Data published in The New England Journal of Medicine and presented during the virtual scientific program of the 2020 ASCO Annual Meeting announced the final results from the overall survival (OS) analysis of the phase III PROSPER trial, which evaluated enzalutamide (ENZA) plus androgen deprivation therapy (ADT) versus placebo (PBO) plus ADT in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). According to the final OS results presented at the ASCO20 Virtual Scientific Program, the addition of ENZA to ADT significantly prolonged OS among men with nmCRPC. 

According to the researchers, preliminary trial results revealed that ENZA significantly improved metastasis-free survival among men who had nmCRPC and rapidly increasing prostate-specific antigen (PSA) levels while ADT was also administered. In this double-blind trial, men with nmCRPC (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive ADT were randomly assigned (in a 2:1 ratio) to receive ENZA at a dose of 160 mg or PBO once daily. OS was evaluated with a group sequential testing procedure and an O’Brien-Fleming–type alpha-spending function. 

As of October 15, 2019, a total of 288 of 933 patients (31%) in the ENZA group and 178 of 468 patients (38%) in the PBO group had died. Median OS was 67.0 months (95% CI, 64.0 to not reached) in the ENZA group and 56.3 months (95% CI, 54.4-63.0) in the PBO group (hazard ratio for death, 0.73; 95% CI, 0.61-0.89; P = .001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the ENZA group and 20 per 100 patient-years in the PBO group. Adverse events in the ENZA group were consistent with those previously reported for ENZA; the most commonly reported events were fatigue and musculoskeletal events. 

The researchers concluded that ENZA treatment resulted in a statistically significant 27% reduced risk of death compared with PBO, demonstrating that initiation of ENZA plus ADT before the onset of detectable metastasis improves OS in men with CRPC and swiftly increasing PSA. This OS benefit ensues despite crossover from the PBO arm to ENZA and higher rates of subsequent antineoplastic therapies in men from the PBO arm. Safety was consistent with that in previous clinical trials. This final OS analysis from PROSPER provides prospective validation of metastasis-free survival as a potential surrogate endpoint for OS in nmCRPC and supports the continued use of ENZA plus ADT as a standard of care in men with nmCRPC and rapidly increasing PSA.

In an interview, lead author and presenter, Dr. Cora Sternberg, clinical director of the Englander Institute for Precision Medicine at Weill Cornell Medicine, said, “Until the emergence of the use of androgen receptor inhibitors in this area, patients with a rapidly rising PSA and nonmetastatic castration-resistant prostate cancer had few options. In PROSPER, treatment with enzalutamide resulted in a clinically meaningful and statistically significant 27% lower risk [for] death for patients.” 

Dr. Sternberg added, “There is a lot of experience now with this drug, and we can expect to see data in earlier disease states with enzalutamide and other agents. For enzalutamide, there is the EMBARK study in high-risk, nonmetastatic hormone-sensitive prostate cancer, and we are awaiting OS data from the ARCHES study in metastatic hormone-sensitive prostate cancer. In the meantime, studies on quality of life, novel imaging and biomarker approaches will help us evaluate and treat our patients.”

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