A meta-analysis of phase 3 trials published in The Lancet showed the strong metastasis-free survival (MFS) boost delivered with a combination of abiraterone acetate (Zytiga), prednisolone, and androgen deprivation therapy (ADT) with or without enzalutamide (Xtandi) versus treatment with ADT alone in patients with high-risk non-metastatic prostate cancer.1
A total of 180 MFS events were observed in the combination therapy arms of the trials compared with 306 events in the ADT-alone control groups after a median follow-up of 72 months. Of the events that took place in the combination groups, 52% were deaths compared with 38% in the control groups. Six-year MFS was 82% and 69% in the combination therapy and control groups, respectively.
“[Patients] with high-risk non-metastatic prostate cancer who receive ADT with combination therapy have significantly better metastases-free survival and overall survival than those who receive ADT alone,” the investigators wrote. “Two years of abiraterone and prednisolone added to ADT and, if indicated, radiotherapy should be considered a new standard treatment for non-metastatic prostate cancer with high-risk features.”
The meta-analysis focused on 2 two randomized phase 3 trials conducted utilizing the Systemic Therapy in Advancing or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE, MRC-PR08) platform. The first compared ADT with ADT plus abiraterone and prednisolone and the second analyzed ADT compared with ADT plus abiraterone, prednisolone, and enzalutamide.
Eligibility criteria required patients to have confirmed prostate adenocarcinoma, a WHO performance status of 0 to 2, and no evidence of distant metastases via conventional imaging. Additionally, patients were required to have high-risk disease or be relapsing with high-risk features.
Protocol recommended that patients receive standard of care ADT for 3 years. Radiotherapy was required after randomization for node-negative patients and encouraged for node-positive patients. The combination therapy regimen consisted of abiraterone acetate at 1000 mg and prednisolone at 5 mg, with or without enzalutamide at 160 mg.
The primary end point for the meta-analysis was MFS. Some key secondary end points included overall survival (OS), cancer-specific survival, failure-free survival, progression-free survival, and toxicity.
A total of 1974 non-metastatic patients were randomly assigned within both trials, including 455 to the control group and 459 to the combination therapy group in the abiraterone trial from November 15, 2011, to January 17, 2014. In the abiraterone and enzalutamide trial, 533 patients were randomized to the control group and 527 received the combination therapy from July 29, 2014, to March 31, 2016.
The median age of patients was 68 years (IQR, 63-73) and the median prostate-specific antigen level was 34 ng/ml (IQR, 14.7-47). Additionally, 39% of patients were node positive. The median time from randomization to combination therapy initiation was 1.4 weeks (IQR, 1.0-2.7), and median time from ADT initiation to combination therapy was 8.4 weeks (IQR, 5.1-11.3).
MFS was significantly longer in the combination therapy groups (not reached [NR]; IQR, not estimable [NE]–NE) vs the control groups (NR; IQR, 97-NE; HR, 0.53; 95% CI, 0.44-0.64; P <.0001).
A subgroup analysis of 294 MFS events in the abiraterone trial and 192 events in the abiraterone and enzalutamide trial highlighted a notable effect in both trials, respectively (abiraterone trial: HR, 0.54; 95% CI, 0.43-0.68; P <.0001; abiraterone/enzalutamide trial: HR, 0.53, 95% CI, 0.39-0.71; P <.0001); thus, there was no evidence of a further MFS boost with the addition of enzalutamide to abiraterone versus abiraterone alone (interaction HR, 1.02; 95% CI, 0.70-1.50; P = 0.91), and there was no evidence of between-trial heterogeneity.
In terms of OS, a total of 147 deaths and 236 deaths in the combination therapy and control groups were observed, respectively. OS was longer in the combination therapy groups (median, NR; IQR, NE–NE) compared with the control groups (median, NR; IQR, 103–NE; HR, 0.60; 95% CI, 0.48-0.73; P <.0001). The 6-year survival rate was 86% in the combination therapy groups compared with 77% in the control groups.
Grade 3 or higher adverse effects (AEs) during the first 24 months were observed in 29% of patients in the abiraterone trial control group and 32% of patients in the abiraterone and enzalutamide trial control group. The combination therapy groups had rates of grade 3 or higher AEs of 37% and 57% in the abiraterone trial and abiraterone enzalutamide trials, respectively.
“These results might suggest that, by preventing relapse and death from prostate cancer, patients treated with combination therapy are more likely to live longer and die from another cause,” the investigators wrote.
1. 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. Lancet. Published online December 23, 2021. doi:10.1016/S0140-6736(21)02437-5