). The appropriate imaging will be chosen as per the local hospital resources 11 12 and policies. We envisage that the majority will perform a combination of a prostate 13 14 MRI, bone scintigraphy, PET-CT/MRI, whole body MRI or CT chest/abdomen/pelvis. 15 16 17 Long-term outcomes 18 Patients will be consentedFor peer for their details review to be linked only to national registries for survival 19 20 information such as NHS Information Centre/Office of National Statistics (ONS) in 21 22 England/Wales and General Register Office in Scotland, Hospital Episode Statistics 23 (HES). This ONS-HES linkage however is an optional consent. 24 25 26 27 STATISTICAL ANALYSES AND SAMPLE SIZE CALCULATION 28 29 30 Embedded Feasibility and Pilot 31 32 We are seeking to determine whether the randomisation of men with metastatic 33 34 disease is feasible and whether men are compliant to the therapy following 35 randomisation. We aim to approach 80 patients from up to 17 centres in the UK over 36 37 a 6-month period to allow us to estimate a 33% recruitment rate with 95% confidence 38 http://bmjopen.bmj.com/ 39 interval width of approximately ± 10 percentage points. 40 41 42 Main phase II component 43 The study will have 80% power to detect a treatment difference with a hazard ratio 0.7 44 45 in favour of any of the intervention arms compared to the control at a two-sided 5.0% on October 1, 2021 by guest. Protected copyright. 46 significance level. This is based on the assumption that the accrual period will be 47 48 uniform over 24 months, that the follow-up period will be 24 months, and that the 49 50 median progression-free survival is 37 months. This calculation may be adjusted 51 52 depending on the compliance rate assessed during the feasibility stage. The overall 53 sample size will be 918 participants considering a 5% loss to follow-up (291 54 55 participants per group, 873 participants for three arms). This will allow the detection of 56 57 an effect size of 9.2% increase in progression free survival at 24 months. 58 59 60

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1 2 3 ADVERSE EVENT REPORTING 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 The Common Terminology Criteria for Adverse Events (CTCAEv5.0) domain will be 7 used to report adverse events [65]. 8 9 10 11 DATA COLLECTION 12 The principal means of data collection from participant visits will be Electronic Data 13 14 Capture (EDC) using the web-based InForm database. All study data will be entered 15 16 into electronic Case Report Forms (eCRFs) in a database provided by the Sponsor. 17 18 All eCRFs will be Forcompleted peer using de-identified review data. only 19 20 21 DATA MONITORING & ARCHIVING 22 23 A combined independent data monitoring and trial steering committee will meet twice 24 a year. All trial documentation, including that held at participating sites and the trial 25 26 coordinating centre, will be archived for a minimum of 10 years following the end of 27 28 the study. 29 30 31 32 TRIAL FUNDING, ORGANISATION AND ADMINISTRATION 33 34 35 IP2-ATLANTA trial was approved by the HRA Wales REC 5 (19/WA0005). IP2- 36 37 ATLANTA is funded by the Wellcome Trust (204998/Z/16/Z). The study will be 38 http://bmjopen.bmj.com/ 39 monitored periodically by trial monitors to assess the progress of the study, verify 40 41 adherence to the protocol, ICH GCP E6 guidelines and other national/international 42 requirements and to review the completeness, accuracy and consistency of the data 43 44 45 46 DISCUSSION on October 1, 2021 by guest. Protected copyright. 47 IP2-ATLANTA is a multicentre, phase II, randomised controlled trial. The study will 48 49 provide Level I evidence on oncological outcomes from prostate minimally invasive 50 51 ablative therapy or radical therapy, in combination with metastasis-directed therapy, 52 53 against standard of care treatment alone, in men with newly-diagnosed hormone 54 sensitive metastatic prostate cancer. If either intervention arm is proven to provide 55 56 significant oncological benefit this will have wide-reaching implications on the current 57 58 standard of care paradigm. 59 60

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1 2 3 CONCLUSION 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 IP2-ATLANTA addresses an important research gap in the role of sequential systemic, 7 local cytoreductive and metastasis-directed interventions in men with newly- 8 9 diagnosed metastatic prostate cancer. 10 11 12 13 TRIAL STATUS 14 15 IP2-ATLANTA is open to recruitment in 10 centres in England and Wales and 16 expected to complete its embedded feasibility pilot phase by late 2020 [66]. 17 18 For peer review only 19 20 Acknowledgements: We would like to thank all the participants, study PI, trial 21 22 clinicians, research nurses, Imperial Clinical Trial Unit staff and other site staff who 23 have been responsible for setting up, recruiting participants and collecting the data for 24 25 the IP2-ATLANTA trial. Further we are grateful for the ongoing support of the Trial 26 27 Management Group and our trial patient representative. Finally, we would like to thank 28 the trial oversight provided by ICTU and our trial funder the Wellcome Trust. 29 30 31 32 Contributors: Conception and design of ATLANTA trial: HUA, MJC, MW, TTS, TD, 33 34 AF, AS, VK, ST, MG, NS, JS, ED, FF, NKN. All authors have read and approved the 35 final manuscript. 36 37 38 http://bmjopen.bmj.com/ 39 Funding: The trial was funded by the Wellcome Trust (204998/Z/16/Z) 40 41 42 Patient consent for publication: Not required. 43 44 45 46 Conflicts of Interest on October 1, 2021 by guest. Protected copyright. 47 Martin J. Connor’s research is support by University College London Hospitals (UCLH) 48 49 Charity and the Wellcome Trust. 50 51 Kamalram Thippu Jayaprakash is currently supported by a research grant from the UK 52 53 National Institute of Health Research (NIHR) Clinical Research Network Eastern. He 54 has received educational/ and travel grants from Bayer UK, Janssen Oncology, Pfizer; 55 56 Roche, Takeda. 57 58 Hashim U. Ahmed's research is supported by core funding from the United Kingdom's 59 National Institute of Health Research (NIHR) Imperial Biomedical Research Centre. 60

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1 2 3 Ahmed currently receives funding from the Wellcome Trust, Prostate Cancer UK, MRC 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 (UK), Cancer Research UK, Sonacare Inc., Trod Medical, and Sophiris Biocorp for 6 7 trials in prostate cancer. Ahmed was a paid medical consultant for Sophiris Biocorp, 8 Sonacare Inc. and BTG in the past 3 years. 9 10 All other authors have no declaration 11 12 13 14 References 15 16 1 Smittenaar CR, Petersen KA, Stewart K, et al. Cancer incidence and mortality 17 projections in the UK until 2035, Br J Cancer 2016;115:1147-55 18 doi:10.1038/bjc.2016.304For peer[doi] [published review Online First: only October 25]. 19 20 21 2 Connor MJ, Shah TT, Horan G, et al. Cytoreductive treatment strategies for de novo 22 metastatic prostate cancer, Nature Reviews Clinical Oncology 2019:1-15. 23 24 3 James ND, Spears MR, Clarke NW, et al. Survival with newly diagnosed metastatic 25 prostate cancer in the “docetaxel era”: data from 917 patients in the control arm of the 26 STAMPEDE trial (MRC PR08, CRUK/06/019), Eur Urol 2015;67:1028-38. 27 28 29 4 Miyake H, Matsushita Y, Watanabe H, et al. Prognostic significance of time to 30 castration resistance in patients with metastatic castration-sensitive prostate cancer, 31 Anticancer Res 2019;39:1391-6. 32 33 5 Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive 34 prostate cancer. N Engl J Med 2019;381:13-24. 35 36 37 6 Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy 38 in metastatic prostate cancer. N Engl J Med 2019;381:121-31. http://bmjopen.bmj.com/ 39 40 7 James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or 41 both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival 42 43 results from an adaptive, multiarm, multistage, platform randomised controlled trial, 44 Lancet 2016;387:1163-77 doi:10.1016/S0140-6736(15)01037-5 [doi] [published 45 Online First: March 19]. 46 on October 1, 2021 by guest. Protected copyright. 47 8 Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration- 48 sensitive prostate cancer, N Engl J Med 2017;377:352-60. 49 50 51 9 Sweeney CJ, Chen Y, Carducci M, et al. Chemohormonal therapy in metastatic 52 hormone-sensitive prostate cancer, N Engl J Med 2015;373:737-46. 53 54 10 Weichselbaum RR, Hellman S. Oligometastases revisited, Nature reviews Clinical 55 oncology 2011;8:378. 56 57 58 11 Connor MJ, Winkler M, Ahmed HU. Survival in Oligometastatic Prostate Cancer - 59 A New Dawn or the Will Rogers Phenomenon? JAMA oncology 2020;6:185-6. 60

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1 2 3 12 Sita-Lumsden A, Dart DA, Waxman J, et al. Circulating microRNAs as potential 4 new biomarkers for prostate cancer, Br J Cancer 2013;108:1925. BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 7 13 Selth LA, Townley SL, Bert AG, et al. Circulating microRNAs predict biochemical 8 recurrence in prostate cancer patients, Br J Cancer 2013;109:641. 9 10 14 Alix-Panabières C, Riethdorf S, Pantel K. Circulating tumor cells and bone marrow 11 micrometastasis, Clinical Cancer Research 2008;14:5013-21. 12 13 14 15 Lorente D, Olmos D, Mateo J, et al. Decline in circulating tumor cell count and 15 treatment outcome in advanced prostate cancer, Eur Urol 2016;70:985-92. 16 17 16 Lilleby W, Stensvold A, Mills IG, et al. Disseminated tumor cells and their prognostic 18 significance in nonmetastaticFor peer prostate review cancer patients, only International journal of cancer 19 2013;133:149-55. 20 21 22 17 Morgan TM, Lange PH, Porter MP, et al. Disseminated tumor cells in prostate 23 cancer patients after radical prostatectomy and without evidence of disease predicts 24 biochemical recurrence, Clinical cancer research 2009;15:677-83. 25 26 18 Weckermann D, Polzer B, Ragg T, et al. Perioperative activation of disseminated 27 28 tumor cells in bone marrow of patients with prostate cancer, J Clin Oncol 29 2009;27:1549-56. 30 31 19 Comen E, Norton L, Massague J. Clinical implications of cancer self-seeding, 32 Nature reviews Clinical oncology 2011;8:369. 33 34 20 Kim M, Oskarsson T, Acharyya S, et al. Tumor self-seeding by circulating cancer 35 36 cells, Cell 2009;139:1315-26. 37 38 21 Nowak DG, Cho H, Herzka T, et al. MYC drives Pten/Trp53-deficient proliferation http://bmjopen.bmj.com/ 39 and metastasis due to IL6 secretion and AKT suppression via PHLPP2, Cancer 40 discovery 2015;5:636-51. 41 42 43 22 Shiozawa Y, Pedersen EA, Havens AM, et al. Human prostate cancer metastases 44 target the hematopoietic stem cell niche to establish footholds in mouse bone marrow, 45 J Clin Invest 2011;121:1298-312. 46 on October 1, 2021 by guest. Protected copyright. 47 23 Sleeman JP. The metastatic niche and stromal progression, Cancer Metastasis 48 Rev 2012;31:429-40. 49 50 51 24 Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone 52 marrow progenitors initiate the pre-metastatic niche, Nature 2005;438:820-7. 53 54 25 Psaila B, Lyden D. The metastatic niche: adapting the foreign soil, Nature Reviews 55 Cancer 2009;9:285-93. 56 57 58 26 Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal 59 metastatic prostate cancer, Nature 2015;520:353. 60

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1 2 3 27 Ryan Phillips, William Yue Shi, Matthew Deek, et al. Outcomes of Observation vs 4 Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer. The ORIOLE BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 Phase 2 Randomized Clinical Trial. JAMA Oncology 2020 [published Online First: Mar 7 26,]. 8 9 28 Palma DA, Olson RA, Harrow S, et al. Stereotactic ablative radiation therapy for 10 the comprehensive treatment of oligometastatic tumors (SABR-COMET): results of a 11 randomized trial, International Journal of Radiation Oncology• Biology• Physics 12 13 2018;102:S3-4. 14 15 29 Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and 16 ipilimumab in a patient with metastatic non–small cell lung cancer, Cancer immunology 17 research 2013;1:365-72. 18 For peer review only 19 30 Strigari L, Mancuso M, Ubertini V, et al. Abscopal effect of radiation therapy: 20 21 Interplay between radiation dose and p53 status, Int J Radiat Biol 2014;90:248-55. 22 23 31 Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal 24 effect in a patient with melanoma, N Engl J Med 2012;366:925-31. 25 26 32 Brooks ED, Chang JY. Time to abandon single-site irradiation for inducing abscopal 27 28 effects, Nature Reviews Clinical Oncology 2018:1. 29 30 33 Kubo M, Satoh T, Ishiyama H, et al. Enhanced activated T cell subsets in prostate 31 cancer patients receiving iodine-125 low-dose-rate prostate brachytherapy, Oncol Rep 32 2018;39:417-24. 33 34 34 Sabel MS. Cryo-immunology: a review of the literature and proposed mechanisms 35 36 for stimulatory versus suppressive immune responses, Cryobiology 2009;58:1-11. 37 38 35 Ablin RJ, Soanes WA, Gonder MJ. Elution of in vivo bound antiprostatic epithelial http://bmjopen.bmj.com/ 39 antibodies following multiple cryotherapy of carcinoma of prostate, Urology 40 1973;2:276-9. 41 42 43 36 Ablin RJ, Soanes WA, Gonder MJ. Prospects for cryo-immunotherapy in cases of 44 metastasizing carcinoma of the prostate, Cryobiology 1971;8:271-9. 45 46 37 Benzon B, Glavaris SA, Simons BW, et al. Combining immune check-point on October 1, 2021 by guest. Protected copyright. 47 blockade and cryoablation in an immunocompetent hormone sensitive murine model 48 of prostate cancer, Prostate cancer and prostatic diseases 2018;21:126-36. 49 50 51 38 Ross AE, Hurley PJ, Tran PT, et al. A pilot trial of pembrolizumab plus prostatic 52 cryotherapy for men with newly diagnosed oligometastatic hormone-sensitive prostate 53 cancer, Prostate cancer and prostatic diseases 2020;23:184-93. 54 55 39 Connor MJ, Winkler M, Ahmed HU. Cytoreductive cryotherapy for newly diagnosed 56 oligometastatic hormone-sensitive prostate cancer, Prostate Cancer and Prostatic 57 58 Diseases 2020:1-2. 59 60

