Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial (2018)

Type of publication:
Randomised controlled trial

Author(s):
Parker, Christopher C; James, Nicholas D; Brawley, Christopher D; Clarke, Noel W; Hoyle, Alex P; Ali, Adnan; Ritchie, Alastair W S; Attard, Gerhardt; Chowdhury, Simon; Cross, William; Dearnaley, David P; Gillessen, Silke; Gilson, Clare; Jones, Robert J; Langley, Ruth E; Malik, Zafar I; Mason, Malcolm D; Matheson, David; Millman, Robin; Russell, J Martin; Thalmann, George N; Amos, Claire L; Alonzi, Roberto; Bahl, Amit; Birtle, Alison; Din, Omar; Douis, Hassan; Eswar, Chinnamani; Gale, Joanna; Gannon, Melissa R; Jonnada, Sai; Khaksar, Sara; Lester, Jason F; O’Sullivan, Joe M; Parikh, Omi A; Pedley, Ian D; Pudney, Delia M; Sheehan, Denise J; *Srihari, Narayanan Nair; Tran, Anna T H; Parmar, Mahesh K B; Sydes, Matthew R; Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators

Citation:
Lancet, Volume 392, Issue 10162, 1–7 December 2018, Pages 2353-2366

Abstract:
BACKGROUND Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy. METHODS We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number CT00268476. FINDINGS Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63-73) and median amount of prostate-specific antigen of 97 ng/mL (33-315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68-0·84; p<0·0001) but not overall survival (0·92, 0·80-1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3-4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398
[38%] with control and 380 [39%] with radiotherapy). INTERPRETATION Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer. FUNDING Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.

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Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol (2018)

Type of publication:
Journal article

Author(s):
Sydes, M R; Spears, M R; Mason, M D; Clarke, N W; Dearnaley, D P; de Bono, J S; Attard, G; Chowdhury, S; Cross, W; Gillessen, S; Malik, Z I; Jones, R; Parker, C C; Ritchie, A W S; Russell, J M; Millman, R; Matheson, D; Amos, C; Gilson, C; Birtle, A; Brock, S; Capaldi, L; Chakraborti, P; Choudhury, A; Evans, L; Ford, D; Gale, J; Gibbs, S; Gilbert, D C; Hughes, R; McLaren, D; Lester, J F; Nikapota, A; O’Sullivan, J; Parikh, O; Peedell, C; Protheroe, A; Rudman, S M; Shaffer, R; Sheehan, D; Simms, M; *Srihari, N; Strebel, R; Sundar, S; Tolan, S; Tsang, D; Varughese, M; Wagstaff, J; Parmar, M K B; James, N D; STAMPEDE Investigators

Citation:
Annals of Oncology : Official Journal of the European Society for Medical Oncology; May 2018; vol. 29 (no. 5); p. 1235-1248

Abstract:
Background Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in systemic therapy for advanced or metastatic prostate cancer: evaluation of drug efficacy: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP versus SOC+DocP. Method Recruitment to SOC+DocP and SOC+AAP overlapped November 2011 to March 2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for≥2years and RT to the primary tumour. Stratified randomisation allocated pts 2:1:2 to SOC; SOC+docetaxel 75mg/m2 3-weekly×6+prednisolone 10mg daily; or SOC+abiraterone acetate 1000mg+prednisolone 5mg daily. AAP duration depended on stage and intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. This was not a formally powered comparison. A hazard ratio (HR) <1 favours SOC+AAP, and HR>1 favours SOC+DocP. Results A total of 566 consenting patients were contemporaneously randomised: 189 SOC+DocP and 377 SOC+AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66years and median PSA 56ng/ml. With median follow-up 4years, 149 deaths were reported. For overall survival, HR=1.16 (95% CI 0.82-1.65); failure-free survival HR=0.51 (95% CI 0.39-0.67); progression-free survival HR=0.65 (95% CI 0.48-0.88); metastasis-free survival HR=0.77 (95% CI 0.57-1.03); prostate cancer-specific survival HR=1.02 (0.70-1.49); and symptomatic skeletal events HR=0.83 (95% CI 0.55-1.25). In the safety population, the proportion reporting≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC+DocP, and 40%, 7% and 1% SOC+AAP; prevalence 11% at 1 and 2 years on both arms. Relapse treatment patterns varied by arm. Conclusions This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events. Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs.Trial registration Clinicaltrials.gov: NCT00268476.

A pilot experience in using a digital app to follow-up prostate cancer patients in Shropshire, UK (2018)

Type of publication:
Conference abstract

Author(s):
*Phan Y.; *Loh A.; *Anandakumar A.; *Umranikar S.; *Elves A.

