Adding enzalutamide to standard first-line treatment improves survival for men with metastatic hormone-sensitive prostate cancer
Enzalutamide was tested in addition to standard of care with or without docetaxel in men with metastatic hormone-sensitive prostate cancer. The planned interim analysis showed an improved overall survival. With this, enzalutamide added to standard of care treatment could be a new option for men with metastatic hormone-sensitive prostate cancer.
Background
Until 2014 testosterone suppression with or without a nonsteroidal antiandrogen (NSAA) was the only therapy for metastatic hormone-sensitive prostate cancer (mHSPC). Improvements in overall survival (OS) for mHSPC patients has come from the agents with survival benefits in castration-resistant prostate cancer (CRPC) docetaxel and abiraterone. Enzalutamide is a potent direct androgen receptor inhibitor with OS benefit in CRPC. Enzalutamide has shown to improve radiographic progression-free survival (PFS) in mHSPC patients with and without prior docetaxel. In the ENZAMET trial, the investigators hypothesised that addition of enzalutamide to testosterone suppression will prolong OS in mHSPC patients with or without concurrent docetaxel treatment.
Trial set-up
The ENZAMET trial is an international randomised phase III study, in which men with mHSPC were randomly assigned (1:1) between March 2014 and March 2017 to receive an injection of a testosterone-suppressing agent (such as goserelin, leuprolide, or degarelix) with either enzalutamide (160 mg/day) or one of three standard NSAAs: bicalutamide, nilutamide, or flutamide. Subgroup analyses to assess possible modulation of the treatment effect were specified a priori and included planned early docetaxel (yes vs no) and volume of disease (high vs low). Primary endpoint was overall survival. Secondary endpoints included clinical PFS, prostate specific antigen PFS and adverse events.
Results
Of the 1,125 men enrolled in the trial, 503 men received early doses of docetaxel and 602 did not. Men were followed for a median of 34 months. Patient baseline characteristics were well balanced between the study arms.
After 3 years, 80% of men with mHSPC who received enzalutamide along with testosterone suppression, with or without early docetaxel, were alive compared with 72% of men who received one of the other three NSAAs in the trial. Overall, there was a 33% decrease in the risk of death in men receiving enzalutamide compared to those who took a NSAA (HR 0.67 [95% CI 0.52-0.86]; p=0.002).
Researchers further analyzed the data to identify the impact of enzalutamide in key groups at the 3-year mark. Of 596 men with a higher amount of disease on imaging scans, 71% taking enzalutamide were alive compared with 64% taking another NSAA. Of 529 men with a low amount of disease on imaging scans, 90% taking enzalutamide were alive compared with 82% taking another NSAA.
The increase in survival with enzalutamide was most obvious in men who did not receive docetaxel: among patients who received enzalutamide without docetaxel, 83% were alive compared with 70% taking another NSAA. Sweeney noted that a survival benefit is not seen with docetaxel in men with a low volume of disease, but that enzalutamide does improve survival in these men. At the time of analysis of the data, 64% of men were still taking enzalutamide compared with 36% of men taking another NSAA.
Serious adverse events (regardless of attribution)within 30 days of study treatment occurred in 42% of men taking enzalutamide compared with 34% of the men taking one of the other NSAAs, commensurate with the different durations of study treatment.
Conclusions
Early enzalutamide improved time to progression and overall survival when added to standard mHSPC therapy consisting of testosterone suppression with or without docetaxel. This makes it an appropriate option for men with metastatic prostate cancer commencing testosterone suppression. The benefit of the addition of enzalutamide was seen in patients with low and high volume metastatic disease, but is associated with more expected toxicity. The treatment could be especially relevant for men who cannot tolerate chemotherapy and have a lower disease burden.
Reference
Sweeney C, Martin A, Zielinski R, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. Presented at ASCO 2019; abstract LBA2.