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1 2 3 40 Tosoian JJ, Gorin MA, Ross AE, et al. Oligometastatic prostate cancer: definitions, 4 clinical outcomes, and treatment considerations, Nature Reviews Urology 2017;14:15. BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 7 41 Khoo V. New concepts in prostate cancer management: the conundrum of 8 managing oligometastatic disease in prostate cancer—through the looking glass 9 darkly, Clin Radiol 2019. 10 11 42 Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for 12 13 newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled 14 phase 3 trial, Lancet 2018;392:2353-66 doi:S0140-6736(18)32486-3 [pii] [published 15 Online First: December 01]. 16 17 43 Boevé LM, Hulshof MC, Vis AN, et al. Effect on survival of androgen deprivation 18 therapy alone comparedFor topeer androgen review deprivation therapy only combined with concurrent 19 radiation therapy to the prostate in patients with primary bone metastatic prostate 20 21 cancer in a prospective randomised clinical trial: data from the HORRAD trial, Eur Urol 22 2019;75:410-8. 23 24 44 Gregucci F, Fiorentino A. Re: Liselotte MS Boevé, Maarten CCM Hulshof, André 25 N. Vis, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to 26 Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the 27 28 Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective 29 Randomized Clinical Trial: Data from the HORRAD Trial. Eur Urol 2019; 75: 410-8. 30 Eur Urol 2019;75:e129. 31 32 45 Thompson IM, Tangen C, Basler J, et al. Impact of previous local treatment for 33 prostate cancer on subsequent metastatic disease, J Urol 2002;168:1008-12. 34 35 36 46 Jang WS, Kim MS, Jeong WS, et al. Does robot‐assisted radical prostatectomy 37 benefit patients with prostate cancer and bone oligometastases? BJU Int 38 2018;121:225-31. http://bmjopen.bmj.com/ 39 40 47 Sooriakumaran P, Karnes J, Stief C, et al. A multi-institutional analysis of 41 perioperative outcomes in 106 men who underwent radical prostatectomy for distant 42 43 metastatic prostate cancer at presentation, Eur Urol 2016;69:788-94. 44 45 48 Sooriakumaran P. Testing radical prostatectomy in men with prostate cancer and 46 oligometastases to the bone: a randomized controlled feasibility trial, BJU Int on October 1, 2021 by guest. Protected copyright. 47 2017;120:E8-E20. 48 49 49 Heidenreich A, Fossati N, Pfister D, et al. Cytoreductive radical prostatectomy in 50 51 men with prostate cancer and skeletal metastases, European urology oncology 52 2018;1:46-53. 53 54 50 Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic 55 prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based 56 study, Eur Urol 2014;65:1058-66 doi:10.1016/j.eururo.2013.11.012 [doi] [published 57 58 Online First: June 01]. 59 60

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1 2 3 51 Rusthoven CG, Jones BL, Flaig TW, et al. Improved survival with prostate radiation 4 in addition to androgen deprivation therapy for men with newly diagnosed metastatic BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 prostate cancer, Journal of Clinical Oncology 2016;34:2835-42. 7 8 52 Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy in patients 9 with prostate cancer and low volume skeletal metastases: results of a feasibility and 10 case-control study, J Urol 2015;193:832-8. 11 12 13 53 Pienta K. A Study of Definitive Therapy to Treat Prostate Cancer (oligo- 14 mets) NCT02716974 . ;2019. 15 16 54 Nickols N, Rettig M. NCT03298087 Systemic and Tumor-Directed Therapy for 17 Oligometastatic Prostate Cancer. 18 For peer review only 19 55 Chapin BF, Mcguire SE, Wang X, et al. No title, A prospective, multicenter, 20 21 randomized phase II trial of best systemic therapy (BST) or BST plus definitive 22 treatment (Surgery or Radiation) of the primary tumor in metastatic prostate cancer. 23 2015. 24 25 56 Nicolaas L. NCT03655886. Testing radical prostatectomy in men with 26 prostate cancer and oligometastases to the bone: 27 28 a randomized controlled feasibility trial (LoMP II). 2018. 29 30 57 Sheng M, Wan L, Liu C, et al. Cytoreductive cryosurgery in patients with bone 31 metastatic prostate cancer: A retrospective analysis, Kaohsiung J Med Sci 32 2017;33:609-15. 33 34 58 Shah TT, Peters M, Eldred-Evans D, et al. Early-Medium-Term Outcomes of 35 36 Primary Focal Cryotherapy to Treat Nonmetastatic Clinically Significant Prostate 37 Cancer from a Prospective Multicentre Registry, Eur Urol 2019. 38 http://bmjopen.bmj.com/ 39 59 Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed 40 therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, 41 multicenter phase II trial, Journal of Clinical Oncology 2017;36:446-53. 42 43 44 60 Siva S, Bressel M, Murphy DG, et al. Stereotactic abative body radiotherapy 45 (SABR) for oligometastatic prostate cancer: a prospective clinical trial, Eur Urol 46 2018;74:455-62. on October 1, 2021 by guest. Protected copyright. 47 48 61 O'Shaughnessy MJ, McBride SM, Vargas HA, et al. A pilot study of a multimodal 49 treatment paradigm to accelerate drug evaluations in early-stage metastatic prostate 50 51 cancer, Urology 2017;102:164-72. 52 53 62 Syndikus I. ISRCTN80146950. A phase III randomised controlled trial of prostate 54 and pelvis versus prostate alone radiotherapy with or without prostate boost 55 (PIVOTALBoost). 2019 [published Online First: March,]. 56 57 58 63 Khoo V. Conventional Care Versus Radioablation (Stereotactic Body 59 Radiotherapy) for Extracranial Oligometastases (CORE) NCT02759783. ;2019. 60

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1 2 3 64 The Faculty of Clinical Oncology of The Royal College of Radiologists. Stereotactic 4 Ablative Body BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 Radiation Therapy (SABR): 7 A Resource. Version 6.1. 2019. 8 9 65 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Common 10 Terminology Criteria 11 for Adverse Events (CTCAE) Version 5.0. 2017. 12 13 14 66 Connor MJ, Shah TT, Sukumar J, et al. Initial experience of the adjuvant treatments 15 to the local tumor for metastatic prostate cancer: Assessment of novel treatment 16 algorithms, a multicenter, phase II randomized controlled trial (IP2-ATLANTA). Journal 17 of Clinical Oncology 2020. 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Table 1. Study primary and secondary endpoints 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 a) Recruitment, randomisation and compliance to allocation 7 PRIMARY 8 ENDPOINT: b) Adverse events 9 Embedded 10 Feasibility Pilot c) Proportion of patients with pathological complete response on post 11 systemic therapy prostate biopsy at 6-9 months. 12 13 14 a) Progression-free survival (PFS) PRIMARY 15 Defined as a composite outcome of biochemical failure; local 16 17 ENDPOINT: progression; lymph node progression or bone metastases progression (new sites); or progression or development of new distant metastases, 18 Phase II For peer review only 19 defined as lymph nodes outside the pelvis, bone or organ involvement 20 or skeletal-related events confirmed as progression as in the 21 STAMPEDE randomised study (Assessment of Progression; 22 Supplementary Material) [42]. 23 24 25 SECONDARY a) Adverse events and side-effect profile 26 b) Predictive factors for PFS and OS in each arm. 27 ENDPOINT: 28 c) Effect on PFS or OS from varying radiotherapy dosage and schedules 29 Phase II d) Effect on PFS and OS stratified by volume and site for local and 30 metastatic disease 31 e) Effect on PFS and OS stratified by the use of metastases directed 32 33 therapy. 34 f) Effect on PFS using an alternative definition of failure, defined as a 35 PSA increase of >/=25% and >/=2ng/mL if PSA was >/=2ng/mL from 36 37 baseline, or a PSA increase of >/=25% if PSA was <2ng/mL at random 38 assignment. http://bmjopen.bmj.com/ 39 g) Effect on PFS using an alternative definition of local progression of a 40 41 soft tissue metastatic lesion: defined as an increase of >/=20% in the 42 largest tumour dimension with a minimum absolute increase of 5mm. 43 Local progression of bone metastases to be assessed using MD 44 45 Anderson Cancer Center–criteria with a >/=25% increase in the size of 46 a measurable lesion on CT or a >/=25% increase in the size of ill- on October 1, 2021 by guest. Protected copyright. 47 defined lesions on CT considered to be progression (1, 2). 48 49 h) Costs and resource utilisation for future cost-effectiveness analyses 50 i) In those men undergoing repeat biopsies after 6-9 months of standard 51 of care systemic therapy, the proportion of patients with negative 52 53 biopsies. 54 j) In those men undergoing repeat prostate/pelvic MRI after 6-9 months 55 of standard of care systemic therapy, the proportion of patients with a 56 57 negative prostate MRI for local tumour. 58 k) In those men undergoing repeat imaging (local prostate/pelvic and / or 59 other body areas) after 6-9 months of standard of care systemic 60

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1 2 3 therapy, the proportion of patients with reduction on imaging of 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 metastatic tumour deposits. 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 Table 2. Study outcome measures 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 a) Compliance to randomised arm 7 PRIMARY 8 OUTCOMES: b) Recruitment and randomisation rate 9 Embedded 10 Feasibility Pilot c) Safety (adverse events) 11 d) Proportion of patients with complete pathological response on post 12 13 SOC systemic therapy prostate biopsies at 6-9 months. 14 15 16 17 a) Progression-free survival (PFS) 18 PRIMARY For peer review only 19 20 OUTCOMES: 21 22 Phase II 23 24 25 26 27 SECONDARY a) Urinary, sexual and rectal side-effects 28 b) Patient-reported outcomes using validated questionnaires OUTCOMES: 29 c) Progression on PSA and imaging and impact of clinical features on 30 Phase II progression 31 32 d) Health-related quality-of-life 33 e) Data on costs and resource utilisation for future cost-effectiveness 34 analysis 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3

4 Table 3. Study visit schedule BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 Post- Screening Treatment Follow-up 6 treatment 7 Visit 1 2 3 4 5 6 7 8 onwards 8 12 28 32 34 9 Every 24 weeks (+/- 4) (year Week (+/-) 0 (+/- 26 (+/-12) (+/- (+/- (+/- 52 (+/- 4) 10 2-4) 4) 12) 12) 12) 11 12 Informed consent X 13 Inclusion & exclusion X 14 criteria 15 Demography X 16 17 Medical history X 18 Vital signs/physical For peer review only As deemed necessary based on medical examination/clinical or X X 19 history and AE review 20 subject assessment 21 PSA Blood Test X X X X X X 22 PROMS X 23 X X X Questionnaires 24 (at 24 months only) 25 Review/reporting of 26 patient AEs/SAEs 27 (may be performed X X X X X X X 28 via a face to face or 29 telephone or email consultation) 30 31 Blood and urine tests including those for X X X At time of failure or at 24, 36, 48 months 32 biobanking 33 1 34 Randomisation X Standard of Care 35 X X X X X X X X 36 Therapy Imaging Tests 37 If not (Combination of but http://bmjopen.bmj.com/ 38 already Recommended but not not limited to CT, X- As deemed necessary performed protocolled 39 rays, PET, MRI, Bone (SOC) 40 Scan) 41 X 42 If not Mandatory in Pilot only. 43 already Prostate MRI During Main Phase can As deemed necessary 44 performed be conducted at clinician 45 (SOC) discretion within standard 46 of care process on October 1, 2021 by guest. Protected copyright. 47 X 48 Mandatory in Pilot only. 49 Biopsy During Main Phase can As deemed necessary 50 be conducted at clinician 51 discretion within standard 52 of care process 53 X Testosterone blood X (recommended 54 As deemed necessary Test (if available) but not 55 mandated) 56 Treatment in X 57 intervention arms 58 59 Removal of catheter X 60 Legend: 1Randomisation should be performed within 7 days from screening visit

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1 2 3 4 5 6 7 Systemic 8 Local Metastasis- 9 Phase II RCT (n = 918) 10 Primary Endpoint: PFS Therapy Treatment Directed 11 12 For peer review only

http://bmjopen.bmj.com/ *Prostate EBRT 13 Eligibility CONTROL 14 ▪ 15 New Metastatic (SOC) 16 Prostate Cancer ADT 17 n = 306 18 (Any T, N ,M1) with 19 ▪ CT Chest, 20 Docetaxel 21 Abdomen, ARM 1 on October 1, 2021 by guest. Protected copyright. 22 or MIAT SABR to 23 Pelvis (MIAT) 24 ▪ Bone Scan Enzalutamide +/- PLND Oligomets 25 n = 306 26 ▪ MRI Prostate or 27 ▪ Prostate Biopsy RANDOMISATION 28 Abiraterone 29 ▪ Fit for ARM 2 30 Acetate* EBRT +/- PLNRT SABR to 31 intervention (RADICAL) 32 (PS 0-2) n = 306 or CRP +/- PLND Oligomets 33 34 35 36 37 Follow-up: Clinical Review, PSA, Imaging if failure suspected 38 12, 26, 28, 32, 34, 52 weeks [Year 1] then 24-weekly for 2 years 39 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 34 of 39

1 2 3 Supplementary Material 4 1.0 Assessment of progression BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 7 Baseline radiological examinations will be performed prior to enrolment. In the pilot 8 only, prostate MRI and biopsy will be repeated at 26 (+/-12) weeks. In the main phase 9 it is not protocol-mandated, that all patients have imaging scans repeated at the same 10 time point (26 weeks +/- 12 weeks) and whenever clinically appropriate, such as in 11 those with a low PSA value at enrolment or when there are concerns for progression 12 13 i.e. biochemical failure, new bone pain, Skeletal Related Event (SRE). Clinicians can, 14 at their own discretion, conduct a repeat MRI and biopsy of the prostate during the 15 main phase. 16 17 The following outcomes should be reported: 18 • BiochemicalFor failure peer review only 19 • Local progression 20 21 • Lymph node progression 22 • Bone metastases progression (new sites) 23 • Progression or development of new distant metastases, defined as lymph 24 nodes outside the pelvis, bone or organ involvement 25 • Skeletal-related events confirmed as progression (see below). 26 27 Biochemical Failure 28 29 For the purposes of this trial, a unique threshold PSA value for biochemical failure is 30 calculated, referred to as the PSA progression value. This value is derived for each 31 patient based on their PSA nadir, defined as the lowest PSA value reported between 32 randomisation and 6 months in the trial. The exact method for deriving the progression 33 value for a patient depends on the value of their PSA nadir, and how this compares to 34 their pre-treatment PSA value (i.e. the extent of the fall in PSA from the starting point). 35 36 37 The PSA progression value is calculated in one of three ways: 38 1. If the lowest recorded PSA value in the 26 weeks following randomisation is http://bmjopen.bmj.com/ 39 more than 4ng/ml and more than 50% of the pre-treatment PSA level then the 40 patient fulfils the criteria for immediate treatment failure. 41 2. For patients whose PSA nadir in the 26 weeks following randomisation is less 42 than or equal to 50% of the pre-treatment PSA level but remains above 4ng/ml, 43 44 biochemical failure will be defined as a rise of 50% above the nadir level. 45 3. For patients whose PSA nadir is less than or equal to 4ng/ml, biochemical 46 failure is defined as at least a 50% rise above the nadir value that is also above on October 1, 2021 by guest. Protected copyright. 47 4ng/ml. 48 49 Confirming biochemical failure: The timing and thus assessment of PSA needs to 50 be considered because rises in PSA can occur due to non-cancer related causes such 51 52 as after procedures, biopsies or urinary tract infection (UTI’s). Confirmatory samples 53 are needed in all cases of a rising PSA, prior to assigning an outcome of biochemical 54 failure. After biochemical failure is confirmed for the first time it need not be reported 55 again. 56 57 In the case that the raised PSA value reaches the progression value, a confirmatory 58 59 PSA test should be performed after at least 1 week or 4 weeks after the completion of 60 treatment in cases of UTI’s, procedures or biopsies. Biochemical failure is confirmed

