Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer.

BACKGROUND: Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported. METHODS: In this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O'Brien-Fleming-type alpha-spending function. RESULTS: As of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P = 0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events. CONCLUSIONS: Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.).

Nadir Prostate-specific Antigen as an Independent Predictor of Survival Outcomes: A Post Hoc Analysis of the PROSPER Randomized Clinical Trial.

PURPOSE: This post hoc analysis of PROSPER evaluated the relationship between depth of PSA decline and clinical outcomes in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer. MATERIALS AND METHODS: PROSPER was an international, randomized, double-blind, placebo-controlled, phase 3 trial that demonstrated significantly improved metastasis-free survival and overall survival with androgen deprivation therapy plus enzalutamide vs placebo. A total of 905 enzalutamide-treated men were included in this post hoc analysis. Metastasis-free survival (primary endpoint) and overall survival (secondary endpoint) were evaluated for 4 mutually exclusive subgroups defined by PSA decline: <50% (reference); ≥50% to <90%; ≥90%, nadir ≥0.2 ng/mL; and ≥90%, nadir <0.2 ng/mL. Medians and 95% confidence intervals were determined using a 12-month landmark analysis; hazard ratios and P values were based on an unstratified Cox proportional analysis model. RESULTS: In enzalutamide-treated men, PSA declines of <50%, ≥50% to <90%, ≥90% with nadir ≥0.2 ng/mL, and ≥90% with nadir <0.2 ng/mL were associated with median metastasis-free survival in months (95% confidence intervals) of 22.1 (14.8-not reached), 34.2 (29.4-not reached), 36.6 (33.4-not reached), and not reached, respectively, and overall survival in months (95% confidence intervals) of 40.8 (31.7-44.9), 54.4 (49.0-67.0), 64.3 (63.4-not reached), and not reached, respectively. CONCLUSIONS: There was a statistically significant correlation between greater depth of PSA decline and improved clinical outcomes, suggesting a previously underappreciated relationship between changes in PSA levels and clinical outcomes in nonmetastatic castration-resistant prostate cancer.

Plain language summary: Can declines in prostate-specific antigen level indicate how long patients with advanced prostate cancer will live when treated with enzalutamide?

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research article originally published in the Journal of Urology. The PROSPER study involved men who had a type of advanced prostate cancer called non-metastatic castration-resistant prostate cancer (nmCRPC). In patients with nmCRPC, their prostate cancer keeps growing even after traditional hormone treatments. In these patients, rising prostate-specific antigen (PSA) levels suggest that cancer is active but CT and bone scans show that it has not spread to other parts of the body. Everyone in this study received androgen deprivation therapy (ADT) either with the medicine enzalutamide or a placebo. Enzalutamide is a medicine that can slow or stop androgens, such as testosterone, from making prostate cancer grow. The main results of the PROSPER study showed that patients with nmCRPC treated with enzalutamide and ADT lived longer than patients treated with placebo and ADT. In this study, researchers wanted to know if the findings were different depending on how much patients' PSA level declined after enzalutamide treatment. Researchers also wanted to know if this made a difference in how long patients lived without the cancer spreading to other parts of their body. WHAT WERE THE RESULTS?: Researchers found that patients with a large decline in PSA level after treatment were more likely to live longer and without their cancer spreading. WHAT DO THE RESULTS MEAN?: This study shows a link between PSA level changes and how long patients with nmCRPC live when treated with enzalutamide and ADT. These results may help health professionals monitor patients with different PSA level changes after enzalutamide treatment. Patients with a large decline in PSA level may not need to be monitored as closely as patients with a small decline in PSA level.

Prostate-specific Antigen Progression in Enzalutamide-treated Men with Nonmetastatic Castration-resistant Prostate Cancer: Any Rise in Prostate-specific Antigen May Require Closer Monitoring.

BACKGROUND: There is no universally accepted definition for prostate-specific antigen (PSA) progression. However, changes in PSA in patients with castration-resistant prostate cancer (CRPC) are used to inform treatment decisions. OBJECTIVE: To determine whether the Prostate Cancer Working Group 2 (PCWG2) definition of PSA progression is adequate to predict radiographic or clinical progression in enzalutamide-treated men with nonmetastatic CRPC (nmCRPC). DESIGN, SETTING, AND PARTICIPANTS: A post hoc, retrospective analysis of men with nmCRPC from PROSPER (NCT02003924) was performed. INTERVENTION: Continued androgen deprivation therapy; patients randomized 2:1 to enzalutamide 160 mg/d or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Metastasis-free survival (MFS) in men with and without PSA progression, defined by PCWG2, and PSA at the time of radiographic progression were assessed. RESULTS AND LIMITATIONS: As of June 28, 2017, in enzalutamide-treated patients, the risk of metastasis or death was increased significantly in those with PSA progression versus those without (hazard ratio [HR] 3.99; 95% confidence interval [CI], 2.95-5.41; p < 0.0001). Median MFS was not reached (NR; 95% CI, NR-NR) in patients without PSA progression and was 22.6 mo (95% CI, 21.9-29.0) in those with PSA progression. In placebo-treated patients, PSA progression was not significantly associated with MFS (HR 1.72; 95% CI, 0.86-3.45; p = 0.1). Median MFS was NR (95% CI, 25.6-NR) in patients without PSA progression and 18.3 mo (95% CI, 14.9-19.4) in those with PSA progression. The median PSA increase from nadir at the time of radiographic progression was 1.4 ng/mL in enzalutamide-treated men and 25.6 ng/mL for the placebo arm. CONCLUSIONS: In men with nmCRPC and rapidly rising PSA, radiographic progression often occurred without PCWG2-defined PSA progression, suggesting that any increase in PSA may warrant closer monitoring. While PCWG2-defined PSA progression was associated with radiographic progression in enzalutamide-treated men, our findings argue for prospective re-evaluation of this threshold. PATIENT SUMMARY: In this report, we looked at changes in prostate-specific antigen (PSA) in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer who no longer respond to testosterone-lowering treatment. We found that even very small changes in PSA while on treatment could be an early indication of disease progression and should trigger closer monitoring.