Citation:
European Urology, Supplements; Mar 2018; vol. 17 (no. 2)

Abstract:
Introduction & Objective: It is not uncommon for patients with cancer to experience physical, mental and social distress, forming a significant burden that has a negative impact on their quality of life. We have piloted a digital app called VitruCare in our hospital in order to address these issues in patients with prostate cancer. More importantly, the app also serves as a communication tool between the hospital medical team and the patients. Materials and Methods: Patients with prostate cancer were invited to use VitruCare in our pilot study. 53 users were followed prospectively. Data on various domains such as “My Goals”, “My Lifestyle”, “My Priorities”, “My Diaries”, and “How Do I Feel Today” were analysed retrospectively. Results: The users of this application have a median age of 72.5 years old. 14% have nodal or bone metastasis, and median time since treatment is 48 months. 60% have completed the lifestyle questionnaire and “How Do I Feel Today” trackers. 20% of the users who completed the lifestyle questionnaire reported anxiety. 42% have used the diary function and 47% have used the secured messaging function. Usage of the lifestyle questionnaire, “How Do I Feel Today” trackers, secured messaging and diary functions does not appear to be age related. Patients who have been treated and further away from treatment in time are more likely to be used the app. Conclusions: The level of engagement in this pilot study reflects the willingness of patients to utilize this innovative app that has the potential to monitor the well-being of patients with prostate cancer out with the constraints of a fixed clinic appointment.

Feasibility of performing MRI prostate before prostate biopsy in a district general hospital in the UK (2017)

Type of publication:
Conference abstract

Author(s):
*Phan Y.; *Loh A.; *Anandakumar A.; *Umranikar S.; *Lynn N.

Citation:
Journal of Endourology; Sep 2017; vol. 31, S2

Abstract:
Introduction & Objective: Men with abnormal digital rectal examination or raised PSA usually undergo
transrectal ultrasound (TRUS) prostate biopsies. NICE guidelines do not recommend routine MRI prostate before prostate biopsy unless they have a previous negative prostate biopsy. However, all men with positive prostate biopsies will have MRI prostates. The recent publication of PROMIS (Prostate MR Imaging Study) trial suggests that MRI prostate can reduce unnecessary biopsies by a quarter and can improve detection of clinically significant cancer. In light of this, we would like to determine if performing MRI prostate before biopsy is likely to increase workload in our radiology department in a district general hospital in the UK. Materials and Methods: Patients who underwent TRUS prostate biopsy between 3 Dec 2015 to 28 April 2016 were identified. Their data were analysed retrospectively. 1 year follow-up was chosen to see how many patients would have had MRIs. Results: 173 patients were listed for prostate biopsies but only 158 patients had biopsies with an average age of 69.8 years old (range: 49-88 years old) and an average PSA of 48.1ug/l (range: 0.5-3283.1ug/l). 57 patients had a negative prostate biopsy during this period. 30/57 patients did not have a MRI at all; 12/57
patients had a MRI after biopsy; 1/57 patient had a MRI as an acute setting after biopsy to look for abscesses; and 14/57 patients had a MRI before biopsy. Conclusions: In our study, 30/158 (19.0%) did not have any MRI prostate in 1 year after their first prostate biopsy. However, it is possible that this group of patients will have a MRI prostate in the second year or later. If we were to perform a MRI prostate before TRUS prostate biopsy for all patients, it would increase 19.0% workload for our radiology department.

A pilot experience in using a digital app to follow-up prostate cancer patients in Shropshire, UK (2017)

Type of publication:
Conference abstract

Author(s):
*Phan Y.; *Loh A.; *Anandakumar A.; *Umranikar S.; *Elves A.

Citation:
Journal of Endourology; Sep 2017; vol. 31, S2

Abstract:
Introduction & Objective: It is not uncommon for patients with cancer to experience physical, mental and social distress, forming a significant burden that has a negative impact on their quality of life. We have piloted a digital app called VitruCare in our hospital in order to address these issues in patients with prostate cancer. More importantly, the app also serves as a communication tool between the hospital medical team and the patients. Materials and Methods: Patients with prostate cancer were invited to use VitruCare in our pilot study. 53 users were followed prospectively. Data on various domains such as “My Goals”, “My Lifestyle”, “My Priorities”, “My Diaries”, and “How Do I Feel Today” were analysed retrospectively. Results: The users of this application have a median age of 72.5 years old. 14% have nodal or bone metastasis, and median time since treatment is 48 months. 60% have completed the lifestyle questionnaire and “How Do I Feel Today” trackers. 20% of the users who completed the lifestyle questionnaire reported anxiety. 42% have used the diary function and 47% have used the secured messaging function. Usage of the lifestyle questionnaire, “How Do I Feel Today” trackers, secured messaging and diary functions does not appear to be age related. Patients who have been treated and further away from treatment in time are more likely to be used the app. Conclusions: The level of engagement in this pilot study reflects the willingness of patients to utilize this innovative app that has the potential to monitor the well-being of patients with prostate cancer out with the constraints of a fixed clinic appointment.

