Enzalutamide in combination with androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer demonstrated significantly improved radiographic progression-free survival versus placebo plus ADT, regardless of baseline prostate-specific antigen levels, according to expanded findings from the ARCHES study.
Arnulf Stenzl, MD
Arnulf Stenzl, MD
Enzalutamide (Xtandi) in combination with androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC) demonstrated significantly improved radiographic progression-free survival (rPFS) versus placebo plus ADT, regardless of baseline prostate-specific antigen (PSA) levels, according to expanded findings from the ARCHES study.1
The PSA finding is important finding because baseline levels are considered a strong prognostic indicator for clinical outcomes in men with mHSPC following ADT,2 Arnulf Stenzl, MD, said in presenting the data during the American Urological Association 2019 Annual Meeting.1
The results suggest the limitations of baseline PSA as a predictive factor among patients who have received prior ADT, Stenzl and colleagues said in their conference abstract.
At the same time, strong improvements in the PSA-related endpoints of time to PSA progression, PSA reduction from baseline, and PSA undetectable rate were also observed with enzalutamide therapy, the abstract noted (Table).1
Overall, after a median follow-up of 14.4 months, median rPFS was not reached for the enzalutamide arm versus 19.4 months for the placebo arm (HR, 0.39; 95% CI, 0.30- 0.50; P <.0001). From March 2016 to October 2018, 1150 men with confirmed mHSPC were randomized 1:1 to enzalutamide (160 mg/day) and ADT or placebo and ADT. Inclusion criteria were ECOG performance status 0 or 1 and prior ADT with a duration of <3 months. For patients with prior treatment with docetaxel, the allowable duration was <6 months. Patients were disqualified if they had radiographic disease progression or rising PSA levels prior to the first day of enrollment.
“Patients were stratified by volume of disease, low versus high, and prior docetaxel therapy for mHSPC,” said Stenzl, medical director of the Department of Urology at the University of Tübingen in Germany. Patients were dropped from the trial if they demonstrated radiographic progression, unacceptable toxicity, or if they initiated other therapy for prostate cancer.
The primary endpoint was rPFS, defined as the time from randomization to the first objective evidence of radiographic disease progression, as assessed by independent central review, or death from any cause within 24 weeks of treatment discontinuation.
Secondary endpoints included time to PSA progression, the rate of undetectable PSA, defined as <0.2 ng/mL, time to castration resistance, and PSA reduction from baseline.
“Patient characteristics were very balanced between the 2 groups, with 574 patients in the enzalutamide arm and 576 patients in the placebo arm,” Stenzl said. “Of note is that 18% of patients in both groups [the enzalutamide arm and the placebo arm] received docetaxel.” Thirteen percent of patients from each group underwent radical prostatectomy as their initial form of treatment. The PSA level at study entry in the enzalutamide arm was a median of 5.4 ng/mL compared with 5.1 ng/mL in the placebo arm.
The enzalutamide arm had 77 events of radiographic progression compared with 185 events in the placebo arm, for a total of 262. Stenzl said there were 25 deaths without radiographic progression, 12 in the enzalutamide arm and 13 in the placebo arm.
In the combination arm subgroup with PSA below or equal to median baseline, median rPFS was not reached for either the treatment or placebo population (HR, 0.37; CI 95%, 0.26-0.54; P <.0001). Among patients in the subgroup with PSA above median baseline, rPFS was not reached versus 16.7 months for treatment versus placebo, respectively (HR, 0.41; CI 95%, 0.29-0.58; P <.0001).
Regarding the secondary endpoint of time to PSA progression, enzalutamide demonstrated an 81% reduction in risk of PSA progression versus placebo (P <.0001) and a 72% reduction in risk of castration resistance (P <.0001). The number of patients with PSA progression with castrate levels of testosterone was lower for enzalutamide plus ADT (32 [6%]) than placebo plus ADT (143 [25%]).
Over the treatment period, patients in the enzalutamide arm achieved a greater decline in PSA from baseline than patients in the placebo arm achieved during the entire treatment period: 92.9% (n = 533) versus 56.8% (n = 327) achieved a ≥50.0% reduction, respectively, and 72.8% (n = 418) versus 30.0% (n = 173) achieved a ≥90.0% reduction. In addition, patients in the enzalutamide arm achieved a greater decline in PSA from baseline to day 29 than patients in the placebo group did during the entire treatment period.
Improvements were also observed in the PSA undetectable rate. A higher proportion of patients in the enzalutamide group had an undetectable PSA (68.1%) compared with those in the placebo group (17.6%). The P value was <.0001.
Stenzl said the adverse events (AEs) were very similar to those reported in previous studies for this setting. In the enzalutamide arm, the most frequently reported AEs of any grade were hot flushes (27.1%), fatigue (19.6%), arthralgia (12.2%), and back pain (7.5%). In the placebo arm, the most frequently reported AEs of any grade were hot flushes (22.3%), fatigue (15.3%), back pain (10.8%), and arthralgia (10.6%). Of the grade ≥3 AEs, hypertension was the most frequently reported in both groups: 3.3% (19) and 1.7% (10) in the treatment and placebo groups, respectively. “Selected AEs of special interest—cognitive impairment, convulsion, falls, [and] fracture— in the treatment arm were not significantly increased compared with other studies and the placebo group,” Stenzl said.
“We can now say that enzalutamide plus ADT significantly improved rPFS in the overall population. Enzalutamide plus ADT also improved rPFS, regardless of baseline PSA,” Stenzl said.