Abiraterone for prostate cancer not previously treated with hormone therapy

STAMPEDE is a multigroup, multistage platform trial protocol investigating the efficacy of additional therapy at the time of inception of primary ADT [ androgen deprivation therapy ] in men with newly diagnosed, locally advanced, or metastatic disease or in those with relapsing disease and poor prognostic features.

The use of ADT plus Abiraterone and Prednisolone as compared with ADT alone was associated with a 71% relative improvement in the time to treatment failure, which translated into a 37% difference in overall survival.
These findings were consistent in patients with metastatic disease and those with nonmetastatic disease, although most deaths have occurred in the patients with metastatic disease.
The between-group difference in survival among the patients with nonmetastatic disease, which is underpinned by a large difference in failure-free survival, occurred even though Abiraterone was administered for 2 years or less in this group.

There was good adherence to Abiraterone, which was associated with acceptable adverse-event rates, with most patients stopping therapy owing to the completion of planned therapy or protocol-defined progression rather than toxic effects.

Adverse events were in line with previous experience in castration-resistant prostate cancer, despite the longer absolute duration of therapy, particularly in the patients with metastatic disease.

Nearly 300 patients are still receiving treatment.

Few patients stopped treatment because of side effects, but there were more grade 3 to 5 adverse events reported in the combination group than in the ADT-alone group.
The lower dose of Prednisolone that was used does not seem to have influenced the rate of pharmacologically relevant severe adverse events, such as hypertension or hypokalemia.

The size of the trial permits some examination of interactions, including those with other treatments known to be effective ( e.g., radiotherapy ) and prognostic factors used for stratification at randomization.

Effects in all subgroups were similar, with no evidence of heterogeneity.

The apparent inconsistency in survival-effect size in men 70 years of age or older is probably an artifact arising from a small number of events; the absolute difference is only 8 deaths ( 74 in the combination group and 82 in the ADT-alone group ).
The result is complicated by a higher risk of death from coexisting conditions and a relatively shorter follow-up among older men, because a higher proportion were recruited later, after recruitment to the Docetaxel comparison in the protocol was completed.

Results for failure-free, progression-free, and prostate cancer–specific survival have shown a benefit of Abiraterone in men regardless of age.

The effect size reported with Abiraterone is a little larger with respect to overall survival and substantially larger with respect to failure-free survival than the effect size reported with the addition of Docetaxel in a similar patient group.

The trial results raise the question of what should be regarded as the contemporary standard of care.
Abiraterone has a better side-effect profile than Docetaxel and is an easier treatment to administer logistically.
Conversely, the treatment duration is longer, some patients have long-term effects of glucocorticoid use, and cost is a consideration.
In the absence of comparative data, patient choice and the ability of health care systems to support the use of these drugs will determine the relative use of Docetaxel and Abiraterone.

Perhaps a more important question is whether the benefits of Docetaxel and Abiraterone can be combined.
Although Docetaxel may work in part by targeting the androgen-receptor pathway, it generally has a different mechanism of action than Abiraterone, and Abiraterone is active after Docetaxel use.
Thus, there may be an additive effect of giving Abiraterone immediately after Docetaxel in prostate cancer not previously treated with hormone therapy.

Some future information will emerge from the STAMPEDE trial, which includes a further comparison involving Abiraterone plus Enzalutamide in which Docetaxel was permitted as part of the standard of care in patients who had undergone randomization starting in 2016.

The PEACE-1 trial also includes patients receiving Docetaxel as part of the standard of care and will help address the question of whether the benefits seen with Docetaxe are overlapping or additional to those seen with Abiraterone.

In conclusion, men with locally advanced or metastatic prostate cancer who received ADT plus Abiraterone and Prednisolone had significantly higher rates of overall and failure-free survival than those who received ADT alone.
In addition, combination therapy was associated with fewer symptomatic skeletal events. ( Xagena )

STAMPEDE Investigators, N Engl J Med 2017; DOI: 10.1056/NEJMoa1702900



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