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1 2 3 if the second value is around the same level or higher. The date of PSA progression 4 should be provided as the date of the first raised PSA that fulfilled the definition for BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 progression. 7 8 A confirmatory PSA is not required if there are other signs of progression e.g. 9 progression of cancer related symptoms (clinical progression) or new radiological 10 progression. 11 12 13 Second line treatment commenced specifically for biochemical failure should not start 14 until the trial definition for biochemical failure has been met. However, if second line 15 treatment does start before the trial definition is met then report the closest PSA value 16 prior to the treatment start date as the progression value. This is not required if second 17 line treatment is being started for other signs of progression e.g. clinical or radiological. 18 For peer review only 19 Testosterone levels: are required when reporting biochemical progression whilst 20 21 receiving hormone treatment to confirm the diagnosis of castrate resistant prostate 22 cancer. 23 24 Local, Lymph Node and Metastatic Failure 25 For each of local, lymph node and distant metastases progression, both the following 26 should be reported: 27 28 • Date of first clinical/symptomatic progression 29 • Date of first objective/radiological progression. 30 31 Skeletal-related Events 32 Skeletal-related events (SREs) are defined as: 33 • Pathological fracture 34 • Spinal cord compression 35 36 • Requirement for RT to bone (e.g. for pain or impending fracture) 37 • Requirement for surgery (e.g. for prevention or management of fracture). 38 http://bmjopen.bmj.com/ 39 All SREs should be investigated further to establish whether or not the patient has 40 progressed and only logged as progression if confirmed clinically or on imaging to be 41 due to metastatic prostate cancer. 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 2.0 Study Management 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 7 All trial documentation, including that held at participating sites and the trial 8 coordinating centre, will be archived for a minimum of 10 years following the end of 9 the study. Subject files and other source data (including copies of protocols, CRFs, 10 original reports of test results, correspondence, records of informed consent, and other 11 documents pertaining to the conduct of the study) must be retained. Documents 12 should be stored in such a way that they can be accessed/data retrieved later. 13 14 Consideration should be given to security and environmental risks. 15 No study document will be destroyed without prior written agreement between the 16 Sponsor and the investigator. Should the investigator wish to assign the study records 17 to another party or move them to another location, written agreement must be obtained 18 For peer review only 19 from the Sponsor. 20 Storage and handling of confidential trial data and documents will be in accordance 21 with the Data Protection Act 2018 (UK). 22 23 24 25 Study Management Structure 26 A Trial Steering Committee (TSC) will be convened including as a minimum an 27 28 Independent Chair, Independent Clinician, the Chief Investigator and Study Manager. 29 The role of the TSC is to provide overall supervision of trial conduct and progress. 30 Details of membership, responsibilities and frequency of meetings will be defined in a 31 separate Charter. 32 33 A Trial Management Group (TMG) will be convened including the Chief Investigator, 34 co-investigators and key collaborators, Study Statistician and Study Manager. The 35 TMG will be responsible for day-to-day conduct of the trial and operational issues. 36 Details of membership, responsibilities and frequency of meetings will be defined in 37 separate Terms of Reference. When necessary, decisions will be referred to the TSC. 38 Meetings will be scheduled in a risk-adapted manner to allow for the review of events http://bmjopen.bmj.com/ 39 40 during the trial. 41 A combined data monitoring and trial steering committee will meet twice a year basis. 42 The composition of this committee will include but not be limited to the Chief 43 Investigator, Trial Statistician, Trial Coordinator, Trials Unit representative, Research 44 45 nurse and Patient representative 46 on October 1, 2021 by guest. Protected copyright. 47 In case of early discontinuation of the study, the Follow-up Visit assessments should 48 49 be performed for each subject, as far as possible. 50 51 The following reasons may result in early discontinuation: 52 53 - Early evidence that a treatment arm is harmful. If only one treatment arm is deemed 54 to be harmful then the remaining arms of the study may continue as planned, 55 56 OR 57 - It is not feasible to reach the planned outcomes (A hazard ration of 0.7 to 1 will make 58 the intervention not worth progressing with given the severe adverse effects 59 associated with it) 60

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1 2 3 The statistical criteria for termination of the study will be detailed in the statistical 4 analysis plan (SAP). BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 7 A study-specific risk assessment will be performed prior to the start of the study to 8 assign a risk category of ‘low’, ‘medium’ or ‘high’ to the trial. Risk assessment will be 9 carried out by the ICTU QA Manager in collaboration with the Study Manager and the 10 result will be used to guide the monitoring plan. The risk assessment will consider all 11 aspects of the study and will be updated as required during the course of the study. 12 13 The study will be monitored periodically by trial monitors to assess the progress of the 14 study, verify adherence to the protocol, ICH GCP E6 guidelines and other 15 national/international requirements and to review the completeness, accuracy and 16 consistency of the data. 17 18 Monitoring proceduresFor and peer requirements review will be documented only in a Monitoring Plan, 19 developed in accordance with the risk assessment. 20 21 22 Quality Control will be performed according to ICTU/ internal procedures. The study 23 may be audited by a Quality Assurance representative of the Sponsor and/or ICTU. 24 All necessary data and documents will be made available for inspection. 25 26 The study may be subject to inspection and audit by regulatory bodies to ensure 27 adherence to GCP and the NHS Research Governance Framework for Health and 28 Social Care (2nd Edition). 29 30 Dissemination of findings 31 Information concerning the study, patent applications, processes, scientific data or 32 33 other pertinent information is confidential and remains the property of the Sponsor. 34 The investigator may use this information for the purposes of the study only. 35 36 It is understood by the investigator that the Sponsor will use information developed in 37 this clinical study in connection with the development of the ablative or radiotherapy 38 or surgical techniques and, therefore, may disclose it as required to other clinical http://bmjopen.bmj.com/ 39 investigators and to Regulatory Authorities. In order to allow the use of the information 40 41 derived from this clinical study, the investigator understands that he/she has an 42 obligation to provide complete test results and all data developed during this study to 43 the Sponsor. 44 45 Verbal or written discussion of results prior to study completion and full reporting 46 should only be undertaken with written consent from the Sponsor. on October 1, 2021 by guest. Protected copyright. 47 48 49 Therefore all information obtained as a result of the study will be regarded as 50 CONFIDENTIAL, at least until appropriate analysis and review by the investigator(s) 51 are completed. 52 53 Permission from the Executive/Writing Committee is necessary prior to disclosing any 54 information relative to this study outside of the Trial Steering Committee. Any request 55 56 by site investigators or other collaborators to access the study dataset must be 57 formally reviewed by the TMG. 58 59 60

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1 2 3 The results may be published or presented by the investigator(s), but the Funder will 4 be given the opportunity to review and comment on any such results for up to 1 month BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 before any presentations or publications are produced. 7 A Clinical Study Report summarising the study results will be prepared and submitted 8 to the REC within a year of the end of study. 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 3.0 Informed Consent Form 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 7 ATLANTA 8 9 Additional Treatments to the Local tumour for metastatic prostate cancer: Assessment of Novel 10 Treatment Algorithms 11 12 13 INFORMED CONSENT FORM 14 15 16 17 Chief Investigator: Professor Hashim U. Ahmed 18 Principal Investigator:For <> only 19 20 21 22 Please initial each box below. 23 Do not tick 24 1 I confirm that I have read and understand the patient information sheet dated 25 _ _ / _ _ / _ _ _ _ (Version ___) for the ATLANTA Study. I have had the 26 opportunity to consider the information, ask questions and have had these 27 answered satisfactorily. 28 I understand that the type of treatment I receive will be allocated using a 29 2 30 randomisation process, and neither myself nor the staff involved in the study 31 can influence this allocation. 32 I understand that if at any point my medical condition changes, it may be 33 3 34 necessary to withdraw from the trial and have treatment options reviewed. This 35 will be discussed with me by clinicians and with my agreement. 36 37 4 I understand that I may be asked questions relating to personal aspects such 38 as about diet and lifestyle from my local research team. http://bmjopen.bmj.com/ 39 5 I understand that my participation is voluntary and that I am free to withdraw at 40 41 any time, without giving reason and without my medical care or legal rights 42 being affected. 43 6 I understand that relevant sections of my medical notes and data collected 44 45 during the study, may be looked at by individuals from the Sponsor of the trial 46 (Imperial College London) and responsible persons authorised by the Sponsor, on October 1, 2021 by guest. Protected copyright. 47 from regulatory authorities or from the NHS Trust, where it is relevant to my 48 taking part in this research. I give permission for these individuals to have 49 access to my records. 50 51 7 I understand that the information collected about me will be used to support 52 other research in future, and may be shared anonymously with other 53 researchers. 54 55 8 I give permission for all standard of care data and samples, including those 56 taken prior to study recruitment, such as surgery specimen and biopsies 57 including tissue, bloods, urine and imaging tests to be used in this study even 58 if I withdraw at any points from the study 59 60

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4 9 I give permission for the researchers to contact me regarding this trial during BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 this trial period. 6 7 10 I agree for my GP and other doctors to be informed of my participation in this 8 study and of any clinical relevant study results 9 10 11 I agree to take part in the above study. 11 12 All the boxes above must be initialled for consent to be 13 valid 14 15 16 Please initial each box below. Do not 17 tick 18 For peer review only 19 20 OPTIONAL 21 12 I give permission for additional blood and urine samples to be taken and be 22 made available for future research where the samples would be stored 23 24 appropriately and the research approved separately (If you do not wish to give 25 this permission, do not initial – you can still participate in the study). 26 13 I give permission for all standard of care samples and data such as surgery 27 28 specimen, biopsies including tissue as well as imaging scans to be made 29 available for future research where the samples and scans would be stored 30 appropriately and the research approved separately (If you do not wish to give 31 this permission, do not initial – you can still participate in the study). 32 33 14 I give permission for any blood, urine and tissue samples, which will look for 34 changes in my genetic material (DNA) as described in the information sheet, to 35 be used in this study. (If you do not wish to give this permission, do not 36 initial – you can still participate in the study). 37 38 15 I give permission for any blood, urine and tissue samples, which will look for http://bmjopen.bmj.com/ 39 changes in my genetic material (DNA) as described in the information sheet, to 40 be used for further ethically approved research in the field of prostate cancer 41 research. (If you do not wish to give this permission, do not initial – you 42 can still participate in the study). 43 44 16 I give permission for my samples and data from any scans to be sent and 45 utilised in research both in the UK and worldwide. All material will be on October 1, 2021 by guest. Protected copyright. 46 anonymous and I will not be identifiable. I understand that I will not be asked 47 48 again for permission to run these additional research tests and I may also not 49 be informed of the results (If you do not wish to give this permission, do not 50 initial – you can still participate in the study). 51 52 17 I give permission for the researchers to contact me in the future regarding the 53 possibility of further studies, but I understand that I am under no obligation to 54 take part in these (If you do not wish to give this permission, do not initial 55 – you can still participate in the study). 56 57 18 I give permission for all samples taken to be biobanked and transferred to the 58 Imperial College Healthcare Tissue Bank (ICHTB) or other UK-based biobank 59 for a period of up to 10 years (or per local policy) and will be used for 60 histological, genomic and epigenetic analysis and for ethically approved future

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Additional Treatments to the Local tumour for metastatic prostate cancer - Assessment of Novel Treatment Algorithms (IP2-ATLANTA): Protocol for a multicentre, phase II randomised controlled trial

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2020-042953.R1

Article Type: Protocol

Date Submitted by the 08-Jan-2021 Author:

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 46 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 1 2 3 Department of Clinical Oncology 4 Brock, Cathryn; Chelsea and Westminster Hospital NHS Foundation 5 Trust, Department of Oncology 6 Pearson, Rachel; Newcastle Upon Tyne Hospitals NHS Foundation Trust, 7 Department of Oncology 8 Anyamene , Nicola; London North West University Healthcare NHS Trust, 9 Department of Oncology Heath , Catherine; University Hospital Southampton NHS Foundation 10 Trust, Department of Radiotherapy 11 Shergill, Iqbal; Wrexham Maelor Hospital, Department of Urology 12 Rai, Bhavan; Newcastle Upon Tyne Hospitals NHS Foundation Trust, 13 Department of Urology 14 Hellawell, Giles; London North West University Healthcare NHS Trust, 15 Department of Urology 16 Mccracken, Stuart; Sunderland Royal Hospital, Department of Urology For peerKhoubehi, Bijan; review Chelsea and Westminster only Healthcare NHS Trust, 17 Department of Urology 18 Mangar, Stephen; Imperial College Healthcare NHS Trust, Department of 19 Oncology 20 Khoo, Vincent; Royal Marsden NHS Foundation Trust, Department of 21 Oncology 22 Dudderidge, Tim; University Hospital Southampton NHS Foundation Trust, Department of Urology 23 Staffurth, John; Velindre Cancer Centre, Research; Cardiff University 24 School of Medicine, Division of Cancer and Genetics 25 Winkler, Mathias; Imperial College London, Department of Surgery and 26 Cancer; Imperial College Healthcare NHS Trust, Imperial Urology 27 Ahmed, Hashim; Imperial College London Division of Surgery, Imperial 28 College London 29 Primary Subject Urology 30 Heading: 31 32 Secondary Subject Heading: Oncology, Surgery, Research methods 33 Prostate disease < UROLOGY, Radiation oncology < RADIOTHERAPY, http://bmjopen.bmj.com/ 34 Keywords: RADIOTHERAPY, UROLOGY, Urological tumours < UROLOGY, 35 Genitourinary imaging < RADIOLOGY & IMAGING 36 37 38 39 40 41 42 on October 1, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 46