Abiraterone for prostate cancer not previously treated with hormone therapy (2017)

Type of publication:
Randomised controlled trial

Author(s):
James, Nicholas D. Ph.D.; de Bono, Johann S. Ph.D.; Spears, Melissa R. M.Sc.; Clarke, Noel W. Ch.M.; Mason, Malcolm D. F.R.C.R.; Dearnaley, David P. F.R.C.R.; Ritchie, Alastair W.S. M.D.; Amos, Claire L. Ph.D.; Gilson, Clare M.R.C.P.; Jones, Rob J. M.B., Ch.B.; Matheson, David Ph.D.; Millman, Robin; Attard, Gerhardt M.D.; Chowdhury, Simon Ph.D.; Cross, William R. F.R.C.S.; Gillessen, Silke M.D.; Parker, Christopher C. M.D.; Russell, Martin J. F.R.C.R.; Berthold, Dominik R. M.D.; Brawley, Chris M.Sc.; Adab, Fawzi F.R.C.R.; Aung, San M.R.C.P.; Birtle, Alison J. F.R.C.R.; Bowen, Jo F.R.C.R.; Brock, Susannah F.R.C.R.; Chakraborti, Prabir F.R.C.R.; Ferguson, Catherine F.R.C.R.; Gale, Joanna B.M.; Gray, Emma F.R.C.R.; Hingorani, Mohan Ph.D.; Hoskin, Peter J. F.R.C.R.; Lester, Jason F. F.R.C.R.; Malik, Zafar I. F.R.C.R.; McKinna, Fiona F.R.C.R.; McPhail, Neil F.R.C.R.; Money-Kyrle, Julian F.R.C.R.; O’Sullivan, Joe Ph.D.; Parikh, Omi F.R.C.R.; Protheroe, Andrew F.R.C.P.; Robinson, Angus F.R.C.R.; *Srihari, Narayanan N. F.R.C.R.; Thomas, Carys M.R.C.P.; Wagstaff, John Ch.B.; Wylie, James F.R.C.R.; Zarkar, Anjali F.R.C.R.; Parmar, Mahesh K.B. D.Phil.; Sydes, Matthew R. M.Sc.; the STAMPEDE Investigators

Citation:
New England Journal of Medicine; Jul 2017; vol. 377 (no. 4); p. 338-351

Abstract:
BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostatespecific
antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476, and Current Controlled Trials number, ISRCTN78818544.)

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Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial (2017)

Type of publication:
Randomised controlled trial

Author(s):
Mason, Malcolm D; Clarke, Noel W; James, Nicholas D; Dearnaley, David P; Spears, Melissa R; Ritchie, Alastair W S; Attard, Gerhardt; Cross, William; Jones, Rob J; Parker, Christopher C; Russell, J Martin; Thalmann, George N; Schiavone, Francesca; Cassoly, Estelle; Matheson, David; Millman, Robin; Rentsch, Cyrill A; Barber, Jim; Gilson, Clare; Ibrahim, Azman; Logue, John; Lydon, Anna; Nikapota, Ashok D; O’Sullivan, Joe M; Porfiri, Emilio; Protheroe, Andrew; *Srihari, Narayanan Nair; Tsang, David; Wagstaff, John; Wallace, Jan; Walmsley, Catherine; Parmar, Mahesh K B; Sydes, Matthew R; STAMPEDE Investigators

Citation:
Journal of clinical oncology : official journal of the American Society of Clinical Oncology; 35, no. 14 (May 2017) p. 1530-1541.

Abstract:
Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned subgroup analyses provide hypotheses for future studies.

