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

Abstract

BackgroundThere 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.MethodsUsing 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.FindingsWe 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.InterpretationAdding 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.

Changes in conditional net survival and dynamic prognostic factors in patients with newly diagnosed metastatic prostate cancer initially treated with androgen deprivation therapy

“…Although our results do not provide a definitive assessment, they strongly support these two factors—the number of bone metastases and biopsy Gleason score—as being risk factors for CSS and OS in patients with newly diagnosed mHNPC. However, the present study did not reveal any impact of visceral metastasis on CSS and OS, perhaps because of the small number of patients compared with the numbers included in the previous trials (14.0%‐18%) …”

Incidence of the adverse effects of androgen deprivation therapy for prostate cancer: a systematic literature review

“…ADT impacted combined CVD morbidity and the risk of specific CV diseases such as myocardial infarction and ischaemic heart disease. Risk was associated with type(7, 28), adverse event grade (22,23,29) and duration of ADT (71). Cardiac mortality was less common but increased risk was identified for all ADT, ADT monotherapy and GnRH agonists (28).…”

“…In other reviews, degarelix reduced the risk of CV events compared to GnRHa, as did IADT (12,15,25). There was a strong association between grade 3 cardiac adverse events and grade 3/4 vascular events and arbiraterone acetate + prednisone compared to placebo (23). This impact was lower for all grade events.…”

“…For vasomotor flashing, enzalutamide had a significant increased risk and anti-androgens a significantly lower risk than other types of ADT (14,15,25,29,57). GnRH agonists and antagonists showed a strong association with hepatotoxicity(58), as did abiraterone acetate, two to three times higher than placebo for men with CRPC (22,23).…”

Novel agents for metastatic hormone‐sensitive prostate cancer – a practice guide for urologists

“…Meta‐analysis of the STAMPEDE and LATITUDE (A study of abiraterone acetate plus low‐dose prednisone plus ADT vs ADT alone in newly diagnosed participants with high‐risk mHNPC) trials studying abiraterone, showed that abiraterone combined with prednisone and ADT resulted in a 38% reduction in risk of death (hazard ratio [HR] 0.62, 95% CI 0.53–0.71) and a 14% increase in overall survival (OS) at 3 years compared with ADT alone . Abiraterone is associated with a two‐fold increase in hypertension and a three‐fold increase in cardiac and hepatic toxicity compared with ADT monotherapy . Hence, it should be avoided in men with uncontrolled hypertension, cardiac failure, pre‐existing liver disease, and poorly controlled diabetes due to use of concomitant prednisone.…”