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4 1 Additional Treatments to the Local tumour for metastatic BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 2 prostate cancer - Assessment of Novel Treatment 7 8 3 Algorithms (IP2-ATLANTA): Protocol for a multicentre, 9 10 11 4 phase II randomised controlled trial 12 5 13 14 6 Martin J. Connor [1,2,3], Taimur T. Shah [1], Katarzyna Smigielska [1,4], Emily Day 15 16 7 [1,4], Johanna Sukumar [1, 4], Francesca Fiorentino [1,4], Naveed Sarwar [5], Michael 17 18 8 Gonzalez [5], AlisonFor Falconer peer [5], Natalia review Klimowska-Nassar only [1, 4], Martin Evans [1, 19 9 4], Olivia Frances Naismith [6], Kamalram Thippu Jayaprakash [7], Derek Price [1], 20 21 10 Shiva Gayadeen [5], Dolan Basak [5], Gail Horan [7], John McGrath [8], Denise 22 23 11 Sheehan [8], Manal Kumar [9], Azman Ibrahim [10], Cathryn Brock [11], Rachel A. 24 25 12 Pearson [12], Nicola Anyamene [13], Catherine Heath [14], Iqbal Shergill [15], Bhavan 26 13 Rai [12], Giles Hellawell [13], Stuart McCracken [16], Bijan Khoubehi [11], Stephen 27 28 14 Mangar [5], Vincent Khoo [17], Tim Dudderidge [14], John Nicholas Staffurth [18], 29 30 15 Mathias Winkler [1,2,3], Hashim U. Ahmed [1,2] 31 16 32 33 17 1. Division of Surgery, Imperial Prostate, Department of Surgery and Cancer, 34 35 18 Faculty of Medicine, Imperial College London, London, UB1 3HW 36 37 19 2. Imperial Urology, Imperial College Healthcare NHS Trust, London, W6 8RF 38 20 3. Department of Urology, West Middlesex University Hospital (WMUH), Chelsea http://bmjopen.bmj.com/ 39 40 21 & Westminster NHS Foundation Trust, Isleworth, Middlesex, TW7 6AF 41 42 22 4. Imperial Clinical Trials Unit (ICTU), School of Public Health, Faculty of Medicine, 43 44 23 Imperial College London, London, W12 7RH 45 24 5. Department of Oncology, Imperial College Healthcare NHS Foundation Trust, 46 on October 1, 2021 by guest. Protected copyright. 47 25 Charing Cross Hospital, London, W6 8RF 48 49 26 6. Radiotherapy Trials Quality Assurance (RTTQA), Department of Physics, The 50 27 Royal Marsden NHS Foundation Trust, London, SW3 6JJf 51 52 28 7.Department of Oncology, Addenbrooke’s Hospital and The Queen Elizabeth 53 54 29 Hospital Kings Lynn NHS Foundation, Norfolk, PE30 4ET 55 56 30 8.Department of Urology & Oncology, Royal Devon & Exeter Hospital, Exeter EX2 57 31 5DW 58 59 60

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1 2 3 32 9.Department of Urology, Arrowe Park Hospital, Wirral University NHS Foundation 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 33 Trust, Merseyside, CH49 5PE 6 7 34 10.Department of Oncology, Clatterbridge Cancer Centre NHS Foundation Trust, 8 35 Wirral, CH63 4JY 9 10 36 11.Department of Urology & Oncology, Chelsea and Westminster Hospital, 11 12 37 Chelsea & Westminster NHS Foundation Trust, SW10 9NH. 13 14 38 12.Department of Urology & Oncology, Northern Centre for Cancer Care, 15 39 Newcastle upon Tyne Hospitals NHS Foundation Trust, NE7 7DN 16 17 40 13.Department of Urology & Oncology, Northwick Park Hospital, London 18 For peer review only 19 41 Northwest University Healthcare NHS Trust, Harrow, HA1 3UJ 20 21 42 14.Department of Urology & Oncology, University Hospital Southampton NHS 22 43 Foundation Trust, Southampton, SO16 6YD 23 24 44 15.Department of Urology, Wrexham Maelor Hospital, Wales, LL13 7TD 25 26 45 16.Department of Urology, Sunderland Royal Hospital, Sunderland, SR4 7TP 27 46 17.Department of Clinical Oncology, The Royal Marsden Hospital & Institute of 28 29 47 Cancer Research, London, SW3 6JJ, 30 31 48 18.School of Medicine, Cardiff University, Cardiff, Wales, CF10 3AT 32 33 49 34 50 Corresponding Author: 35 36 51 Mr. Martin J. Connor 37 38 52 Division of Surgery http://bmjopen.bmj.com/ 39 40 53 Department of Surgery & Cancer 41 54 Imperial College London 42 43 55 Room 5L.28 44 45 56 Charing Cross Lab Block on October 1, 2021 by guest. Protected copyright. 46 57 [email protected] 47 48 58 49 50 59 Keywords: prostate cancer, metastatic, radiotherapy, radical prostatectomy, 51 52 60 cytoreductive, SABR, stereotactic radiotherapy, high intensity focussed ultrasound, 53 61 cryotherapy, oligo-metastatic disease, metastasis directed therapy. 54 55 56 57 58 59 60

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1 2 3 63 Abstract 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 64 Introduction: Survival in men diagnosed with de novo synchronous metastatic 6 7 65 prostate cancer has increased following the use of upfront systemic treatment, using 8 66 chemotherapy and other novel androgen receptor targeted agents, in addition to 9 10 67 standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis- 11 12 68 directed interventions are hypothesised to confer additional survival benefit. In this 13 14 69 setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the 15 70 addition of sequential multi-modal local and metastasis-directed treatments compared 16 17 71 to standard care alone. 18 For peer review only 19 72 20 21 73 Methods: A phase II, prospective, multi-centre, three-arm randomised controlled trial 22 23 74 incorporating an embedded feasibility pilot. All men with new histologically diagnosed, 24 75 hormone-sensitive, metastatic prostate cancer, within four months of commencing 25 26 76 ADT and of performance status 0 to 2 are eligible. Patients will be randomised to: 27 28 77 Control (Standard of Care [SOC]) OR Intervention 1 (minimally invasive ablative 29 30 78 therapy to prostate +/- pelvic lymph node dissection [PLND]) OR Intervention 2 31 79 (cytoreductive radical prostatectomy +/- PLND OR prostate radiotherapy +/- pelvic 32 33 80 lymph node radiotherapy [PLNRT]). Metastatic burden will be pre-specified using the 34 35 81 CHAARTED definition. Men with low burden disease in intervention arms are eligible 36 37 82 for metastasis-directed therapy, in the form of stereotactic ablative body radiotherapy 38 83 (SABR) or surgery. Standard systemic therapy will be administered in all arms With http://bmjopen.bmj.com/ 39 40 84 ADT +/- upfront systemic chemotherapy or androgen receptor agents. Patients will be 41 42 85 followed-up for a minimum of two-years. Primary outcome: PFS. Secondary outcomes 43 86 include: predictive factors for PFS and overall survival; urinary, sexual and rectal side- 44 45 87 effects. Embedded feasibility sample size is 80, with 918 patients required in the main 46 on October 1, 2021 by guest. Protected copyright. 47 88 phase II component. Study recruitment commenced in April 2019, with planned follow- 48 49 89 up completed by April 2024. 50 51 90 52 53 91 Ethics and dissemination: Approved by the Health Research Authority (HRA) 54 92 Research Ethics Committee Wales-5 (19/WA0005). Study results will be submitted for 55 56 93 publication in peer-reviewed journals. 57 58 94 59 95 Registration details: NCT03763253; ISCRTN58401737 60

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1 2 3 96 4 97 STRENGTHS AND LIMITATIONS OF THIS STUDY BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 98 7 99 1. IP2-ATLANTA addresses an important research gap in the role of local and 8 9 100 metastasis-directed therapy in men with newly-diagnosed metastatic prostate 10 11 101 cancer. 12 102 2. This is the first phase II trial to include cytoreductive minimally invasive ablative 13 14 103 therapy alongside cytoreductive radical prostatectomy and prostate 15 16 104 radiotherapy. 17 18 105 3. The IP2-ATLANTAFor peerstudy builds review on the clinical benefitsonly derived from metastasis- 19 106 directed therapy (stereotactic ablative body radiotherapy and/or surgery) in a 20 21 107 previously untreated cohort of men with advanced disease. 22 23 108 4. Due to invasive interventions, blinding is not possible in the IP2-ATLANTA 24 25 109 study. 26 27 110 28 29 111 30 31 112 32 33 113 34 35 36 114 37

115 http://bmjopen.bmj.com/ 38 39 116 40 41 117 42 43 118 44 119 45 46 120 on October 1, 2021 by guest. Protected copyright. 47 48 121 49 122 50 51 123 52 53 54 55 56 57 58 59 60

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1 2 3 124 INTRODUCTION 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 125 Overall, 47,000 men are diagnosed with prostate cancer each year in the United 6 7 126 Kingdom (UK) [1]. Approximately, 4,500 of these men this will be diagnosed with de 8 127 novo synchronous metastatic disease at presentation [1]. As with the United States, 9 10 128 where just under 8% present with metastatic disease and where the annual burden is 11 12 129 predicted to reach approximately 15,000 cases by 2025, so the prediction for the same 13 14 130 magnitude is likely for the UK [2]. 15 131 16 17 132 Traditionally, such men were managed with androgen deprivation therapy (ADT) 18 For peer review only 19 133 alone, via medical or surgical castration [2]. Unfortunately the median time to the 20 21 134 emergence of a castrate resistant state is in the order of 11 to 18 months, limiting 22 135 overall survival (OS) to 3.5 years [3, 4]. Promisingly, the reported OS in this group 23 24 136 has now risen to a median 4.8 years with the addition of upfront systemic agents, such 25 26 137 as Docetaxel, Enzalutamide, Abiraterone Acetate or Apalutamide [5-9]. 27 138 28 29 139 Moving beyond early systemic therapy escalation there has been an increased focus 30 31 140 on the role of local cytoreductive and metastasis-directed interventions (primarily 32 33 141 stereotactic ablative body radiotherapy [SABR]) to gain additional oncological benefit 34 142 [2]. This is in part based upon the emergence of the ‘oligo-metastatic state’, which may 35 36 143 exhibit different biological characteristics to poly-metastatic prostate cancer [10]. 37 38 144 http://bmjopen.bmj.com/ 39 40 145 Such men present with a clinically-defined favourable metastatic burden, and are 41 146 hypothesised to occupy an intermediate state between ‘locally advanced’ and ‘poly- 42 43 147 metastatic’ disease [10, 11]. It is postulated, but not proven, that men exhibiting such 44 45 148 disease patterns gain most benefit in progression-free survival (PFS) and OS resulting on October 1, 2021 by guest. Protected copyright. 46 149 from localised cancer control achieved via cytoreductive interventions [2, 10]. 47 48 150 49 50 151 IP2-ATLANTA STUDY HYPOTHESIS 51 52 152 We hypothesise that men with metastatic disease who undergo treatment of the local 53 153 tumour in the form of either radical therapy (cytoreductive radical prostatectomy (CRP) 54 55 154 or external-beam radiotherapy (EBRT)), or minimally invasive ablative therapy (MIAT), 56 57 155 combined with metastases-directed therapy (MDT), will improve progression-free 58 156 survival in comparison patients who receive standard of treatment alone. 59 60

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1 2 3 157 PATHOBIOLOGICAL BASIS FOR LOCAL CYTOREDUCTIVE & METASTASIS 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 158 DIRECTED THERAPY 6 7 159 The pathobiological basis underpinning local cytoreductive and metastasis-directed 8 160 therapy in prostate cancer is not fully delineated[2]. Local prostate cytoreduction is 9 10 161 thought to primarily impact on tumour-derived factors such as cytokines, chemokines 11 12 162 and microRNAs [12, 13]. In particular, prostate tumour cell shedding and 13 14 163 dissemination has been shown to occur earlier, with the detection of circulating tumour 15 164 cells (CTCs) in blood and disseminated tumour cells (DTCs) in bone marrow of 16 17 165 patients staged as non-metastatic on conventional imaging (i.e. bone scintigraphy) 18 For peer review only 19 166 [14-18]. 20 167 21 22 168 This has led to a comparison to the “self-seeding” hypothesis, as described in other 23 24 169 solid organ malignancies involving the breast and colon [19, 20]. It posits that the 25 26 170 return of CTCs or DTCs from distant secondary sites alters the primary tumour 27 171 microenvironment (TME), via release of matrix metalloproteinases (e.g. matrix 28 29 172 metalloproteinase-1) and cytokines (e.g. CXC-motif chemokine 1) [19, 20]. Such 30 31 173 circulation may lead not only to “self-seeding” but also the remodelling of a “pre- 32 174 metastatic niche” at new distant sites [19, 21, 22]. Bone marrow-derived 33 34 175 haematopoietic cells localise to support pre-metastatic niche’s, promoting the local 35 36 176 environment for colonisation [14, 16] [22]. 37 38 177 http://bmjopen.bmj.com/ 39 178 Furthermore, investigators utilising multifocal sequencing approaches have revealed 40 41 179 the present of primary-tumour-to-metastasis, but also surprisingly, metastasis-to- 42 43 180 metastasis transfer of clonal tumour cells [23]. This subsequently lead to the 44 45 181 exploration of metastasis-directed therapy [24, 25]. Such interventions are 46 182 hypothesised to have an effect on distant tumours via the release of tumour antigens, on October 1, 2021 by guest. Protected copyright. 47 48 183 damage-associated molecular patterns (DAMPs), and local activation of immune cells 49 50 184 (including cytotoxic T-cells) [26-29]. This has been coined the ‘abscopal effect’ and is 51 185 associated with the generation of a systemic anti-tumour immune response. Evidence 52 53 186 for such a response in prostate cancer remains sparse [24, 30]. 54 55 187 56 57 188 Immune-mediate responses may not be limited to cytotoxic radiotherapy, with 58 189 minimally invasive ablative therapy (MIAT), such as the ‘cryo-immunological response’ 59 60 190 [31]. Similar to the cytotoxic abscopal response, the clinical translation of such

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1 2 3 191 observed responses is unclear [2]. Early local prostate cryotherapy case series 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 192 reported spontaneous distant regression of metastasis, although this has not been 6 7 193 replicated in the contemporary literature [31, 32]. Furthermore, clinical augmentation 8 194 of prostate cryotherapy by immune-checkpoint inhibitors (e.g. anti-programmed cell 9 10 195 death-1 antibody, PD-1) also demonstrated pre-clinical promise, but proved 11 12 196 disappointing when translated into early phase clinical studies [33, 34] [35]. 13 14 197 15 198 When taken collectively, removal of the primary tumour and possibly its metastatic 16 17 199 sites, may lead to a disruption in these immune-mediated pathological relationships 18 For peer review only 19 200 and result in regression of metastases with a prolonged cancer-specific survival 20 21 201 (CSS). 22 202 23 24 203 CATEGORISING METASTATIC BURDEN 25 26 204 A key research barrier at present is that there is no universally accepted definition for 27 205 oligometastatic disease, which varies depending on the anatomical site (nodal, 28 29 206 burden, visceral), absolute number (1 to 7), temporal pattern (outside vertebral bodies 30 31 207 or pelvis) and diagnostic imaging utilised (conventional or molecular) [11]. 32 208 Consequently there is also no accepted definition for ‘high’ versus ‘low’ volume 33 34 209 disease [10, 36, 37]. At present oncology trials exploring systemic therapy have 35 36 210 frequently adopted the use of the CHAARTED definition of metastatic disease burden. 37 38 211 High burden disease is defined as four or more bone metastases with one or more http://bmjopen.bmj.com/ 39 212 metastasis located outside the vertebral bodies or pelvis, and/or visceral metastasis 40 41 213 present [9, 38]. 42 43 214 44 45 215 CYTOREDUCTIVE PROSTATE RADIOTHERAPY 46 216 Two randomised studies (STAMPEDE and HORRAD) have evaluated the role of on October 1, 2021 by guest. Protected copyright. 47 48 217 cytoreductive local prostate radiotherapy in this cohort [38, 39]. 49 50 218 51 219 The Systemic Therapy in Advancing Or Metastatic Prostate Cancer: Evaluation Of 52 53 220 Drug Efficacy (STAMPEDE) collaborators explored the role of local prostate 54 55 221 radiotherapy in 2,061 men with newly diagnosed metastatic prostate cancer receiving 56 57 222 ADT, with 18% also receiving Docetaxel [38]. Although no OS advantage was 58 223 demonstrated (HR 0.92, [95% CI 0.80-1.06]; p=0.27) in all burden metastatic disease, 59 60 224 radiotherapy did improve failure-free survival (HR 0·76, [95% CI 0·68–0·84];

