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 Clarke1, Nicholas D James2, Malcolm D Mason3, Daniel Abersold4, David P Dearnaley5, Johann S de Bono5, Christopher Parker5, Mahesh KB Parmar6, Alastair WS Ritchie1, J Martin Russell7, Melissa R Spears6, George Thalmann4, Matthew R Sydes6 for the STAMPEDE investigators

1Dept of Urology, The Christie NHS Foundation Trust, Manchester, UK; 2School of Cancer Sciences, University of Birmingham, UK; 3Cardiff University, UK; 4Dept of Urology, University of Bern, Switzerland;5Institute of Cancer Research/Royal Marsden Hosp, Sutton, UK; 6MRC Clinical Trials Unit, London, UK; 7Beatson 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 TanyNanyM+ histologically confirmed prostate adenocarcinoma OR multiple sclerotic bone metastases with PSA≥100ng/ml without histologically confirmation of prostate adenocarcinoma

OutcomesTable 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 & InformationEmail: stampede@ctu.mrc.ac.ukTrial website: www.stampede-trial.orgMRC CTU: www.ctu.mrc.ac.uk

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     296Local progression     44Lymph nodes progression

    21

Distant metastases progn

    120

PCa death     140Other death     29Total number of events

345 169  

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.

BackgroundSTAMPEDE (www.stampedetrial.org) 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. MethodsNewly 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-2013. We report overall survival (OS) and failure-free survival (FFS) from randomisation by primary disease characteristics.  Results3,984 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 35-379) 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. ConclusionSurvival, 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.

New HT 101 patients 37 29 21 18

Chemotherapy 15

Radiotherapy 15

Bisphosphonate

Abiraterone

Figure 5: Time to subsequent therapy received from

a) randomisation & b) FFS event

Patient Characteristics Failure-Free Survival Overall Survival

N %Patient Characteristic/ Grouping

2yr FFS(95% CI)

Hazard Ratio*(95% CI)

2yr Survival(95% CI)

Hazard Ratio*(95% CI)

682 100 All 31 (26, 35) - 71 (66, 75) -Metastases Groupings425 62 Bone only 31 (25, 37) 1.00 73 (67, 78) 1.00

83 12 Soft Tissue only 53 (39, 66) 0.51 (0.35, 0.74) 87 (73, 94)0.35 (0.18, 0.67)

174 26 Bone & Soft Tissue 18 (11, 27) 1.44 (1.13, 1.82) 57 (46, 67)1.55 (1.11, 2.16)

Nodal Status220 32 N0 33 (25, 41) 1.00 76 (67, 83) 1.00

400 59 N+ 32 (26, 38) 0.90 (0.71, 1.14) 68 (62, 74)1.12 (0.80, 1.58)

62 9 NX 20 (9, 33) 1.08 (0.74, 1.56) 69 (53, 81)1.11 (0.65, 1.88)

Bone Metastases & Nodal Status Grouping165 44 Bone & N0 33 (24, 41) 1.00 76 (66, 83) 1.00

207 56 Bone & N+ 33 (23, 43) 0.86 (0.63, 1.16) 70 (59, 78)1.20 (0.79, 1.83)

Initial Gleason sum score category9 2 2 - 6 38 (9, 68) 1.00 57 (8, 89) 1.00

104 21 7 40 (28, 52) 0.83 (0.33, 2.08) 81 (70, 89)0.78 (0.18, 3.31)

391 77 8 - 10 31 (26, 37) 1.09 (0.45, 2.66) 68 (62, 74)1.21 (0.30, 4.92)

Age Group481 71 Under 70 29 (24, 34) 1.00 69 (62, 74) 1.00

201 29 70 or over 36 (27, 44) 0.87 (0.69, 1.10) 76 (67, 83)0.96 (0.69, 1.33)

WHO performance status491 72 0 33 (28, 39) 1.00 79 (74, 84) 1.00

181 27 1 26 (19, 35) 1.58 (1.25, 1.99) 52 (42, 62)2.40 (1.75, 3.30)

10 1 2 NR 3.24 (1.52, 6.88) 29 (4, 61)3.57 (1.56, 8.16)

PSA Nadir+

295 63 <4 49 (41, 55) 1.00 82 (76, 87) 1.00

173 37 ≥4 31 (20, 44) 1.42 (1.02, 1.97) 60 (51, 68)2.61 (1.87, 3.62)

PSA at diagnosis (quintiles)137 20 Lowest 43 (32, 54) 1.00 73 (61, 82) 1.00

136 20 2 38 (27, 48) 1.06 (0.74, 1.52) 69 (57, 79)0.80 (0.48, 1.32)

137 20 3 30 (19, 40) 1.30 (0.92, 1.85) 71 (59, 80)0.97 (0.60, 1.56)

136 20 4 23 (14, 33) 1.57 (1.11, 2.22) 75 (63, 83)0.94 (0.58, 1.51)

136 20 Highest 21 (12, 30) 1.94 (1.39, 2.72) 66 (54, 76)1.27 (0.80, 2.02)

Tumour status71 10 ≤T2 51 (36, 64)  1.00 74 (57, 85) 1.00

388 57 T3 31 (25, 37) 1.32 (0.89, 1.96) 73 (67, 79)1.20 (0.68, 2.11)

160 23 T4 26 (17, 36) 1.93 (1.26, 2.95) 66 (54, 75)1.58 (0.86, 2.90)

62 9 TX 20 (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 relevant599 88 Bone +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.

32 5 Lung 

14 2 Liver 208 31 Distant Nodes  Key46 7 Other  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 1.26-2.9)

2: Up and about >50% of waking hours, capable of self-care

Key Eligibility Criteria:High risk newly-diagnosed non-metastatic node-negative disease

ORNewly-diagnosed metastatic or node-positive disease

ORPreviously treated with radical surgery and/or radiotherapy, now

relapsingAND

Fit for all protocol treatment and follow-up

Allocated to control arm

N=1,185

Allocated to research arms

N=2,799

MetastaticN=726

Non-metastatic

N=459   

Randomised

N=3,984

Newly-diagnosed

N=692

Relapsing

N=34   

Diagnosed more than

6 months prior randn

N=10Included 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.

8.2

(5.7

, 11.

3)

11.6

(5.

3, 3

2.9)

26.9 (14.4, 38.3)0.00

0.25

0.50

0.75

1.00

Prop

ortio

n ev

ent-

free

174 38(81) 10(17) 6(3) 0(0) 0(0)Bone & soft tissue425 121(160) 47(36) 19(10) 6(5) 1(1)Bone only83 38(17) 19(9) 11(5) 6(1) 1(0)Soft tissue only

Number at risk

0 12 24 36 48 60Time from randomisation (Months)

Soft tissue only Bone only Bone & soft tissue

11.8 (10.8, 13.3) 41.5 (36.0, 45.4)

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n ev

ent-

free

0 12 24 36 48 60Time from randomisation (Months)

682 197(258) 76(62) 36(18) 12(6) 2(1)FFS Event682 362(52) 192(61) 93(33) 31(18) 7(4)Death

Number at risk

Death FFS Event

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n st

arting

tre

atm

ent

682 367 192 94Abiraterone682 341 178 85Bisphosphonate682 331 164 79Radiotherapy682 323 159 71Chemotherapy682 255 99 47New HT

Number at risk

Randn 12 24 36Time from randomisation (Months)

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n st

arting

tre

atm

ent

345 167 59 13Abiraterone345 137 48 9Bisphosphonate345 129 45 8Radiotherapy345 112 35 3Chemotherapy345 46 14 1New HT

Number at risk

0 12 24 36Time from FFS event (Months)

New HT Chemotherapy Radiotherapy Bisphosphonate Abiraterone