Prostate philosophy.

Top Line: The two biggest superstars in systemic therapy for prostate cancer co-star in a new trial as a combined regimen.
The Study: We’re talking, of course, about enzalutamide (a third-generation androgen receptor inhibitor) and abiraterone (a 17-alpha hydroxylase inhibitor). Both are great options to prolong survival in men with metastatic castration-resistant prostate cancer (mCRPC), but both eventually spawn resistance. The science behind their potential synergy is that enzalutamide resistance seems to occur via upregulated androgen-receptors ramping up androgen production—a messed up positive feedback loop that could be thwarted by abiraterone cutting off the extra androgen production. To test this convoluted hypothesis, the convoluted phase 3 PLATO trial was designed. It enrolled over 500 men with chemo-naive mCRPC who all received daily enzalutamide as standard of care. Prostate specific antigen (PSA) levels were measured at 13 and 21 weeks from enrollment, and those with stable levels were allowed to continue on study while those with elevated levels were kicked out for being too bad. Talk about kicking a guy while he’s down. Anyway, the better prostate cancers continued on enzalutamide until a PSA elevation of at least 25% and 2 ng/mL above nadir (n=251). These men were then randomized to single agent abiraterone versus abiraterone in combo with continued enzalutamide. Unfortunately, the primary endpoint of progression-free survival was exactly the same in both arms at a median of 6 months. Decidedly different were side effects, which were worse with the combo therapy.
Bottom Line: The addition of abiraterone doesn’t ameliorate enzalutamide resistance, despite the convincing shadows cast in preclinical studies. Maybe try a taxane instead. | Attard, J Clin Oncol 2018


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