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1 2 3 225 p<0·0001) [38]. Nevertheless, in the pre-specified subgroup of men with the 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 226 CHAARTED definition of low burden disease, a significant OS was reported (3-year 6 7 227 OS 81% vs 73%, HR 0.68, [95% CI 0.52–0.90]; p=0.007). As with any sub-group 8 228 analyses this data needs it be interpreted cautiously. Furthermore, radiotherapy 9 10 229 treatment (weekly or daily) had acceptable side-effects with only a 5% grade 3-4 11 12 230 adverse event rate [38]. 13 14 231 15 232 The HORRAD phase three trial randomised 432 men to ADT with or without local 16 17 233 prostate radiotherapy [39]. In accordance with STAMPEDE, no significant difference 18 For peer review only 19 234 in OS was observed between the two groups (median 45 months in experimental arm 20 21 235 versus 43 months with ADT alone; HR 0.90, [95% CI 0.70–1.14]; p = 0.40), though 22 236 there was a non-significant trend towards improved overall survival in the 160 patients 23 24 237 with low volume metastatic disease treated with radiotherapy (HR 0.68, 95% CI 0.42- 25 26 238 1.10). This study however was criticised for its lack of pre-specified metastatic burden 27 239 (including no knowledge of visceral disease) and potential underpowered sample size 28 29 240 [40]. Both trials took place at a time when upfront systemic agents had not been fully 30 31 241 introduced and thus the true “additive” effect of local prostate radiotherapy in a 32 33 242 contemporary cohort remains unclear [2]. 34 243 35 36 244 CYTOREDUCTIVE RADICAL PROSTATECTOMY 37 38 245 Historical data from the Southwest Oncology Group (SWOG) 8894 trial randomising http://bmjopen.bmj.com/ 39 246 1,286 men with metastatic disease to bilateral orchidectomy with placebo or flutamide 40 41 247 demonstrated, that a subgroup of men who underwent previous radical prostatectomy 42 43 248 had a significantly reduced risk of death (HR 0.77, [95% CI 0.53–0.80]) [41]. Building 44 45 249 on this, numerous retrospective series and registry data (e.g. Surveillance, 46 250 Epidemiology, and End Results, SEER) have reported improved OS and CSS in men on October 1, 2021 by guest. Protected copyright. 47 48 251 who undergo cytoreductive radical prostatectomy with low-burden or predominantly 49 50 252 osseous disease [42-47]. 51 52 253 53 254 At present, prospective evidence is limited to a 61-patient case-control study 54 55 255 conducted by Heidenreich and colleagues [48]. Performed in men with <4 metastases 56 57 256 and no visceral or extensive lymph node metastases, with a serum PSA level <1.0 58 257 ng/ml after neoadjuvant ADT, cytoreductive radical prostatectomy (CRP) and 59 60 258 extended pelvic lymph node dissection (ePLND) led to a 12.1 month improvement in

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1 2 3 259 PFS compared to the control arm ADT alone (38.6 months vs 26.5 months; p = 0.0032) 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 260 [48]. There were no reported Grade 4 or 5 Clavien-Dindo classification complications 6 7 261 within this study, confirming the surgical feasibility reported in previous retrospective 8 262 studies [42, 43]. 9 10 263 11 12 264 Multiple confirmatory randomised (NCT01751438 [BST]; NCT03655886 [LoMP II]) 13 14 265 and single-arm studies (TRoMbone; NCT02716974; NCT03298087) are ongoing with, 15 266 or without, MDT in this cohort [44, 49-52]. 16 17 267 18 For peer review only 19 268 CYTOREDUCTIVE MINIMALLY INVASIVE ABLATIVE THERAPY (MIAT) 20 269 With regard to cytoreductive MIAT, a single retrospective study evaluating whole-gland 21 22 270 cryotherapy in 23 men with a favourable response to 6-months ADT (PSA <1.0 ng/ml), 23 24 271

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1 2 3 290 METASTASIS-DIRECTED THERAPY 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 291 In men with recurrent distant oligometastases, a number of early phase clinical trials 6 7 292 (STOMP,ORIOLE, POPSTAR) have demonstrated promise with metastases-directed 8 293 therapy (either SABR or metastatectomy), mainly with regards to improving ADT-free 9 10 294 and early PFS [24, 55-57]. It is unclear the impact of such interventions on OS [24, 55, 11 12 295 56]. 13 14 296 15 297 In de novo oligometastatic disease, a single pilot study including 20 men underwent 16 17 298 sequential systemic therapy (ADT), surgery (cytoreductive radical prostatectomy + 18 For peer review only 19 299 PLND +/- RPLND), and consolidation SABR to visible bone metastasis [58]. A novel 20 300 endpoint of “undetectable PSA (

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1 2 3 324 PATIENT AND PUBLIC INVOLVEMENT 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 325 A patient-involvement focus group was held with six patients who had advanced or 6 7 326 metastatic prostate cancer, to determine initial patient acceptability and gauge 8 327 important opinions on the proposed amendment and study design. Four patients had 9 10 328 previously received radiotherapy as either their primary or secondary treatment. 11 12 329 Comments from the group discussion were recorded along with anonymous 13 14 330 questionnaires, which the patients returned, by post after the meeting. Two patient 15 331 and public involvement (PPI) representatives were present during the HRA REC 16 17 332 assessment. They will continue to be involved throughout the duration of the trial with 18 For peer review only 19 333 the Trial Management Group and other patients not involved in the direct management 20 21 334 of the study will be on the independent Trials Steering Committee. 22 335 23 336 STUDY POPULATION 24 25 337 Men who are willing to undergo local therapy to the prostate and selective metastases- 26 338 directed therapy for newly diagnosed metastatic prostate cancer in addition to 27 28 339 standard care systemic treatment upfront. 29 30 340 31 341 ELIGIBILITY 32 33 342 34 343 INCLUSION CRITERIA 35 36 344 1. Diagnosed with prostate cancer within 6 months of screening visit 37 38 345 2. Metastatic disease (Any T, Any N, M1+) of any grade, stage or Prostate Specific http://bmjopen.bmj.com/ 39 40 346 Antigen (PSA) level. 41 347 3. Fit to undergo standard of care systemic treatment for metastatic disease and both 42 43 348 minimally invasive therapy and prostate EBRT/cytoreductive radical 44 45 349 prostatectomy. on October 1, 2021 by guest. Protected copyright. 46 350 4. Performance status 0-2. 47 48 351 5. Histologically-proven local tumour. 49 50 352 51 52 353 EXCLUSION CRITERIA 53 354 1. Patient did not undergo and/or is unable to undergo standard of care baseline 54 55 355 imaging tests for confirmation of metastatic status (CT abdomen/pelvis AND chest 56 57 356 X-ray (or CT chest) AND radioisotope bone scan (or whole body imaging such as 58 357 MRI or PET imaging as alternative to all preceding scans mentioned here) AND 59 60 358 prostate MRI.

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1 2 3 359 2. Prior exposure to long-term androgen deprivation therapy or hormonal therapy for 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 360 the treatment of prostate cancer unless started within 4 months of screening visit. 6 7 361 3. Prior chemotherapy or local or systemic therapy for treatment of prostate cancer 8 362 (apart from ADT or hormonal therapy as outlined above). 9 10 363 11 12 364 IDENTIFICATION OF PATIENTS & CONSENT 13 14 365 All men diagnosed with prostate cancer who go to a multidisciplinary team meeting or 15 366 a tumour board as well as any man meeting the eligibility criteria prior to tumour board 16 17 367 discussion will be identified for screening. Members of the tumour board will identify 18 For peer review only 19 368 patients suitable for IP2-ATLANTA. The treating clinicians will mention the study and 20 21 369 then the local research nurses/fellows, clinical trial coordinators, clinical trial 22 370 practitioners or the treating clinicians will then approach the patient if they are 23 24 371 interested. A Patient Information Sheet (PIS) will be given, or if agreed, emailed or 25 26 372 posted out to the patient. Those patients already aware of the diagnosis can be 27 373 approached by telephone to enquire as to their interest in the study so that a PIS can 28 29 374 be then be sent out by email or post prior to a clinical visit. Patients will be given as 30 31 375 much time as they need to read the PIS before consenting to participate (with a 32 33 376 minimum of 24 hours). 34 377 35 36 378 RANDOMISATION 37 38 379 Stratified randomisation will take into account the following variables to create 16 http://bmjopen.bmj.com/ 39 40 380 strata in total: 41 381 42 43 382 - Intent to treat pelvic lymph nodes?: yes versus no 44 45 383 - Metastatic burden: low versus high (CHAARTED definition) [9]. on October 1, 2021 by guest. Protected copyright. 46 384 - Intent to use systemic agent (i.e. Docetaxel, Abiraterone Acetate, Enzalutamide, 47 48 385 Apalutamide)?: yes versus no 49 50 386 - Intent to use metastases directed therapy?: yes versus no 51 52 387 53 388 TRIAL TREATMENT 54 389 55 56 390 CONTROL ARM (STANDARD OF CARE) 57 58 391 Standard of care systemic treatment regimen is determined by the treating clinician 59 60 392 and will be declared upfront prior to randomisation. The decision as to which SOC

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1 2 3 393 systemic treatment is initiated should be made with reference to the current National 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 394 Institute for Health and Care Excellence (NICE) and regional NHS clinically 6 7 395 commissioned guidelines [59]. Presently, Docetaxel is recommended for use in all 8 396 men with newly diagnosed metastatic prostate cancer who do not have significant co- 9 10 397 morbidities [59, 60]. Alternatively, new anti-androgen compounds, including but not 11 12 398 limited to, Abiraterone Acetate or Enzalutamide, are permitted if approved by regional 13 14 399 NHS clinically commissioned guidelines [59, 61]. 15 400 16 17 401 If radiotherapy is planned for local disease in men randomised to the SOC arm with 18 For peer review only 19 402 low volume metastases, then this will be declared prior to randomisation by the 20 21 403 treating clinician. For men with low burden disease, external beam prostate 22 404 radiotherapy will be permitted and defined by the Local Radiotherapy Standard 23 24 405 Operating Procedure (SOP) which reflects NHS clinically commissioned guidelines 25 26 406 [62]. The use of PLNRT and/or MDT will not be permitted in the control arm. Palliative 27 407 prostate radiotherapy for locoregional symptom control in men with high burden 28 29 408 (>/=4) metastases will be permitted as per local clinical practice. Palliative bone 30 31 409 radiotherapy for symptoms and prevention of fracture will be permitted in all men as 32 33 410 per local clinical practice. 34 411 35 412 INTERVENTION ARMS 36 37 413 Whilst discussing the intervention arms we should also consider the impact that SOC 38 http://bmjopen.bmj.com/ 39 414 systemic treatment may have on down-staging the local tumour. As the SOC systemic 40 41 415 treatment would be administered prior to any local MIAT or CRP/EBRT in the 42 416 intervention arms 1 and 2, an attempt at reclassifying the residual disease with a 43 44 417 prostate MRI and biopsies would be pragmatic. This is to prevent patients from 45 46 418 developing adverse events from unnecessary local treatment when they have no on October 1, 2021 by guest. Protected copyright. 47 48 419 evidence of residual disease. Patients with positive post-SOC biopsies would then 49 420 receive the local treatment as outlined below. Randomisation would occur at 50 51 421 enrolment with planned intention to treat (ITT) and per-protocol analyses. 52 53 422 54 423 Biopsies at 6-9 months from initiation of SOC systemic therapy are part of the protocol 55 56 424 during the embedded feasibility pilot. As we currently do not know the significance of 57 58 425 residual disease after SOC systemic therapy, even if determined to be low-volume and 59 60 426 low-grade, all patients with positive biopsies will be offered local treatment as per

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1 2 3 427 randomisation. The pilot stage would obtain a point estimate of the magnitude of this 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 428 response and also patient acceptability of a post-systemic therapy prostate biopsy [63- 6 7 429 66]. Taken collectively this will assist in informing the study investigators of their 8 430 ongoing utility in the main phase II component, where they are not presently 9 10 431 mandated. 11 12 432 13 14 433 INTERVENTION ARM 1: MIAT 15 434 MIAT to the prostate with or without PLND in addition to SOC systemic treatment. 16 17 435 The exact treatment protocol and modality used (cryotherapy or high-intensity 18 For peer review only 19 436 focused ultrasound [HIFU]) will be set within the trial MIAT SOP. For those patients 20 21 437 who are undergoing MIAT no local prostate radiotherapy will be given as part of the 22 438 intervention. Radiotherapy can be administered for palliative reasons. PLND will be 23 24 439 performed based on presence of resectable disease, patient fitness and 25 26 440 consent/discussion with operating surgeon, as set out in the trials PLND with MIAT 27 441 SOP. Cases may be referred for multidisciplinary discussion to the ATLANTA MIAT 28 29 442 Quality Assurance Board. 30 31 443 32 33 444 INTERVENTION ARM 2: RADICAL THERAPY 34 445 In addition to SOC systemic treatment, radical therapy involves either: i) cytoreductive 35 36 446 radical prostatectomy, with or without PLND, or ii) prostate EBRT, with or without 37 38 447 simultaneous PLNRT. The actual modality will be based on physician and patient http://bmjopen.bmj.com/ 39 40 448 preference as well as patient co-morbidities and performance status. 41 449 42 43 450 The surgical technique is at the discretion and expertise of the surgical team but will 44 45 451 reflect current UK surgical practice, laid down in the cytoreductive radical on October 1, 2021 by guest. Protected copyright. 46 452 prostatectomy SOP. Trial surgeons must meet minimum case volume and optimal 47 48 453 complication outcomes prior to operating in this trial. Further, they must receive peer- 49 50 454 approval from the IP2-ATLANTA Surgeons Quality Assurance Board. For patients who 51 52 455 are undergoing prostatectomy no local prostate radiotherapy will be given as part of 53 456 the intervention. Radiotherapy can be given subsequently for palliative reasons. 54 55 457 56 57 458 Two local prostate radiotherapy dose and fractionation options are available: 58 459 59 60

