The STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate cancer:Evaluation of Drug Efficacy) study is a large multi-stage multi-arm randomized control trial being conducted in the United Kingdom to assess the utility of novel therapeutic agents in conjunction with ADT. Currently being tested are abiraterone, enzalutamide, zoledronic acid, docetaxol, celecoxib and radiotherapy.
In today’s presentation, the authors present an update regarding the abiraterone arm of the study. This was presented as a late-breaking abstract.
Men with locally-advanced or metastatic prostate cancer (PCa) were included in this study. Newly diagnosed patients with N1 or M1 disease, or any two of the following: Stage T3/4, PSA >= 40 ng/mL, or Gleason score 8-10. For patients with prior radical prostatectomy or radiotherapy, they could enroll if they had more than 1 of the following: PSA >= 4 ng/mL and PSADT < 6 months, PSA >= 20, N1 disease or M1 disease.
The standard of care [SOC] (comparison arm) was ADT for 2 or more years; interestingly, treatment with radiotherapy (RT) was mandated in patients with N0M0 disease, while strongly encouraged for N1M0 patients. Patients were randomized 1:1 to SOC or SOC+abiraterone acetate (1000 mg) + prednisone 5 mg daily. This contrasts to the prednisone 5 mg bid dosing previously used concomitantly with abiraterone.
Duration was based on stage and receipt of RT – patients not receiving RT and M1 patients were continued until PSA, radiographic or clinical progression. Patients receiving RT or those who opted against radiation were treated for 2 years or until progression (whichever came first).
Primary outcomes were overall survival (OS) and failure-free survival (FFS), where failure was defined as PSA failure, local failure, lymph node failure, distant metastases or prostate cancer death. PSA failure was specifically defined as PSA fall < 50% (immediate failure) or, in patients who had an initial PSA fall > 50%, a 50% rise from 24 week PSA nadir or PSA >4 ng/mL. Secondary outcome measures reported here today were: toxicity and skeletal-related events.
Of note, the authors noted that on trial design, comparison to control for survival had 90% power at 2.5% 1-sided alpha for hazard ratio (HR) of 0.75, and required ~267 control arm deaths. Their aim was for a 25% relative improvement in OS.
Over a three-year period, they had rapid accrual of 1,917 patients, who were then randomized into the two arms – 957 arm A (SOC) and 960 into arm G (SOC+AAP).
In terms of demographics, both groups were balanced: patients were predominantly metastatic (52% M1, 20% N+M0, 28% N0M0), median PSA 53 ng/dL, and 99% treated with LHRH analogues. 22% were WHO performance status 1-2. 41% were planned for RT – 96% of N0M0 patients, 62% of the N+M0 patients. Median follow-up for the cohort was 40 months (3.3 years).
There were 262 control arm deaths, of which 82% were PCa-related (cancer-specific mortality).
Overall survival was the primary outcome of the study. There was a 37% relative improvement in overall survival (HR 0.63, p < 0.0001), one of the biggest survival advantages seen in this disease space. There were 262 events in the control arm and 184 events in the SOC+AAP arm. On Forrest Plot split on stratification factors, there was no significant evidence of heterogeneity based on any of the factors – this includes M0/M1 status (p=0.37). It should be noted that for the M0 patients, while there was improvement, the range crossed 1 (HR 0.75, 95%CI 0.48-1.18) – however, the number of events were quite low during the follow-up period (44 arm A, 34 arm G).
Failure-free survival was the main secondary outcome. There was 535 events in the control arm and 248 events in the SOC+AAP arm. There was 71% improvement in time to failure (HR 0.29, p < 0.0001), with an early split in the KM curves. Again, there was no different in any of the subsets on Forrest plot, including M0/M1 status (p=0.085).
In terms of skeletal related events (SREs), there was a reduction in SREs, particularly in the M1 cohort. There was a 55% reduction in SREs in the M1 subset analysis.
When looking at treatment progression, 89% of the SOC arm went on to next line of therapy, while 79% of the SOC+AAP arm moved on. The SOC+AAP arm more often went on to docetaxel chemotherapy while the SOC was more likely to move on to enzalutamide or abiraterone.
SOC+AAP was relatively well tolerated. As expected, the rate of Grade 3-5 adverse events (AEs) were higher in the SOC+AAP arm (47% vs. 33%), and were primarily cardiovascular (HTN, MI, cardiac dysrhythmias) or hepatic (transaminitis) in nature.
Treatment compliance was also reviewed. In the subset scheduled for 2 years of therapy, 17% stopped due to excess toxicity, but only 1% stopped due to progression – 69% completed treatment. In the subset scheduled for duration to progression, 52% had disease progression, while 21% stopped due to toxicity, and only 5% completed treatment.
Based on this data, the authors conclude that the OS benefits and FFS benefits of AA+P in conjunction with ADT as first line therapy for hormone-sensitive metastatic or locally advanced prostate cancer are significant, and should result in a change in management. Abiraterone should be considered up front with ADT.
Questions: During the Q&A session, the following questions were asked:
1. Dr. D’Amico: In the 28% of patients who M0, the HR 0.75 for OS benefit (95%CI 0.48-1.18) is based on a very small number of events. Do you think with more patients and longer-follow-up, this will reach significance?
- Dr. James: Forrest plot and subset analysis suggests that there was no significant heterogeneity based on M0/M1 status, so yes, there is likely benefit in the M0 cohort as well.
2. Role of patient age in terms of response?
- Dr. James: Due to competing enrollment in the docetaxel arm, the number of older patients enrolled in arm G was low early on. This increased when the docetaxel arm closed enrollment, but as a result, their follow-up is shorter. He can’t say more today, but they have completed a meta-analysis in conjunction with LATITUDE investigators, and those results will be discussed tomorrow.
These results, taken in conjunction with the results of the LATITUDE trial (abstract LBA3), are compelling new evidence for the earlier utilization of abiraterone up front along with ADT for hormone-sensitive metastastic and advanced prostate cancer. We look forward to the meta-analysis of these two studies for more concrete results, but these initial results appear very promising.
Presented By: Nicholas D. James
Co-Authors: Johann S. De Bono, Melissa Ruth Spears, Noel Clarke, Malcolm David Mason, David P. Dearnaley, Alastair W S Ritchie, J. Martin Russell, Clare Gilson, Robert J. Jones, Silke Gillessen, David Matheson, San Aung, Alison J. Birtle, Simon Chowdhury, Joanna Gale, Zafar Malik, Joe M. O'Sullivan, Mahesh K B Parmar, Matthew Robert Sydes
Institution(s): Queen Elizabeth Hospital, Coventry, United Kingdom; The Institute of Cancer Research and The Royal Marsden Hospital, London, United Kingdom; MRC Clinical Trials Unit at UCL, London, United Kingdom; The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom; Cardiff University, Cardiff, United Kingdom; The Royal Marsden Hospital and The Institute of Cancer Research, London, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom; University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; Kantonsspital, St. Gallen, Switzerland; Leeds Beckett University, Leeds, United Kingdom; Royal Devon and Exeter Hospital, Exeter, United Kingdom; Rosemere Cancer Centre, Royal Preston Hospital, Preston, United Kingdom; Guy's, King's, and St Thomas' Hospitals, London, United Kingdom; Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom; Clatterbridge Cancer Centre, Bebington, United Kingdom; Belfast City Hospital, Belfast, United Kingdom
Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA