Survival with newly diagnosed metastatic prostate cancer in the “docetaxel era”: Data from >600 patients in the control arm of the STAMPEDE trial (MRC PR08, CRUK/06/019) Noel W Clarke 1, Nicholas D James 2, Malcolm D Mason 3, Daniel Abersold 4, David P Dearnaley 5, Johann S de Bono 5, Christopher Parker 5, Mahesh KB Parmar 6, Alastair WS Ritchie 1, J Martin Russell 7, Melissa R Spears 6, George Thalmann 4, Matthew R Sydes 6 for the STAMPEDE investigators 1 Dept of Urology, The Christie NHS Foundation Trust, Manchester, UK; 2 School of Cancer Sciences, University of Birmingham, UK; 3 Cardiff University, UK; 4 Dept of Urology, University of Bern, Switzerland; 5 Institute of Cancer Research/Royal Marsden Hosp, Sutton, UK; 6 MRC Clinical Trials Unit, London, UK; 7 Beatson West of Scotland Cancer Centre, Glasgow, UK Abstract (data updated since abstract submitted to ASCO) Subsequent Therapies Received Data Collection & Analysis Aim Patient Characteristics & Prognosis Population of Interest  What is the prognosis for patients with newly diagnosed metastatic disease and does this appear to have changed over time?  Should sites scan for nodes in those patients with distant metastases?  What treatments are patients receiving following progression?  All newly diagnosed (within 6 months of randomisation) patients with confirmed metastatic status randomised to control arm A of the STAMPEDE trial between Oct-2005 and Mar-2013 were included in this prospective cohort study.  All patients received standard of care androgen deprivation therapy (ADT) which consisted of orchidectomy, luteinising hormone-releasing hormone (ant)agonists, or maximum androgen blockade. Upon progression treatment given was at the discretion of the consulting clinician.  Details of the original trial can be found published elsewhere.  Baseline characteristics were collected via randomisation and baseline forms for details of patient demographics, metastatic site and diagnosis date, any planned radiotherapy, nodal and tumour status and additional treatments received.  Outcome details were obtained from follow-up and progression forms.  Data frozen: Apr-2013  Kaplan-Meier estimates for assessing the survival curves were produced; individuals not reporting an event were censored at the date of last contact.  Survival estimates are reported here according to the following groupings:  Site of metastases (Bone only, Soft Tissue only, Bone & Soft Tissue)  Nodal status at baseline (N0, N+, NX)  Bone metastases and nodal status (Bone & N0, Bone & N+)  Initial Gleason sum score category (2-6, 7, 8-10)  Age group at randomisation (under 70, 70 or over)  WHO performance status  PSA nadir (< 4, ≥4)  PSA at diagnosis (quintiles)  Tumour status (≤T2, T3, T4, TX) Survival outcomes reported are the intermediate and definitive primary outcome measures for the trial: failure-free survival and overall survival, with estimates of both median survival and survival at two years. Number of deaths due to prostate cancer (PCa) compared to other causes, on those whose death had been reviewed, were also tabulated. *Includes patients with high-risk newly diagnosed disease AND either T any N any M + histologically confirmed prostate adenocarcinoma OR multiple sclerotic bone metastases with PSA≥100ng/ml without histologically confirmation of prostate adenocarcinoma Outcomes Table 1: Patient characteristics at baseline and outcome survival times. Research Support  Cancer Research UK provides grant funding  MRC provides core funding support  Pfizer provides drug and an educational grant  Novartis provides drug and an educational grant  Sanofi-Aventis provides