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

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 ≥2 years and RT to the primary tumour. Stratified randomisation allocated pts 2 : 1 : 2 to SOC; SOC + docetaxel 75 mg/m2 3-weekly×6 + prednisolone 10 mg daily; or SOC + abiraterone acetate 1000 mg + prednisolone 5 mg 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 66 years and median PSA 56 ng/ml. With median follow-up 4 years, 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.

Figure 1.

Activity-by-time diagram: patients included in this comparison. SOC, standard-of-care; Doc, docetaxel; Abi, abiraterone acetate+prednisone/prednisolone. Boxes represents periods of recruitment (x-axis) to each of the trial arms (y-axis). The blue boxes represent recruitment periods contributing to this analysis; the green boxes other recruitment period, past and future, contributing to other aspects of the STAMPEDE. The squares represent the time point of the first key comparative analyses for each comparison in pink and for this comparison in blue.

Figure 2.

CONSORT diagram. SOC, standard-of-care; DocP, docetaxel+prednisolone/prednisone; AAP, abiraterone acetate+prednisolone/prednisone. Selection of patients for this comparison.

Figure 3.

Efficacy analysis—survival, metastases-free survival, failure-free survival, skeletal-related events. Kaplan–Meier (survival) plots for the key efficacy outcome measures. Each step down the y-axis represents an event. The number of patients contributing information (at risk) over time since randomisation is shown under the table. The number of patients with an event between these points is shown in brackets. The number of patients censored in a time window is not shown, but is calculable as the difference between the number of patients at risk at two times points and the number of patients with events, e.g. in Figure 3E between 0 and 6 months on the SOC+AAP arm (377−362)−12=3 patients are censored.

Figure 4.

Depiction of disease state over time.

Figure 5.

Time from randomisation to reported starting docetaxel, AAP, enzalutamide or AR-targeting therapy. Kaplan–Meier (survival) plots showing cumulative incidence of exposure to treatments after randomisation. Each step up the y-axis represents an event, namely starting that particular treatment. The number of patients contributing information (at risk) over time since randomisation is shown under the table. The number of patients with an event between these points is shown in brackets. For example, in Figure 4C between 24 and 36 months after randomisation, 4 patients on the SOC+DocP arm report starting abiraterone and (150−129)−4 are 17 are censored and may start in the future.

Figure 6.

Time from failure-free survival event to subsequent treatment by allocated treatment. Kaplan–Meier (survival) plots showing cumulative incidence of exposure to treatments after a failure-free survival (FFS) event. Doc, docetaxel; AAP, abiraterone acetate + prednisolone; Enz, enzalutamide. Each step up the y-axis represents an event, namely starting that particular treatment.