Primary analysis of data from two randomised controlled phase III studies performed within a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to androgen-deprivation therapy (ADT) in a patient population of men with high-risk non-metastatic prostate cancer indicates that a combination treatment is associated with significantly higher rates of metastasis-free survival compared with ADT alone. Findings from a meta-analysis that pooled events from both studies are published by Prof. Gerhardt Attard of the Cancer Institute, University College London in London, UK and STAMPEDE colleagues on 23 December 2021 in The Lancet.
The authors wrote in the background that men with high-risk non-metastatic prostate cancer are treated with ADT for 3 years, often combined with radiotherapy. These two open-label, phase III studies were performed at 113 sites in the UK and Switzerland. Eligible patients had high-risk or relapsing with high-risk features non-metastatic prostate cancer and a WHO performance status of 0 to 2.
High-risk disease was defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8–10, and prostate-specific antigen (PSA) concentration ≥40 ng/mL. High-risk features considered ≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse.
Local radiotherapy of 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules was mandated for node negative and encouraged for node positive disease.
In both studies, patients were randomly assigned 1:1 to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate 1000 mg daily and oral prednisolone 5 mg daily (combination treatment group). In the second study with no overlapping controls, the combination treatment group also received enzalutamide 160 mg daily orally. ADT was given for 3 years and combination treatment for 2 years, except if local radiotherapy was omitted when treatment could be delivered until progression.
The primary endpoint of the meta-analysis was metastasis-free survival. Secondary endpoints were overall survival (OS), prostate cancer-specific survival, biochemical failure-free survival, progression-free survival (PFS), and toxicity and adverse events.
Efficacy was assessed in the intention-to-treat population and safety according to the treatment started within randomised allocation.
The investigators randomly assigned to treatment 1974 patients between 15 November 2011 and 31 March 31. The first study allocated 455 patients to the control group and 459 to combination treatment, and the second study, which included enzalutamide, allocated 533 patients to the control group and 527 patients to combination treatment.
Median age across all groups was 68 years and median PSA 34 ng/ml. A total of 774 patients (39%) were node positive and 1684 patients (85%) were planned to receive radiotherapy.
With median follow-up of 72 months, there were 180 metastasis-free survival events in the combination treatment groups and 306 in the control groups. Metastasis-free survival was significantly longer in the combination treatment groups than in the control groups with hazard ratio (HR) 0.53 (95% confidence interval [CI] 0.44–0.64; p < 0.0001).
Six-year metastasis-free survival was 82% in the combination treatment group and 69% in the control group.
There was no evidence of a difference in metatasis-free survival when enzalutamide and abiraterone acetate were administered concurrently compared with abiraterone acetate alone (interaction HR 1.02; p = 0.91) and no evidence of between study heterogeneity.
Furthermore, OS (HR 0.60, 95% CI 0.48–0.73; p < 0.0001), prostate cancer-specific survival (HR 0.49, 0.37–0.65; p < 0.0001), biochemical failure-free survival (HR 0.39, 0.33–0.47; p < 0.0001), and PFS (HR 0.44, 0.36–0.54; p < 0.0001) were also significantly longer in the combination treatment groups than in the control groups.
Adverse events grade 3 or higher during the first 24 months were reported in 169 of 451 patients (37%) in the combination treatment and 130 of 455 patients (29%) in the control group of the abiraterone study and 298 of 513 patients (58%) in the combination treatment and 172 of 533 patients (32%) in the control group of the abiraterone and enzalutamide study.
Two most common events, more frequent in the combination treatment groups, were hypertension and alanine transaminitis. Seven grade 5 adverse events were reported; none in the control groups, three in the abiraterone acetate and prednisolone group of which one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder, and four in the abiraterone acetate and prednisolone with enzalutamide group with two events each of septic shock and sudden death.
The authors concluded that abiraterone acetate with prednisolone should be considered as a new standard treatment for this population.
This work was funded by Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas.
Attard G, Murphy L, Clarke NW, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. The Lancet; Published online 23 December 2021. DOI: https://doi.org/10.1016/S0140-6736(21)02437-5