drug and an educational grant  Janssen provides drug and an educational grant Contacts & Information Trial website: MRC CTU: Figure 4: Combinations of subsequent therapies ever received (including numbers receiving that combination). Example – of all patients who report an FFS event 37 report only ever receiving both new hormone therapy and chemotherapy at any time following their failure-free survival event. N.B. Numbers are not given for combinations with less than 10 patients; 46 patients do not report receiving any therapies post-failure- free survival event. The majority of patients reporting being on chemotherapy are on docetaxel, and the majority of patients reporting subsequent bisphosphonate are on zoledronic acid. Failure Free Survival Overall Survival Total number of events Biochemical Failure  296 Local progression  44 Lymph nodes progression  21 Distant metastases progn  120 PCa death 140 Other death  29 Total number of events Conclusions Further Reading  Failure-free survival is shorter than anticipated from pre-trial projections but overall survival is longer.  Approximately 70% of time from diagnosis with metastatic disease is spent after a failure-free survival event.  Patients with lymph node-only disease have significantly better outcomes than bone-only disease.  Patients with bone and lymph node disease have significantly worse outcomes than bone-only disease.  There is no clear pattern in the choice of therapy for the first on-trial failure-free survival event.  Parker CC, Sydes MR, Mason MD et al. Prostate radiotherapy for men with metastatic disease: A new comparison in the STAMPEDE trial. Clinical Oncology 2013; 25 (5)  Sydes MR, Parmar MKB, Mason MD et al. Flexible trial design in practice – stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials 2012; 13 (168)  Sydes MR Parmar, MKB James, ND et al. Issues in applying multi-arm multi-stage (MAMS) methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial. Trials 2009; 10 (39) Figure 1: Selection criteria for newly-diagnosed M1 patients in the control arm. Background STAMPEDE ( recruits men with newly diagnosed or rapidly relapsing prostate cancer (PCa) that is metastatic (M1) or high-risk locally advanced, all commencing long-term androgen deprivation therapy (ADT) for the first time. This is now the largest therapeutic RCT in PCa. We report survival outcomes for newly diagnosed M1 control arm men in order to inform future trials in this setting. Methods Newly diagnosed men with M1 disease in the trial’s control arm (standard of care: ADT alone for at least 2yr), diagnosed up to 6 months prior to randomisation, were identified from trial records in Apr We report overall survival (OS) and failure-free survival (FFS) from randomisation by primary disease characteristics. Results 3,984 men were recruited to STAMPEDE Oct-2005 to Mar-2013, including a control arm cohort of 682 M1 men with newly-diagnosed disease. This cohort has median age at randomisation 65yr (quartiles 60-70), median PSA 108 (quartiles ) IU/l; metastases to bone only (B) 425 (62%), soft tissue only (ST) 83 (12%) or bone and soft tissue (B+ST) 174 (26%). ST was mainly lymph nodes. Median time from diagnosis to randomisation is 68 days (max 180 days). Median duration of ADT prior to randomisation is 47 days (max 105 days). There were 169 deaths, of which 140 were from PCa. Median OS from randomisation is 42 months, with 2-yr OS 71% (95%CI 66, 75) in this cohort; B 73% (95%CI 67, 78), ST 87% (95%CI 73, 94), B+ST 57% (95%CI 46, 67). Median FFS is 12 months, driven by rising PSA; 2-yr FFS 31% (95%CI 26, 35). Median time from FFS event to death was 20 months. Additional data on relapse therapies presented. Conclusion Survival, and particularly FFS, remains relatively poor for men presenting with M1 disease starting long-term ADT, despite potential access when castration-resistant (CRPC) to docetaxel and other newer therapies. Better first-line therapy is required; STAMPEDE will report many comparisons in the future. Different M1 patterns may vary prognostically. Men with M1 disease will now spend most time in a state of CRPC, which has important implications for clinicians and trialists. Figure 5: Time to subsequent therapy received from a) randomisation & b) FFS event Patient CharacteristicsFailure-Free SurvivalOverall Survival N% Patient Characteristic/ Grouping 2yr FFS (95% CI) Hazard Ratio* (95% CI) 2yr Survival (95% CI) Hazard Ratio* (95% CI) All31 (26, 35)-71 (66, 75) - Metastases Groupings 42562Bone only31 (25, 37) (67, 78) Soft Tissue only53 (39, 66)0.51 (0.35, 0.74)87 (73, 94)0.35 (0.18, 0.67) 17426Bone & Soft Tissue18 (11, 27)1.44 (1.13, 1.82)57 (46, 67)1.55 (1.11, 2.16) Nodal Status 22032N033 (25, 41) (67, 83) N+32 (26, 38)0.90 (0.71, 1.14)68 (62, 74)1.12 (0.80, 1.58) 629NX20 (9, 33)1.08 (0.74, 1.56)69 (53, 81)1.11 (0.65, 1.88) Bone Metastases & Nodal Status Grouping 16544Bone & N033 (24, 41) (66, 83) Bone & N+33 (23, 43)0.86 (0.63, 1.16)70 (59, 78)1.20 (0.79, 1.83) Initial Gleason sum score category (9, 68) (8, 89) (28, 52)0.83 (0.33, 2.08)81 (70, 89)0.78 (0.18, 3.31) (26, 37)1.09 (0.45, 2.66)68 (62, 74)1.21 (0.30, 4.92) Age Group 48171Under 7029 (24, 34) (62, 74) or over36 (27, 44)0.87 (0.69, 1.10)76 (67, 83)0.96 (0.69, 1.33) WHO performance status (28, 39) (74, 84) (19, 35)1.58 (1.25, 1.99)52 (42, 62)2.40 (1.75, 3.30) 1012NR3.24 (1.52, 6.88)29 (4, 61)3.57 (1.56, 8.16) PSA Nadir <449 (41, 55) (76, 87) ≥431 (20, 44)1.42 (1.02, 1.97)60 (51, 68)2.61 (1.87, 3.62) PSA at diagnosis (quintiles) 13720Lowest43 (32, 54) (61, 82) (27, 48)1.06 (0.74, 1.52)69 (57, 79)0.80 (0.48, 1.32) (19, 40)1.30 (0.92, 1.85)71 (59, 80)0.97 (0.60, 1.56) (14, 33)1.57 (1.11, 2.22)75 (63, 83)0.94 (0.58, 1.51) 13620Highest21 (12, 30)1.94 (1.39, 2.72)66 (54, 76)1.27 (0.80, 2.02) Tumour status 7110≤T251 (36, 64) (57, 85) T331 (25, 37)1.32 (0.89, 1.96)73 (67, 79)1.20 (0.68, 2.11) 16023T426 (17, 36)1.93 (1.26, 2.95)66 (54, 75)1.58 (0.86, 2.90) 629TX20 (10, 34)2.32 (1.42, 3.77)64 (46, 77)1.86 (0.95, 3.62) Metastatic site *Cox models adjusted for age at randomisation where relevant 59988Bone + Analyses for PSA nadir were based on a landmark start time for patients of 6 months. Two year survival is therefore survival at 18 months from the landmark. 325Lung 142Liver 20831Distant Nodes Key 467Other NR = not reached WHO performance status is defined as Continuous Variables 0: Normal activity without restriction; Median age = 65y (IQR 60-70) 1: Strenuous activity restricted, can do light work; Median time from Pca diagnosis to randn = 2.2m (IQR )2: Up and about >50% of waking hours, capable of self-care Key Eligibility Criteria: High risk newly-diagnosed non-metastatic node-negative disease OR Newly-diagnosed metastatic or node-positive disease OR Previously treated with radical surgery and/or radiotherapy, now relapsing AND Fit for all protocol treatment and follow-up Allocated to control arm N=1,185 Allocated to research arms N=2,799 Metastatic N=726 Non-metastatic N=459 Randomised N=3,984 Newly-diagnosed N=692 Relapsing N=34 Diagnosed more than 6 months prior rand n N=10 Included in these analyses* N=682 Figure 2: Failure-free and overall survival for newly-diagnosed M1 patients in the STAMPEDE trial. Figure 3: Failure-free survival split by metastatic site.