Conclusion. Enzalutamide treatment was associated with significantly longer PFS and OS compared with standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression.
Commentary
The current study shows that the addition of enzalutamide to standard androgen deprivation therapy (ADT) improves OS and PFS in men with newly diagnosed metastatic, hormone-sensitive prostate cancer. Until recently, antiandrogen therapy had been the standard of care for these men; however, with the advent of novel antiandrogen agents, outcomes in men with metastatic prostate cancer in both the androgen-sensitive and castrate-resistant settings have steadily improved.1-5 In the castrate-resistant setting, enzalutamide has previously been shown to improve survival in chemotherapy-naïve patients and those previously exposed to docetaxel chemotherapy.5-7 Similarly, in the hormone-sensitive setting the combination of ADT with either abiraterone or chemotherapy has been shown to improve outcomes. In the phase 3 LATITUDE and STAMPEDE trials, the combination of abiraterone plus prednisone and ADT resulted in a 30% and 37% improvement in OS, respectively.1,2 Six cycles of docetaxel in combination with ADT also resulted in a 37% increase in OS in those with high-volume metastatic disease.3
The current study adds to the growing body of literature suggesting that combination therapy in the upfront, hormone-sensitive setting improves outcomes. In the CHAARTED trial, the combination of docetaxel and ADT improved survival in men with high-volume disease, but it did not seem to benefit those with lower-volume disease.3 However, the current data suggests a survival advantage with enzalutamide with low-volume disease as well. The use of docetaxel was similar between the 2 groups, and this suggests that the benefits of enzalutamide cannot be attributed to early integration of docetaxel. It is important to note that the subgroup analysis of those who received early docetaxel showed that these patients did not experience the same survival benefit as those who did not receive docetaxel. However, this trial was not powered for this analysis, and thus it should be interpreted with caution. PFS benefit was maintained across those who received and did not receive early docetaxel. Also worth noting is the increased docetaxel-related toxicity in the combination docetaxel and enzalutamide arm of this study. The neurological toxicity of enzalutamide was again noted, with 7 seizure events documented in this study.
Because this report on the ENZAMET study is an interim analysis, it will be important to follow these outcomes as the data set matures to ensure these effects are maintained over time. Additionally, it will be important to see what implications the addition of enzalutamide have on quality of life measures, as these data have not yet been published.
Applications for Clinical Practice
The ENZAMET study provides evidence that in men with metastatic, hormone-sensitive prostate cancer receiving ADT, the addition of enzalutamide improves PFS and OS. In men who received early docetaxel, enzalutamide was associated with increased toxicity. Additionally, while PFS was improved in men who received enzalutamide and docetaxel, OS was not improved. The neurologic toxicities of enzalutamide should be considered, particularly in those with a prior history of seizure disorders. Based on these data, enzalutamide in combination with ADT represents a reasonable treatment option in men with metastatic, hormone-sensitive prostate cancer.
—Daniel Isaac, DO, MS