Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: A systematic review and meta-analysis

Abstract

Background: There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT.

Methods: Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis.

Findings: We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 × 10^-10), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 × 10^-36) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death.

Interpretation: Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom.

Keywords: Abiraterone; Androgen deprivation therapy; Meta-analysis; Metastases; Prostate cancer; Systematic review.

Fig. 1

PRISMA flow diagram of trial identification, screening, eligibility and inclusion. ASCO, American Society of Clinical Oncology; AUA, American Urological Association; EAU, European Association of Urology; ECCO, European Cancer Organisation; ESMO, European Society for Medical Oncology; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses.

Fig. 2

Effect of adding AAP to ADT on (A) overall survival and (clinical/radiological) progression-free survival (B) in men with mHSPC. Each filled square denotes the HR for that trial comparison, with the horizontal lines showing the 95% CI. The size of the square is directly proportional to the amount of information contributed by a trial. The diamond represents a (fixed-effect) meta-analysis of the trial HRs, with the centre of this diamond indicating the HR and the extremities the 95% CI. AAP, abiraterone acetate plus prednisone/prednisolone; ADT, androgen deprivation therapy; CI, confidence interval; HR, hazard ratio; mHSPC, metastatic hormone-sensitive prostate cancer.

Fig. 3

Effect of adding AAP to ADT on overall survival by nodal status, Gleason sum score and performance status. Each filled square denotes the HR for each subgroup of men defined by, Gleason sum score, nodal status and PS within each trial, with the horizontal lines showing the 95% CI. The size of the square is directly proportional to the amount of information contributed by a subgroup. Each filled circle denotes the HR for the interaction between the effect of chemotherapy and these subgroups for each trial, with the horizontal lines showing the 95% CI. The size of each circle is directly proportional to the amount of information contributed by a trial. The open circle represents a (fixed-effect) meta-analysis of the interaction HRs, with the horizontal line showing the 95% CI. AAP, abiraterone acetate plus prednisone/prednisolone; ADT, androgen deprivation therapy; CI, confidence interval; HR, hazard ratio; PS, performance status.

Fig. 4

Effect of adding AAP to ADT on overall survival by age group. Labelling and conventions as in Fig. 3. AAP, abiraterone acetate plus prednisone/prednisolone; ADT, androgen deprivation therapy; CI, confidence interval; HR, hazard ratio.

Fig. 5

Effect of adding AAP to ADT on grade III–IV and grade V adverse events. Apart from a Peto OR (rather than hazard ratio) measure of effect, labelling and conventions are as in Fig. 2. AAP, abiraterone acetate plus prednisone/prednisolone; ADT, androgen deprivation therapy; CI, confidence interval; OR, odds ratio.