Compared with leuprolide therapy alone, enzalutamide plus leuprolide improved metastasis-free survival in patients with prostate cancer with high-risk biochemical recurrence, a study shows. “Enzalutamide monotherapy was also superior to leuprolide alone,” the investigators report. “The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life.”
The phase 3 EMBARK trial included 1,068 patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Randomization to enzalutamide 160 mg daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group) had these effects on a primary endpoint of metastasis-free survival: “The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P <0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P = 0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures.”
Editorial: “The definition of benefit is arguably our greatest hurdle,” writes an editorialist. “The need for lengthy follow-ups and the near impossibility of controlling for the influence of subsequent therapies in an evolving landscape make prostate cancer–specific survival an impractical end point. Metastasis-free survival still requires prolonged follow-up and is confounded by the proportion of non–prostate cancer deaths in this population and by the emergence of increasingly sensitive imaging that detects metastases earlier. Eugonadal progression-free survival might make the case for early intermittent treatment: because current standards include lifelong ADT in men with detectable metastases, delaying their detection or progression may decrease the total on-treatment time during a life with prostate cancer, even if overall survival is unchanged. Patient-reported outcome measures also contribute critical information, but whether such measures accurately capture the full patient experience and which differences in these measures could be clinically meaningful remain unclear. In the end, because ‘there is more to life than death,’ a single measure is unlikely to encompass the complexity of clinical benefit in men with biochemical recurrence. Various carefully assessed end points will need to be weighed on the risk–benefit balance to determine which way a new treatment strategy tilts the scale for each individual patient.”