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1 2 3 460 . 60Gy in 20 fractions. Treating the prostate to 60Gy and the seminal vesicles 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 461 to 47Gy using a simultaneous integrated boost administered over 27 days. If 6 7 462 the pelvic lymph nodes are to be treated then this will be done simultaneously 8 463 to a dose of 47Gy in 20 fractions (if treated). 9 10 464 . 74-78Gy in 37-39 fractions. Treat the prostate to 74-78Gy and the seminal 11 12 465 vesicles to 60Gy, using as simultaneous integrated boost. If the pelvic lymph 13 14 466 nodes are to be treated then this will done simultaneously to a dose of 55Gy in 15 467 37-39 fractions (in accordance to same fractions employed for treating the 16 17 468 prostate and seminal vesicles). 18 For peer review only 19 469 20 21 470 The principles of pelvic nodal treatment within the study will follow those of the 22 471 PIVOTALboost study (nodal arm-B), with variation to allow both dose and fractionation 23 24 472 regimes [67]. Quality assurance for radiotherapy will be completed by the UK national 25 26 473 Radiotherapy Trials Quality Assurance (RTTQA) team. 27 474 28 29 475 METASTASES-DIRECTED THERAPY: INTERVENTION ARMS 1 & 2 30 31 476 In men with low-burden disease in both intervention arms 1 and 2, MDT, may be used 32 33 477 but intent-to-use MDT is to be declared prior to randomisation. In the case of a 34 478 metastatic recurrence after MDT, a re-treatment with MDT would be allowed if there 35 36 479 were new metastatic areas/locations. The imaging reporting of metastases as well as 37 38 480 doses and protocol for MDT will be defined and determined by the Imaging Reporting http://bmjopen.bmj.com/ 39 40 481 SOP and Metastases-Directed Therapy SOP. 41 482 42 43 483 SABR should not be delivered whilst concurrent chemotherapy is being delivered. 44 45 484 Concurrent hormonal therapy is acceptable. SABR delivered to metastases must be on October 1, 2021 by guest. Protected copyright. 46 485 completed within 3 months of: prostate radiotherapy +/- PLNRT OR cytoreductive 47 48 486 radical prostatectomy +/- PLND OR MIAT +/- PLND. Constraints on the dose and 49 50 487 fractionations by anatomical site mirror all those defined in the SABR UK consortium 51 52 488 guidelines v.6.1 guidelines (2019) or, if absent, in CORE Trial Radiotherapy, Planning 53 489 & Delivery guidelines v.2.0 (2018) [68, 69]. Quality assurance for SABR will be 54 55 490 completed by the RTTQA body. 56 57 491 58 492 59 60 493

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1 2 3 494 STUDY ENDPOINTS & OUTCOME MEASURES 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 495 Primary and secondary endpoints for the study are presented in Table 1. Study 6 7 496 outcome measures are presented in Table 2. 8 497 9 10 498 FOLLOW-UP 11 499 12 500 Follow-up will consist of 12-weekly serum PSA tests in the first year and 2-weekly 13 14 501 thereafter, until mortality or 4 years after initial randomisation, whichever is first (Table 15 16 502 3.). PROMS will be collected every 6-months in the first year and annually thereafter, 17 18 503 until mortality or 4For years after peer initial randomisation, review whichever only is first. Minimum follow- 19 504 up for each patient will be 2 years. However, yearly follow-up will continue long term 20 21 505 alongside linkage to national database. 22 23 506 24 507 25 508 PATIENT REPORTED OUTCOME MEASURES 26 509 27 28 510 The European Organisation for the Research and Treatment of Cancer (EORTC), 29 30 511 Core Quality of Life Questionnaire-C30 (QLQ-C30), with prostate-specific, fatigue, 31 512 elderly, general and bone metastases modules, International Prostatic Symptoms 32 33 513 Score (IPSS), The Expanded Prostate Cancer Index Composite Bowel and Bladder 34 35 514 (EPIC) and International Index of Erectile Function 5 (IIEF15) will be used. The 36 37 515 EuroQol (EQ-5D-5L) will be used in the study as a generic measure of health-related 38 516 quality-of-life which can be linked to public preferences. These data will be used to http://bmjopen.bmj.com/ 39 40 517 calculate quality-adjusted life-years as part of a future health economic evaluation. 41 42 518 Patients agreeing to return questionnaires on quality-of-life will continue to complete 43 44 519 quality of life data for 4 years after enrolment. 45 520 46 on October 1, 2021 by guest. Protected copyright. 47 521 STUDY VISITS 48 522 49 50 523 Follow up visits for the administration of SOC therapy and clinical review will occur in 51 52 524 accordance with the local hospitals follow-up protocols. In the intervention arms, of the 53 525 embedded feasibility pilot only, a prostate MRI, systematic and targeted transrectal or 54 55 526 transperineal biopsy will be performed at 6-9 months following the initiation of the SOC 56 57 527 therapy. In the main phase II component, these procedures can be carried out by local 58 528 centres at the discretion of local clinicians and when they are, data should be collected 59 60 529 on their outcomes.

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1 2 3 530 For those randomised to MIAT or CRP/EBRT, a date for treatment(s) will be booked 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 531 in accordance with the local hospital waiting lists. Removal of the urethral catheter 6 7 532 after MIAT or CRP will occur after a minimum period of 7-days during a hospital visit 8 533 or can be removed either at the GP surgery or at a local hospital to the patient. 9 10 534 11 12 535 Further clinical reviews will occur as SOC visits at 12, 26, 28, 32, 34 and 52 weeks in 13 14 536 the 1st year and 24-weekly intervals thereafter until mortality or 2 years after 15 537 enrolment, whichever is first. 16 17 538 18 For peer review only 19 539 Further Follow-up Imaging 20 540 Follow-up imaging to determine response from treatment on primary and metastatic 21 22 541 disease will not be protocolled but we recommend imaging to take place when there 23 542 is suspicion of progression, such as patients with a rising PSA (i.e. biochemical 24 25 543 failure). The appropriate imaging will be chosen as per the local hospital resources 26 27 544 and policies. We envisage that the majority will perform a combination of a prostate 28 29 545 MRI, bone scintigraphy, PET-CT/MRI, whole body MRI or CT chest/abdomen/pelvis. 30 546 31 547 Long-term outcomes 32 33 548 Patients will be consented for their details to be linked to national registries for survival 34 35 549 information such as NHS Information Centre/Office of National Statistics (ONS) in 36 37 550 England/Wales and General Register Office in Scotland, Hospital Episode Statistics 38 551 (HES). This ONS-HES linkage however is an optional consent. http://bmjopen.bmj.com/ 39 40 552 41 42 553 43 554 STATISTICAL ANALYSES AND SAMPLE SIZE CALCULATION 44 45 555 on October 1, 2021 by guest. Protected copyright. 46 556 Embedded Feasibility and Pilot 47 48 557 We are seeking to determine whether the randomisation of men with metastatic 49 50 558 disease is feasible and whether men are compliant to the therapy following 51 52 559 randomisation. We aim to approach 80 patients from up to 17 centres in the UK over 53 560 a 6-month period to allow us to estimate a 33% recruitment rate with 95% confidence 54 55 561 interval width of approximately ± 10 percentage points. 56 57 562 58 563 59 564 60 565

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1 2 3 566 Main phase II component 4 567 The study will have 80% power to detect a treatment difference with a hazard ratio 0.7 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 568 in favour of any of the intervention arms compared to the control at a two-sided 5.0% 7 8 569 significance level. This is based on the assumption that the accrual period will be 9 10 570 uniform over 24 months, that the follow-up period will be 24 months, and that the 11 571 median progression-free survival is 37 months. This calculation may be adjusted 12 13 572 depending on the compliance rate assessed during the feasibility stage. The overall 14 15 573 sample size will be 918 participants considering a 5% loss to follow-up (291 16 17 574 participants per group, 873 participants for three arms). This will allow the detection of 18 575 an effect size of 9.2%For increase peer in progression review free survival only at 24 months. 19 20 576 21 22 577 ADVERSE EVENT REPORTING 23 24 578 The Common Terminology Criteria for Adverse Events (CTCAEv5.0) domain will be 25 26 579 used to report adverse events [70]. 27 580 28 29 581 DATA COLLECTION 30 31 582 The principal means of data collection from participant visits will be Electronic Data 32 33 583 Capture (EDC) using the web-based InForm database. All study data will be entered 34 584 into electronic Case Report Forms (eCRFs) in a database provided by the Sponsor. 35 36 585 All eCRFs will be completed using de-identified data. 37 38 586 http://bmjopen.bmj.com/ 39 587 DATA MONITORING & ARCHIVING 40 41 588 A combined independent data monitoring and trial steering committee will meet twice 42 43 589 a year. All trial documentation, including that held at participating sites and the trial 44 45 590 coordinating centre, will be archived for a minimum of 10 years following the end of 46 591 the study. on October 1, 2021 by guest. Protected copyright. 47 48 592 49 50 593 ETHICS AND DISSEMINATION 51 52 594 This trial was approved by the Health Research Authority (HRA) Research Ethics 53 595 Committee Wales (REC5; 19/WA0005). The results will be submitted for publication 54 55 596 in peer-reviewed journals and submitted to the REC within a year of the end of the 56 57 597 study. 58 598 59 60 599

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1 2 3 600 TRIAL FUNDING, ORGANISATION AND ADMINISTRATION 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 601 6 7 602 IP2-ATLANTA trial was approved by the HRA Wales REC 5 (19/WA0005). IP2- 8 603 ATLANTA is funded by the Wellcome Trust (204998/Z/16/Z). The study will be 9 10 604 monitored periodically by trial monitors to assess the progress of the study, verify 11 12 605 adherence to the protocol, ICH GCP E6 guidelines and other national/international 13 14 606 requirements and to review the completeness, accuracy and consistency of the data 15 607 16 17 608 DISCUSSION 18 For peer review only 19 609 IP2-ATLANTA is a multicentre, phase II, randomised controlled trial. The study will 20 21 610 provide Level I evidence on oncological outcomes from prostate minimally invasive 22 611 ablative therapy or radical therapy, in combination with metastasis-directed therapy, 23 24 612 against standard of care treatment alone, in men with newly-diagnosed hormone 25 26 613 sensitive metastatic prostate cancer. If either intervention arm is proven to provide 27 614 significant oncological benefit this will have wide-reaching implications on the current 28 29 615 standard of care paradigm. 30 31 616 32 33 617 CONCLUSION 34 35 618 IP2-ATLANTA addresses an important research gap in the role of sequential systemic, 36 37 619 local cytoreductive and metastasis-directed interventions in men with newly- 38 620 diagnosed metastatic prostate cancer. http://bmjopen.bmj.com/ 39 40 621 41 42 622 TRIAL STATUS 43 623 IP2-ATLANTA is open to recruitment in 13 centres in England and Wales and 44 45 624 expected to complete its embedded feasibility pilot phase by late 2020 [71]. 46 on October 1, 2021 by guest. Protected copyright. 47 625 48 49 626 Acknowledgements: We would like to thank all the participants, study PI, trial 50 627 clinicians, research nurses, Imperial Clinical Trial Unit staff and other site staff who 51 52 628 have been responsible for setting up, recruiting participants and collecting the data for 53 54 629 the IP2-ATLANTA trial. Further we are grateful for the ongoing support of the Trial 55 56 630 Management Group and our trial patient representative. Finally, we would like to thank 57 631 the trial oversight provided by ICTU and our trial funder the Wellcome Trust. 58 59 632 60

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1 2 3 633 Contributors: Conception and design of ATLANTA trial: HUA, MJC, MW, TTS, TD, 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 634 AF, VK, MG, NS, JS, ED, FF, NKN, ME. All authors have read and approved the final 6 7 635 manuscript: MJC, TTS, KS, ED, JS, FF, NS, MG, AF, NKN, ME, OFN, KTJ, DP, SG, 8 636 DB, GH, JM, DS, MK, AI, CB, RAP, NA, CH, lS, BR, GH, SM, BK, SM, VK, TD, JNS, 9 10 637 MW, HUA. 11 12 638 13 14 639 Funding: The trial was funded by the Wellcome Trust (204998/Z/16/Z) 15 640 16 17 641 Patient consent for publication: Not required. 18 For peer review only 19 642 20 21 643 Conflicts of Interest 22 644 Martin J. Connor’s research is support by University College London Hospitals (UCLH) 23 24 645 Charity and the Wellcome Trust. 25 26 646 Kamalram Thippu Jayaprakash is currently supported by a research grant from the UK 27 647 National Institute of Health Research (NIHR) Clinical Research Network Eastern. He 28 29 648 has received educational/ and travel grants from Bayer UK, Janssen Oncology, Pfizer; 30 31 649 Roche, Takeda. 32 33 650 Hashim U. Ahmed's research is supported by core funding from the United Kingdom's 34 651 National Institute of Health Research (NIHR) Imperial Biomedical Research Centre. 35 36 652 Ahmed currently receives funding from the Wellcome Trust, Prostate Cancer UK, MRC 37 38 653 (UK), Cancer Research UK, Sonacare Inc., Trod Medical, and Sophiris Biocorp for http://bmjopen.bmj.com/ 39 40 654 trials in prostate cancer. Ahmed was a paid medical consultant for Sophiris Biocorp, 41 655 Sonacare Inc. and BTG in the past 3 years. 42 43 656 All other authors have no declaration 44 45 657 on October 1, 2021 by guest. Protected copyright. 46 658 47 48 659 References 49 50 660 1 Smittenaar CR, Petersen KA, Stewart K, et al. Cancer incidence and mortality 51 661 projections in the UK until 2035, Br J Cancer 2016;115:1147-55 52 662 doi:10.1038/bjc.2016.304 [doi] [published Online First: October 25]. 53 54 55 663 2 Connor MJ, Shah TT, Horan G, et al. Cytoreductive treatment strategies for de novo 56 664 metastatic prostate cancer, Nature Reviews Clinical Oncology 2019:1-15. 57 58 665 3 James ND, Spears MR, Clarke NW, et al. Survival with newly diagnosed metastatic 59 666 prostate cancer in the “docetaxel era”: data from 917 patients in the control arm of the 60 667 STAMPEDE trial (MRC PR08, CRUK/06/019), Eur Urol 2015;67:1028-38.

