Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials

Summary

Background

In advanced prostate cancer, androgen suppression (AS) by surgery or drugs controls testicular hormone secretion, and the further addition of an antiandrogen such as nilutamide, flutamide, or cyproterone acetate is referred to as maximum androgen blockade (MAB). The aim of this overview was to compare the effects on the duration of survival of MAB and of AS alone.

Methods

The collaborative meta–analysis of 27 randomised trials involved central reanalysis of the data on each of 8275 men (98% of those ever randomised in trials of MAB vs AS) with metastatic (88%) or locally advanced (12%) prostate cancer. Half were over 70 years of age, and follow–up was typically for about 5 years.

Findings

5932 (72%) men have died; of the deaths for which causes were provided, about 80% were attributed to prostate cancer. 5–year survival was 25·4% with MAB versus 23·6% with AS alone, a non–significant gain of 1·8% (SE 1·3; logrank 2p=0·11). There was no significant heterogeneity in the treatment effect (MAB vs AS) with respect to age or disease stage. The results for cyproterone acetate, which accounted for only a fifth of the evidence, appeared slightly unfavourable to MAB (5–year survival 15·4% MAB vs 18·1% AS alone; difference -2·8% [SE 2·4]; logrank 2p=0·04 adverse), whereas those for nilutamide and flutamide appeared slightly favourable (5–year survival 27·6% MAB vs 24·7% AS alone; difference 2·9% [SE 1·3]; logrank 2p=0·005). Non–prostate–cancer deaths (although not clearly significantly affected by treatment) accounted for some of the apparently adverse effects of cyproterone acetate.

Interpretation

In advanced prostate cancer, addition of an antiandrogen to AS improved the 5–year survival by about 2% or 3% (depending on whether the analysis includes or excludes the cyproterone acetate trials), but the range of uncertainty as to the true size of this benefit runs from about 0% to about 5%.

Introduction

In advanced prostate cancer the main systemic treatment is androgen suppression (AS), either by surgical castration (orchiectomy) or by long–term use of a luteinising–hormone–releasing–hormone agonist. Testosterone from the testes provides much, but not all, of the normal androgenic activity, and this activity can be eliminated by AS. The low plasma concentrations of androgens that remain after AS, which are chiefly of adrenal origin, could still have some stimulatory effect on any hormone–sensitive parts of the prostate cancer, but any such residual effect can be further reduced by addition of long–term treatment with an antiandrogen such as nilutamide, flutamide, or cyproterone acetate. Such combination of AS with an antiandrogen is referred to as maximum androgen blockade (MAB).

Since the early 1980s, there have been many randomised trials comparing MAB with AS alone but, on average, they involved only a few hundred patients each, allowing wide scope for the play of chance to affect their survival results. Hence, unduly selective emphasis on some of the more favourable (or just on the adverse) trial results could well be misleading. A meta–analysis of all these results would, however, involve much larger numbers than any single trial, thereby not only limiting the play of chance but also discouraging unduly selective emphasis on particular trial results (or on other particular subsets of the overall evidence).

This report is of a collaborative meta–analysis (or overview) of the mortality findings from all the available trials of MAB versus AS in advanced prostate cancer, with central reanalysis of the data from each randomised individual. It includes more studies and longer follow–up than the previous such meta–analysis,¹ and hence involves almost twice as many deaths (plus some information as to which of those deaths were thought not to have been caused by prostate cancer).