The androgen receptor–signaling inhibitor enzalutamide (Xtandi) is reported to differ from conventional antiandrogen agents in that it inhibits androgen receptor nuclear translocation, DNA binding, and coactivator recruitment, has a greater affinity for the androgen receptor, and induces tumor shrinkage (rather than growth retardation) in xenograft models. Results of the AFFIRM study, recently reported in The New England Journal of Medicine by Howard I. Scher, MD, and colleagues,1 indicate that enzalutamide treatment significantly prolongs overall survival, radiographic progression-free survival, time to prostate-specific antigen (PSA) progression, and time to skeletal-related events in men with castration-resistant prostate cancer who have already received chemotherapy.
The AFFIRM trial formed the basis for the recent approval of enzalutamide for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.2
In the double-blind, multicenter AFFIRM trial,1 1,199 patients with castration-resistant prostate cancer who had received at least one chemotherapy regimen containing docetaxel were randomized (2:1) to receive oral enzalutamide at 160 mg once daily (n = 800) or placebo (n = 399). Treatment was continued until radiographic confirmation of disease progression requiring initiation of new systemic antineoplastic treatment.
Since enzalutamide has been associated with a lowered seizure threshold, patients with a history of or risk factors for seizure or who were taking medications known to decrease seizure threshold were excluded from the trial. All patients continued androgen deprivation therapy, and patients were permitted to start or continue corticosteroid treatment during the study. The primary endpoint of the trial was overall survival.
Patients in the enzalutamide and placebo groups were well-matched for baseline characteristics. The median age in both groups was 69 years, with 26% and 27% of patients aged 75 years or older, and similar proportions of patients had Gleason score > 7 (50% vs 52%), ECOG performance status of 0 or 1 (91% vs 92%), pain score ≥ 4 (28% vs 29%), one prior chemotherapy regimen (72% vs 74%), bisphosphonate use at baseline (43% in both groups), prior radiation therapy (71% vs 72%), bone disease (92% vs 92%, with 38% in both groups having > 20 lesions), soft-tissue disease (71% vs 69%), PSA progression at baseline (89% vs 90%), and radiographic progression at baseline (59% in both groups).
The median number of prior docetaxel cycles was 8.5 in the enzalutamide group and 8.0 in the placebo group, and median PSA levels were 108 ng/mL and 128 ng/mL, respectively. In total, 48% of patients on enzalutamide recipients and 46% of those on placebo received corticosteroids during the study.2
Study Stopped Early, Benefit across Subgroups
At the time of a preplanned interim analysis, median durations of treatment were 8.3 months in the enzalutamide group and 3.0 months in the placebo group. The median duration of follow-up to determine survival status was 14.4 months. Median overall survival was 18.4 months with enzalutamide vs 13.6 months with placebo, representing a significant 37% reduction in risk of death with enzalutamide (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.53–0.75, P < .001). The trial was thus stopped early and placebo patients were offered enzalutamide treatment.
The overall survival benefit of enzalutamide was consistent across all subgroups examined, including those based on age, baseline pain intensity, geographic region, and type of disease progression at study entry. On multivariate analysis, the effect of enzalutamide on overall survival was maintained (HR = 0.58, 95% CI = 0.49–0.70, P < .001) after adjustment for stratification and prognostic factors, including ECOG score, pain score, type of progression at study entry, visceral disease at entry, baseline hemoglobin, and baseline alkaline phosphatase.
Systemic antineoplastic treatments were used after discontinuation of study treatment in 42% of enzalutamide patients and 61% of placebo patients. Treatments included abiraterone acetate (Zytiga) in 21% of patients on enzalutamide and 24% of patients on placebo, and cabazitaxel (Jevtana) in 14% and 10%, respectively; both agents have been shown to prolong survival in this setting.
Significant improvements with enzalutamide treatment were shown for all secondary endpoints, including PSA response (≥ 50% decrease from baseline; 54% vs 2%), soft-tissue response (29% vs 4%), Functional Assessment of Cancer Therapy–Prostate quality-of-life response (43% vs 18%), time to PSA progression (median, 8.3 vs 3.0 months), radiographic progression-free survival (median, 8.3 vs 2.9 months, HR = 0.40), and time to first skeletal-related event (median, 16.7 vs 13.3 months)—all P < .001.
Adverse events occurring in at least 10% of patients on enzalutamide and with at least a 2% greater frequency than in patients receiving placebo included fatigue (34% vs 29%), diarrhea (21% vs 18%), hot flash (20% vs 10%), musculoskeletal pain (14% vs 10%), and headache (12% vs 6%). Grade 3 or higher adverse events occurred in 45% of enzalutamide recipients and 53% of placebo recipients. The median time to any initial grade 3 or higher adverse event was 8.4 months longer in the enzalutamide group (12.6 vs 4.2 months), indicating improved long-term control of disease-related symptoms.
Hypertension occurred in 6.6% of patients on enzalutamide and 3.3% of patients on placebo. However, the frequency of hyperglycemia, weight gain, hyperlipidemia, and glucose intolerance was similar in the two groups, suggesting that enzalutamide was not associated with excess risk of developing metabolic syndrome..
Serious adverse events occurred in 34% of the enzalutamide group vs 39% of the placebo group. Adverse events resulted in discontinuation of study treatment in 8% vs 10% and adverse events led to death in 3% vs 4%. Among clinically significant adverse events, cardiac disorders occurred in 6% of both groups. Seizure occurred in five patients on enzalutamide (0.6%) and in none of those on placebo.
As stated by the investigators, “Enzalutamide, a once-daily oral hormone treatment, is administered without the need for concomitant prednisone, which has been postulated to activate androgen-receptor signaling. This novel agent is anticipated to join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a benefit in men with castration-resistant cancer. These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy. Clinical trials of enzalutamide in earlier-stage prostate cancer are ongoing.” For information on how to use enzalutamide in the clinic, see here. ■
1. Scher HI, Fizazi K, Saad F, et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. August 15, 2012 (early release online).
2. XTANDI® (enzalutamide) capsules prescribing information. Astellas Pharma US, Inc, August 2012. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203415lbl.pdf. Accessed September 11, 2012.