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1 2 3 668 4 Miyake H, Matsushita Y, Watanabe H, et al. Prognostic significance of time to 4 669 castration resistance in patients with metastatic castration-sensitive prostate cancer, BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 670 Anticancer Res 2019;39:1391-6. 7 8 671 5 Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive 9 672 prostate cancer. N Engl J Med 2019;381:13-24. 10 11 673 6 Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy 12 13 674 in metastatic prostate cancer. N Engl J Med 2019;381:121-31. 14 15 675 7 James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or 16 676 both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival 17 677 results from an adaptive, multiarm, multistage, platform randomised controlled trial, 18 678 Lancet 2016;387:1163-77For peer doi:10.1016/S0140-6736(15)01037-5 review only [doi] [published 19 679 Online First: March 19]. 20 21 22 680 8 Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration- 23 681 sensitive prostate cancer, N Engl J Med 2017;377:352-60. 24 25 682 9 Sweeney CJ, Chen Y, Carducci M, et al. Chemohormonal therapy in metastatic 26 683 hormone-sensitive prostate cancer, N Engl J Med 2015;373:737-46. 27 28 29 684 10 Weichselbaum RR, Hellman S. Oligometastases revisited, Nature reviews Clinical 30 685 oncology 2011;8:378. 31 32 686 11 Connor MJ, Winkler M, Ahmed HU. Survival in Oligometastatic Prostate 33 687 Cancerâ€”A New Dawn or the Will Rogers Phenomenon? JAMA oncology 2020;6:185- 34 688 6. 35 36 37 689 12 Sita-Lumsden A, Dart DA, Waxman J, et al. Circulating microRNAs as potential 38 690 new biomarkers for prostate cancer, Br J Cancer 2013;108:1925. http://bmjopen.bmj.com/ 39 40 691 13 Selth LA, Townley SL, Bert AG, et al. Circulating microRNAs predict biochemical 41 692 recurrence in prostate cancer patients, Br J Cancer 2013;109:641. 42 43 44 693 14 Alix-Panabières C, Riethdorf S, Pantel K. Circulating tumor cells and bone marrow 45 694 micrometastasis, Clinical Cancer Research 2008;14:5013-21. 46 on October 1, 2021 by guest. Protected copyright. 47 695 15 Lorente D, Olmos D, Mateo J, et al. Decline in circulating tumor cell count and 48 696 treatment outcome in advanced prostate cancer, Eur Urol 2016;70:985-92. 49 50 51 697 16 Lilleby W, Stensvold A, Mills IG, et al. Disseminated tumor cells and their prognostic 52 698 significance in nonmetastatic prostate cancer patients, International journal of cancer 53 699 2013;133:149-55. 54 55 700 17 Morgan TM, Lange PH, Porter MP, et al. Disseminated tumor cells in prostate 56 701 cancer patients after radical prostatectomy and without evidence of disease predicts 57 58 702 biochemical recurrence, Clinical cancer research 2009;15:677-83. 59 60

21 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 46

1 2 3 703 18 Weckermann D, Polzer B, Ragg T, et al. Perioperative activation of disseminated 4 704 tumor cells in bone marrow of patients with prostate cancer, J Clin Oncol BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 705 2009;27:1549-56. 7 8 706 19 Comen E, Norton L, Massague J. Clinical implications of cancer self-seeding, 9 707 Nature reviews Clinical oncology 2011;8:369. 10 11 708 20 Kim M, Oskarsson T, Acharyya S, et al. Tumor self-seeding by circulating cancer 12 13 709 cells, Cell 2009;139:1315-26. 14 15 710 21 Shiozawa Y, Pedersen EA, Havens AM, et al. Human prostate cancer metastases 16 711 target the hematopoietic stem cell niche to establish footholds in mouse bone marrow, 17 712 J Clin Invest 2011;121:1298-312. 18 For peer review only 19 713 22 Sleeman JP. The metastatic niche and stromal progression, Cancer Metastasis 20 21 714 Rev 2012;31:429-40. 22 23 715 23 Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal 24 716 metastatic prostate cancer, Nature 2015;520:353. 25 26 717 24 Ryan Phillips, William Yue Shi, Matthew Deek, et al. Outcomes of Observation vs 27 28 718 Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer. The ORIOLE 29 719 Phase 2 Randomized Clinical Trial. JAMA Oncology 2020 [published Online First: Mar 30 720 26,]. 31 32 721 25 Palma DA, Olson RA, Harrow S, et al. Stereotactic ablative radiation therapy for 33 722 the comprehensive treatment of oligometastatic tumors (SABR-COMET): results of a 34 723 randomized trial, International Journal of Radiation Oncology• Biology• Physics 35 36 724 2018;102:S3-4. 37 38 725 26 Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and http://bmjopen.bmj.com/ 39 726 ipilimumab in a patient with metastatic non–small cell lung cancer, Cancer immunology 40 727 research 2013;1:365-72. 41 42 43 728 27 Strigari L, Mancuso M, Ubertini V, et al. Abscopal effect of radiation therapy: 44 729 Interplay between radiation dose and p53 status, Int J Radiat Biol 2014;90:248-55. 45 46 730 28 Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal on October 1, 2021 by guest. Protected copyright. 47 731 effect in a patient with melanoma, N Engl J Med 2012;366:925-31. 48 49 732 29 Brooks ED, Chang JY. Time to abandon single-site irradiation for inducing abscopal 50 51 733 effects, Nature Reviews Clinical Oncology 2018:1. 52 53 734 30 Kubo M, Satoh T, Ishiyama H, et al. Enhanced activated T cell subsets in prostate 54 735 cancer patients receiving iodine-125 low-dose-rate prostate brachytherapy, Oncol Rep 55 736 2018;39:417-24. 56 57 58 737 31 Sabel MS. Cryo-immunology: a review of the literature and proposed mechanisms 59 738 for stimulatory versus suppressive immune responses, Cryobiology 2009;58:1-11. 60

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1 2 3 739 32 Ablin RJ, Soanes WA, Gonder MJ. Prospects for cryo-immunotherapy in cases of 4 740 metastasizing carcinoma of the prostate, Cryobiology 1971;8:271-9. BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 7 741 33 Benzon B, Glavaris SA, Simons BW, et al. Combining immune check-point 8 742 blockade and cryoablation in an immunocompetent hormone sensitive murine model 9 743 of prostate cancer, Prostate cancer and prostatic diseases 2018;21:126-36. 10 11 744 34 Ross AE, Hurley PJ, Tran PT, et al. A pilot trial of pembrolizumab plus prostatic 12 13 745 cryotherapy for men with newly diagnosed oligometastatic hormone-sensitive prostate 14 746 cancer, Prostate cancer and prostatic diseases 2020;23:184-93. 15 16 747 35 Connor MJ, Winkler M, Ahmed HU. Cytoreductive cryotherapy for newly diagnosed 17 748 oligometastatic hormone-sensitive prostate cancer, Prostate Cancer and Prostatic 18 749 Diseases 2020:1-2.For peer review only 19 20 21 750 36 Tosoian JJ, Gorin MA, Ross AE, et al. Oligometastatic prostate cancer: definitions, 22 751 clinical outcomes, and treatment considerations, Nature Reviews Urology 2017;14:15. 23 24 752 37 Khoo V. New concepts in prostate cancer management: the conundrum of 25 753 managing oligometastatic disease in prostate cancer—through the looking glass 26 754 darkly, Clin Radiol 2019. 27 28 29 755 38 Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for 30 756 newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled 31 757 phase 3 trial, Lancet 2018;392:2353-66 doi:S0140-6736(18)32486-3 [pii] [published 32 758 Online First: December 01]. 33 34 759 39 Boevé LM, Hulshof MC, Vis AN, et al. Effect on survival of androgen deprivation 35 36 760 therapy alone compared to androgen deprivation therapy combined with concurrent 37 761 radiation therapy to the prostate in patients with primary bone metastatic prostate 38 762 cancer in a prospective randomised clinical trial: data from the HORRAD trial, Eur Urol http://bmjopen.bmj.com/ 39 763 2019;75:410-8. 40 41 764 40 Gregucci F, Fiorentino A. Re: Liselotte MS Boevé, Maarten CCM Hulshof, André 42 43 765 N. Vis, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to 44 766 Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the 45 767 Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective 46 768 Randomized Clinical Trial: Data from the HORRAD Trial. Eur Urol 2019; 75: 410-8. on October 1, 2021 by guest. Protected copyright. 47 769 Eur Urol 2019;75:e129. 48 49 770 41 Thompson IM, Tangen C, Basler J, et al. Impact of previous local treatment for 50 51 771 prostate cancer on subsequent metastatic disease, J Urol 2002;168:1008-12. 52 53 772 42 Jang WS, Kim MS, Jeong WS, et al. Does robot‐assisted radical prostatectomy 54 773 benefit patients with prostate cancer and bone oligometastases? BJU Int 55 774 2018;121:225-31. 56 57 58 775 43 Sooriakumaran P, Karnes J, Stief C, et al. A multi-institutional analysis of 59 776 perioperative outcomes in 106 men who underwent radical prostatectomy for distant 60 777 metastatic prostate cancer at presentation, Eur Urol 2016;69:788-94.

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1 2 3 778 44 Sooriakumaran P. Testing radical prostatectomy in men with prostate cancer and 4 779 oligometastases to the bone: a randomized controlled feasibility trial, BJU Int BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 780 2017;120:E8-E20. 7 8 781 45 Heidenreich A, Fossati N, Pfister D, et al. Cytoreductive radical prostatectomy in 9 782 men with prostate cancer and skeletal metastases, European urology oncology 10 783 2018;1:46-53. 11 12 13 784 46 Culp SH, Schellhammer PF, Williams MB. Might men diagnosed with metastatic 14 785 prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based 15 786 study, Eur Urol 2014;65:1058-66 doi:10.1016/j.eururo.2013.11.012 [doi] [published 16 787 Online First: June 01]. 17 18 788 47 Rusthoven CG,For Jones BL,peer Flaig TW, review et al. Improved only survival with prostate radiation 19 789 in addition to androgen deprivation therapy for men with newly diagnosed metastatic 20 21 790 prostate cancer, Journal of Clinical Oncology 2016;34:2835-42. 22 23 791 48 Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy in patients 24 792 with prostate cancer and low volume skeletal metastases: results of a feasibility and 25 793 case-control study, J Urol 2015;193:832-8. 26 27 28 794 49 Pienta K. A Study of Definitive Therapy to Treat Prostate Cancer (oligo- 29 795 mets) NCT02716974 . ;2019. 30 31 796 50 Nickols N, Rettig M. NCT03298087 Systemic and Tumor-Directed Therapy for 32 797 Oligometastatic Prostate Cancer. 33 34 798 51 Chapin BF, Mcguire SE, Wang X, et al. No title, A prospective, multicenter, 35 36 799 randomized phase II trial of best systemic therapy (BST) or BST plus definitive 37 800 treatment (Surgery or Radiation) of the primary tumor in metastatic prostate cancer. 38 801 2015. http://bmjopen.bmj.com/ 39 40 802 52 Nicolaas L. NCT03655886. Testing radical prostatectomy in men with 41 803 prostate cancer and oligometastases to the bone: 42 43 804 a randomized controlled feasibility trial (LoMP II). 2018. 44 45 805 53 Sheng M, Wan L, Liu C, et al. Cytoreductive cryosurgery in patients with bone 46 806 metastatic prostate cancer: A retrospective analysis, Kaohsiung J Med Sci on October 1, 2021 by guest. Protected copyright. 47 807 2017;33:609-15. 48 49 808 54 Shah TT, Peters M, Eldred-Evans D, et al. Early-Medium-Term Outcomes of 50 51 809 Primary Focal Cryotherapy to Treat Nonmetastatic Clinically Significant Prostate 52 810 Cancer from a Prospective Multicentre Registry, Eur Urol 2019. 53 54 811 55 Siva S, Bressel M, Murphy DG, et al. Stereotactic abative body radiotherapy 55 812 (SABR) for oligometastatic prostate cancer: a prospective clinical trial, Eur Urol 56 813 2018;74:455-62. 57 58 59 60

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1 2 3 814 56 Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed 4 815 therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 816 multicenter phase II trial, Journal of Clinical Oncology 2017;36:446-53. 7 8 817 57 Connor MJ, Smith A, Miah S, et al. Targeting oligometastasis with stereotactic 9 818 ablative radiation therapy or surgery in metastatic hormone-sensitive prostate cancer: 10 819 a systematic review of prospective clinical trials, European Urology Oncology 2020. 11 12 13 820 58 O'Shaughnessy MJ, McBride SM, Vargas HA, et al. A pilot study of a multimodal 14 821 treatment paradigm to accelerate drug evaluations in early-stage metastatic prostate 15 822 cancer, Urology 2017;102:164-72. 16 17 823 59 NICE, Guideline Updates Team UK. Prostate cancer: diagnosis and management, 18 824 2019. For peer review only 19 20 21 825 60 National Institute for Health and Care Excellence. Prostate cancer: diagnosis 22 826 and management 23 827 [B] Evidence review for docetaxel in people with 24 828 hormone sensitive prostate cancer [NG131] . 2019. 25 26 829 61 Scottish Medicines Consortium. Abiraterone acetate with prednisone or 27 28 830 prednisolone for the 29 831 treatment of newly diagnosed high risk metastatic hormone sensitive prostate cancer 30 832 in 31 833 adult men in combination with androgen deprivation therapy [SMC2215]. 2020. 32 33 834 62 NHS England Clinical Commissioning. External beam radiotherapy for patients 34 835 presenting with hormone sensitive, low volume metastatic prostate cancer at the time 35 36 836 of diagnosis [P200802P] (URN: 1901) . 2020. 37 38 837 63 Köllermann J, Caprano J, Budde A, et al. Follow-up of nondetectable prostate http://bmjopen.bmj.com/ 39 838 carcinoma (pT0) after prolonged PSA-monitored neoadjuvant hormonal therapy 40 839 followed by radical prostatectomy, Urology 2003;62:476-80. 41 42 43 840 64 Bream MJ, Dahmoush L, Brown JA. pT0 Prostate Cancer: predictive 44 841 clinicopathologic features in an American population, Current urology 2013;7:14. 45 46 842 65 McKay RR, Ye H, Xie W, et al. Evaluation of intense androgen deprivation before on October 1, 2021 by guest. Protected copyright. 47 843 prostatectomy: a randomized phase II trial of enzalutamide and leuprolide with or 48 844 without abiraterone, Journal of Clinical Oncology 2019;37:923. 49 50 51 845 66 Evans AJ. Treatment effects in prostate cancer, Modern Pathology 2018;31:110- 52 846 21. 53 54 847 67 Syndikus I. ISRCTN80146950. A phase III randomised controlled trial of prostate 55 848 and pelvis versus prostate alone radiotherapy with or without prostate boost 56 849 (PIVOTALBoost). 2019 [published Online First: March,]. 57 58 59 850 68 Khoo V. Conventional Care Versus Radioablation (Stereotactic Body 60 851 Radiotherapy) for Extracranial Oligometastases (CORE) NCT02759783. ;2019.