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Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): Survival results from an adaptive, multiarm, multistage, platform randomised controlled trial (2016)

Type of publication:
Journal article

Author(s):
James N.D., Sydes M.R., Clarke N.W., Mason M.D., Dearnaley D.P., Spears M.R., Ritchie A.W.S., Parker C.C., Russell J.M., Attard G., De Bono J., Cross W., Jones R.J., Thalmann G., Amos C., Matheson D., Millman R., Alzouebi M., Beesley S., Birtle A.J., Brock S., Cathomas R., Chakraborti P., Chowdhury S., Cook A., Elliott T., Gale J., Gibbs S., Graham J.D., Hetherington J., Hughes R., Laing R., McKinna F., McLaren D.B., O’Sullivan J.M., Parikh O., Peedell C., Protheroe A., Robinson A.J., *Srihari N., Srinivasan R., Staffurth J., Sundar S., Tolan S., Tsang D., Wagstaff J., Parmar M.K.B.

Citation:
The Lancet, March 2016, vol./is. 387/10024(1163-1177)

Abstract:
Background
Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.
Methods
Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m<sup>2</sup>) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2.5% one-sided alpha for hazard ratio (HR) 0.75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).
Findings
2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0.94, 95% CI 0.79-1.11; p=0.450), 81 months (41 to not reached) for SOC + Doc (0.78, 0.66-0.93; p=0.006), and 76 months (39 to not reached) for SOC + ZA + Doc (0.82, 0.69-0.97; p=0.022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.
Interpretation
Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.
Funding
Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

Link to more details or full-text: http://www.sciencedirect.com/science/article/pii/S0140673615010375

Failure-Free Survival and Radiotherapy in Patients With Newly Diagnosed Nonmetastatic Prostate Cancer: Data From Patients in the Control Arm of the STAMPEDE Trial (2016)

Type of publication:
Journal article

Author(s):
James, Nicholas D, Spears, Melissa R, Clarke, Noel W, Dearnaley, David P, Mason, Malcolm D, Parker, Christopher C, Ritchie, Alastair W S, Russell, J Martin, Schiavone, Francesca, Attard, Gerhardt, de Bono, Johann S, Birtle, Alison, Engeler, Daniel S, Elliott, Tony, Matheson, David, O’Sullivan, Joe, Pudney, Delia, *Srihari, Narayanan, Wallace, Jan, Barber, Jim, Syndikus, Isabel, Parmar, Mahesh K B, Sydes, Matthew R, STAMPEDE Investigators

Citation:
JAMA oncology, Mar 2016, vol. 2, no. 3, p. 348-357

Abstract:
The natural history of patients with newly diagnosed high-risk nonmetastatic (M0) prostate cancer receiving hormone therapy (HT) either alone or with standard-of-care radiotherapy (RT) is not well documented. Furthermore, no clinical trial has assessed the role of RT in patients with node-positive (N+) M0 disease. The STAMPEDE Trial includes such individuals, allowing an exploratory multivariate analysis of the impact of radical RT. To describe survival and the impact on failure-free survival of RT by nodal involvement in these patients. Cohort study using data collected for patients allocated to the control arm (standard-of-care only) of the STAMPEDE Trial between October 5, 2005, and May 1, 2014. Outcomes are presented as hazard ratios (HRs) with 95% CIs derived from adjusted Cox models; survival estimates are reported at 2 and 5 years. Participants were high-risk, hormone-naive patients with newly diagnosed M0 prostate cancer starting long-term HT for the first time. Radiotherapy is encouraged in this group, but mandated for patients with node-negative (N0) M0 disease only since November 2011. Long-term HT either alone or with RT, as per local standard. Planned RT use was recorded at entry. Failure-free survival (FFS) and overall survival. A total of 721 men with newly diagnosed M0 disease were included: median age at entry, 66 (interquartile range [IQR], 61-72) years, median (IQR) prostate-specific antigen level of 43 (18-88) ng/mL. There were 40 deaths (31 owing to prostate cancer) with 17 months’ median follow-up. Two-year survival was 96% (95% CI, 93%-97%) and 2-year FFS, 77% (95% CI, 73%-81%). Median (IQR) FFS was 63 (26 to not reached) months. Time to FFS was worse in patients with N+ disease (HR, 2.02 [95% CI, 1.46-2.81]) than in those with N0 disease. Failure-free survival outcomes favored planned use of RT for patients with both N0M0 (HR, 0.33 [95% CI, 0.18-0.61]) and N+M0 disease (HR, 0.48 [95% CI, 0.29-0.79]). Survival for men entering the cohort with high-risk M0 disease was higher than anticipated at study inception. These nonrandomized data were consistent with previous trials that support routine use of RT with HT in patients with N0M0 disease. Additionally, the data suggest that the benefits of RT extend to men with N+M0 disease. clinicaltrials.gov Identifier: NCT00268476; ISRCTN78818544.