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1 2 3 852 69 The Faculty of Clinical Oncology of The Royal College of Radiologists. Stereotactic 4 853 Ablative Body BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 854 Radiation Therapy (SABR): 7 855 A Resource. Version 6.1. 2019. 8 9 856 70 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. Common 10 857 Terminology Criteria 11 858 for Adverse Events (CTCAE) Version 5.0. 2017. 12 13 14 859 71 Connor MJ, Shah TT, Sukumar J, et al. Initial experience of the adjuvant treatments 15 860 to the local tumor for metastatic prostate cancer: Assessment of novel treatment 16 861 algorithms, a multicenter, phase II randomized controlled trial (IP2-ATLANTA). Journal 17 862 of Clinical Oncology 2020. 18 For peer review only 19 863 20 21 864 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 865 Table & Figure Legends 4 866 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 867 Table 1. Study primary and secondary endpoints 7 868 8 9 869 Table 2. Study outcome measures 10 870 11 1 12 871 Table 3. Study visit schedule. Legend: Randomisation should be performed within 7 13 872 days from screening visit 14 873 15 874 Figure 1. Study Flowchart. Legend: MIAT – Minimally invasive ablative therapy; CRP 16 875 – Cytoreductive Radical Prostatectomy; PLND – Pelvic Lymph Node Dissection; 17 876 PLNRT – Pelvic Lymph Node Radiotherapy; EBRT – External Beam Radiotherapy. 18 For peer review only 19 877 *Systemic therapy is not limited to listed agents, *Prostate only EBRT may be perform 20 878 in selected men with low-burden disease, if declared prior to randomisation and local 21 879 SOC. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 880 Table 1. Study primary and secondary endpoints 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 a) Recruitment, randomisation and compliance to allocation 7 PRIMARY 8 ENDPOINT: b) Adverse events 9 Embedded 10 Feasibility Pilot c) Proportion of patients with pathological complete response on post 11 systemic therapy prostate biopsy at 6-9 months. 12 13 14 a) Progression-free survival (PFS) PRIMARY 15 Defined as a composite outcome of biochemical failure; local 16 17 ENDPOINT: progression; lymph node progression or bone metastases progression (new sites); or progression or development of new distant metastases, 18 Phase II For peer review only 19 defined as lymph nodes outside the pelvis, bone or organ involvement 20 or skeletal-related events confirmed as progression as in the 21 STAMPEDE randomised study (Assessment of Progression; 22 Supplementary Material) [42]. 23 24 25 SECONDARY a) Adverse events and side-effect profile 26 b) Predictive factors for PFS and OS in each arm. 27 ENDPOINT: 28 c) Effect on PFS or OS from varying radiotherapy dosage and schedules 29 Phase II d) Effect on PFS and OS stratified by volume and site for local and 30 metastatic disease 31 e) Effect on PFS and OS stratified by the use of metastases directed 32 33 therapy. 34 f) Effect on PFS using an alternative definition of failure, defined as a 35 PSA increase of >/=25% and >/=2ng/mL if PSA was >/=2ng/mL from 36 37 baseline, or a PSA increase of >/=25% if PSA was <2ng/mL at random 38 assignment. http://bmjopen.bmj.com/ 39 g) Effect on PFS using an alternative definition of local progression of a 40 41 soft tissue metastatic lesion: defined as an increase of >/=20% in the 42 largest tumour dimension with a minimum absolute increase of 5mm. 43 Local progression of bone metastases to be assessed using MD 44 45 Anderson Cancer Center–criteria with a >/=25% increase in the size of 46 a measurable lesion on CT or a >/=25% increase in the size of ill- on October 1, 2021 by guest. Protected copyright. 47 defined lesions on CT considered to be progression (1, 2). 48 49 h) Costs and resource utilisation for future cost-effectiveness analyses 50 i) In those men undergoing repeat biopsies after 6-9 months of standard 51 of care systemic therapy, the proportion of patients with negative 52 53 biopsies. 54 j) In those men undergoing repeat prostate/pelvic MRI after 6-9 months 55 of standard of care systemic therapy, the proportion of patients with a 56 57 negative prostate MRI for local tumour. 58 k) In those men undergoing repeat imaging (local prostate/pelvic and / or 59 other body areas) after 6-9 months of standard of care systemic 60

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1 2 3 therapy, the proportion of patients with reduction on imaging of 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 metastatic tumour deposits. 6 881 7 882 8 883 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 884 Table 2. Study outcome measures 4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 a) Compliance to randomised arm 7 PRIMARY 8 OUTCOMES: b) Recruitment and randomisation rate 9 Embedded 10 Feasibility Pilot c) Safety (adverse events) 11 d) Proportion of patients with complete pathological response on post 12 13 SOC systemic therapy prostate biopsies at 6-9 months. 14 15 16 17 a) Progression-free survival (PFS) 18 PRIMARY For peer review only 19 20 OUTCOMES: 21 22 Phase II 23 24 25 26 27 SECONDARY a) Urinary, sexual and rectal side-effects 28 b) Patient-reported outcomes using validated questionnaires OUTCOMES: 29 c) Progression on PSA and imaging and impact of clinical features on 30 Phase II progression 31 32 d) Health-related quality-of-life 33 e) Data on costs and resource utilisation for future cost-effectiveness 34 analysis 35 36 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1 2 3 4 5 6 7 Systemic 8 Local Metastasis- 9 Phase II RCT (n = 918) 10 Primary Endpoint: PFS Therapy Treatment Directed 11 12 For peer review only

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4 BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 7 8 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and 9 related documents* 10 11 Page Section/item Item Description 12 13 No. No 14 Administrative information 15 16 1 Title 1 Descriptive title identifying the study design, 17 18 For peerpopulation, review interventions, only and, if applicable, trial 19 acronym 20 21 3 Trial registration 2a Trial identifier and registry name. If not yet 22 registered, name of intended registry 23 24 3 2b All items from the World Health Organization Trial 25 Registration Data Set 26 27 2 Protocol version 3 Date and version identifier 28 29 3,19 Funding 4 Sources and types of financial, material, and other 30 31 support 32 1,2,19 Roles and 5a Names, affiliations, and roles of protocol 33 34 , 20 responsibilities contributors 35 36 1, 20 5b Name and contact information for the trial sponsor 37 38 19, 20 5c Role of study sponsor and funders, if any, in study http://bmjopen.bmj.com/ 39 design; collection, management, analysis, and 40 interpretation of data; writing of the report; and the 41 decision to submit the report for publication, 42 43 including whether they will have ultimate authority 44 over any of these activities 45 46 19, 20 5d Composition, roles, and responsibilities of the on October 1, 2021 by guest. Protected copyright. 47 coordinating centre, steering committee, endpoint 48 adjudication committee, data management team, 49 50 and other individuals or groups overseeing the trial, 51 if applicable (see Item 21a for data monitoring 52 committee) 53 54 55 56 57 58 59 60

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1 2 Introduction 3 4 5-10 Background and 6a Description of research question and justification BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 rationale for undertaking the trial, including summary of 6 7 relevant studies (published and unpublished) 8 examining benefits and harms for each intervention 9 10 5-10 6b Explanation for choice of comparators 11 12 5 Objectives 7 Specific objectives or hypotheses 13 14 3, 10, Trial design 8 Description of trial design including type of trial (eg, 15 11, 12 parallel group, crossover, factorial, single group), 16 allocation ratio, and framework (eg, superiority, 17 equivalence, noninferiority, exploratory) 18 For peer review only 19 20 Methods: Participants, interventions, and outcomes 21 22 11 Study setting 9 Description of study settings (eg, community clinic, 23 academic hospital) and list of countries where data 24 will be collected. Reference to where list of study 25 sites can be obtained 26 27 11 Eligibility criteria 10 Inclusion and exclusion criteria for participants. If 28 29 applicable, eligibility criteria for study centres and 30 individuals who will perform the interventions (eg, 31 surgeons, psychotherapists) 32 33 5, 12- Interventions 11a Interventions for each group with sufficient detail to 34 15 allow replication, including how and when they will 35 36 be administered 37 38 12-15 11b Criteria for discontinuing or modifying allocated http://bmjopen.bmj.com/ 39 interventions for a given trial participant (eg, drug 40 dose change in response to harms, participant 41 request, or improving/worsening disease) 42 43 12-15 11c Strategies to improve adherence to intervention 44 45 protocols, and any procedures for monitoring 46 adherence (eg, drug tablet return, laboratory tests) on October 1, 2021 by guest. Protected copyright. 47 48 12-15 11d Relevant concomitant care and interventions that 49 are permitted or prohibited during the trial 50 51 16 Outcomes 12 Primary, secondary, and other outcomes, including 52 the specific measurement variable (eg, systolic 53 blood pressure), analysis metric (eg, change from 54 55 baseline, final value, time to event), method of 56 aggregation (eg, median, proportion), and time 57 point for each outcome. Explanation of the clinical 58 relevance of chosen efficacy and harm outcomes is 59 60 strongly recommended

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1 2 Fig 1, Participant timeline 13 Time schedule of enrolment, interventions 3 Table (including any run-ins and washouts), 4 3 assessments, and visits for participants. A BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 schematic diagram is highly recommended (see 7 Figure) 8 9 17-18 Sample size 14 Estimated number of participants needed to 10 achieve study objectives and how it was 11 determined, including clinical and statistical 12 13 assumptions supporting any sample size 14 calculations 15 16 17-18 Recruitment 15 Strategies for achieving adequate participant 17 enrolment to reach target sample size 18 For peer review only 19 Methods: Assignment of interventions (for controlled trials) 20 21 Allocation: 22 23 12 Sequence 16a Method of generating the allocation sequence (eg, 24 generation computer-generated random numbers), and list of 25 any factors for stratification. To reduce 26 27 predictability of a random sequence, details of any 28 planned restriction (eg, blocking) should be 29 provided in a separate document that is 30 unavailable to those who enrol participants or 31 32 assign interventions 33 34 12 Allocation 16b Mechanism of implementing the allocation 35 concealment sequence (eg, central telephone; sequentially 36 mechanism numbered, opaque, sealed envelopes), describing 37 any steps to conceal the sequence until 38 http://bmjopen.bmj.com/ 39 interventions are assigned 40 41 12 Implementation 16c Who will generate the allocation sequence, who 42 will enrol participants, and who will assign 43 participants to interventions 44 45 N/A Blinding (masking) 17a Who will be blinded after assignment to 46 interventions (eg, trial participants, care providers, on October 1, 2021 by guest. Protected copyright. 47 outcome assessors, data analysts), and how 48 49 N/A 17b If blinded, circumstances under which unblinding is 50 51 permissible, and procedure for revealing a 52 participant’s allocated intervention during the trial 53 54 55 56 57 58 59 60

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1 2 Methods: Data collection, management, and analysis 3

4 18 Data collection 18a Plans for assessment and collection of outcome, BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 methods baseline, and other trial data, including any related 6 processes to promote data quality (eg, duplicate 7 8 measurements, training of assessors) and a 9 description of study instruments (eg, 10 questionnaires, laboratory tests) along with their 11 reliability and validity, if known. Reference to where 12 13 data collection forms can be found, if not in the 14 protocol 15 16 18 18b Plans to promote participant retention and 17 complete follow-up, including list of any outcome 18 For peerdata review to be collected only for participants who 19 discontinue or deviate from intervention protocols 20 21 18 Data management 19 Plans for data entry, coding, security, and storage, 22 23 including any related processes to promote data 24 quality (eg, double data entry; range checks for 25 data values). Reference to where details of data 26 management procedures can be found, if not in the 27 28 protocol 29 30 17-18 Statistical methods 20a Statistical methods for analysing primary and 31 secondary outcomes. Reference to where other 32 details of the statistical analysis plan can be found, 33 if not in the protocol 34 35 17-18 20b Methods for any additional analyses (eg, subgroup 36 37 and adjusted analyses) 38 http://bmjopen.bmj.com/ 39 17-18 20c Definition of analysis population relating to protocol 40 non-adherence (eg, as randomised analysis), and 41 any statistical methods to handle missing data (eg, 42 multiple imputation) 43 44 Methods: Monitoring 45 46 18 Data monitoring 21a Composition of data monitoring committee (DMC); on October 1, 2021 by guest. Protected copyright. 47 summary of its role and reporting structure; 48 49 statement of whether it is independent from the 50 sponsor and competing interests; and reference to 51 where further details about its charter can be 52 found, if not in the protocol. Alternatively, an 53 54 explanation of why a DMC is not needed 55 56 18 21b Description of any interim analyses and stopping 57 guidelines, including who will have access to these 58 interim results and make the final decision to 59 terminate the trial 60

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1 2 18 Harms 22 Plans for collecting, assessing, reporting, and 3 managing solicited and spontaneously reported 4 adverse events and other unintended effects of trial BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 interventions or trial conduct 7 8 18 Auditing 23 Frequency and procedures for auditing trial 9 conduct, if any, and whether the process will be 10 independent from investigators and the sponsor 11 12 Ethics and dissemination 13 14 18-19 Research ethics 24 Plans for seeking research ethics 15 approval committee/institutional review board (REC/IRB) 16 17 approval 18 For peer review only 19 18-19, Protocol 25 Plans for communicating important protocol 20 12, amendments modifications (eg, changes to eligibility criteria, 21 Suppl outcomes, analyses) to relevant parties (eg, 22 2.0 investigators, REC/IRBs, trial participants, trial 23 24 registries, journals, regulators) 25 26 12, Consent or assent 26a Who will obtain informed consent or assent from 27 Suppl potential trial participants or authorised surrogates, 28 3.0 and how (see Item 32) 29 30 12, 26b Additional consent provisions for collection and use 31 Suppl of participant data and biological specimens in 32 33 3.0 ancillary studies, if applicable 34 35 17-18 Confidentiality 27 How personal information about potential and 36 enrolled participants will be collected, shared, and 37 maintained in order to protect confidentiality before, http://bmjopen.bmj.com/ 38 during, and after the trial 39 40 20 Declaration of 28 Financial and other competing interests for 41 42 interests principal investigators for the overall trial and each 43 study site 44 45 19, Access to data 29 Statement of who will have access to the final trial 46 Suppl dataset, and disclosure of contractual agreements on October 1, 2021 by guest. Protected copyright. 47 2.0 that limit such access for investigators 48 49 Suppl Ancillary and post- 30 Provisions, if any, for ancillary and post-trial care, 50 2.0 trial care and for compensation to those who suffer harm 51 52 from trial participation 53 54 55 56 57 58 59 60

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1 2 19, Dissemination policy 31a Plans for investigators and sponsor to 3 Suppl communicate trial results to participants, 4 2.0 healthcare professionals, the public, and other BMJ Open: first published as 10.1136/bmjopen-2020-042953 on 25 February 2021. Downloaded from 5 6 relevant groups (eg, via publication, reporting in 7 results databases, or other data sharing 8 arrangements), including any publication 9 restrictions 10 11 31b Authorship eligibility guidelines and any intended 12 13 use of professional writers 14 31c Plans, if any, for granting public access to the full 15 16 protocol, participant-level dataset, and statistical 17 code 18 For peer review only 19 Appendices 20 21 Suppl Informed consent 32 Model consent form and other related 22 3.0 materials documentation given to participants and authorised 23 24 surrogates 25 26 Suppl Biological specimens 33 Plans for collection, laboratory evaluation, and 27 3.0 storage of biological specimens for genetic or 28 molecular analysis in the current trial and for future 29 use in ancillary studies, if applicable 30 31 *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 32 Explanation & Elaboration for important clarification on the items. Amendments to the 33 34 protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT 35 Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” 36 license. 37 38 http://bmjopen.bmj.com/ 39 40 41 42 43 44 45 46 on October 1, 2021 by guest. Protected copyright. 47 48 49 50 51 52 53 54 55 56 57 58 59 60

6 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml