Astellas wish to announce that Xtandi has been approved for patients with metastatic castration-resistant prostate cancer (mCRPC) who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy and in whom chemotherapy is not yet clinically indicated.
Although chemotherapy has been shown to improve overall and progression-free survival in men with metastatic prostate cancer, many patients do not receive such therapy primarily because of pre-existing medical conditions or associated toxic effects. Thus, there is a need for effective, convenient, and less toxic therapies.
Xtandi (enzalutamide) is a potent androgen receptor signalling inhibitor that blocks several steps in the androgen receptor signalling pathway, even in the setting of androgen receptor overexpression and in prostate cancer cells resistant to anti-androgens. This new indication for Xtandi is supported by the PREVAIL study comparing enzalutamide with placebo in patients with mCRPC without prior chemotherapy.1
Study design
PREVAIL was a phase III, randomised, double-blind, placebo-controlled study evaluating the clinical benefit of enzalutamide in chemotherapy-naïve patients with mCRPC. A total of 1,717 men were randomised to receive either enzalutamide 160mg or placebo once daily.
The trial had co-primary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS). In addition to the co-primary endpoint measures, secondary endpoints included time until initiation of chemotherapy, time until first skeletal-related event (SRE), best overall soft-tissue response, time until prostate-specific antigen (PSA) progression, and decline in the PSA level of ≥ 50% from baseline.
81% improvement in rPFS with Xtandi
At 12 months of follow-up, the rate of rPFS was 65% with enzalutamide and 14% with placebo. Treatment with enzalutamide, as compared with placebo, resulted in an 81% reduction in the risk of radiographic progression or death (hazard ratio [HR], 0.19; p<0.001). The median rPFS was not reached in the enzalutamide group, as compared with 3.9 months in the placebo group.
29% improvement in OS with Xtandi at interim analysis
At the planned interim analysis for OS when 540 deaths were observed, treatment with enzalutamide demonstrated a statistically significant improvement in OS compared to treatment with placebo with a 29% reduction in risk of death (p < 0.0001).1
Xtandi continued to demonstrate significant OS benefit at final analysis
The median OS was reached at 35.3 months for enzalutamide-treated patients and 31.3 months for placebo-treated patients (HR, 0.77) at the final analysis (see Fig1).2
Figure 1. Enzalutamide continues to demonstrate a significant OS benefit at the final analysis
Click on image to enlarge
All secondary endpoints favoured Xtandi
The superiority of enzalutamide over placebo was shown with respect to all secondary end points. Enzalutamide delayed median time to chemotherapy by 17 months (HR, 0.35), delayed time until first SRE by 28% (HR, 0.72), overall soft-tissue response (59% vs 5%), significantly delayed time until PSA progression (HR, 0.17), and rate of decline of ≥ 50% in PSA (78% vs 3%) (p<0.001 for all comparisons).
Safety profile
The benefit of enzalutamide was achieved with a favourable safety profile. The median time until the first event of grade ≥ 3 was 22.3 months with enzalutamide and 13.3 months with placebo. The most common event of grade ≥ 3 in enzalutamide-treated patients was hypertension. Other adverse events reported more frequently with enzalutamide included fatigue, back pain, hot flush and falls.1
Conclusion
In chemotherapy-naïve patients with mCRPC, treatment with enzalutamide significantly delayed radiographic disease progression or death, the need for cytotoxic chemotherapy, significantly improved OS, and was generally well-tolerated.
References:
- Beer T.M. et al. N Engl J Med 2014;371:424-33.
- Tombal B. Abstract presented at EAU 30th Anniversary Congress, Madrid, Spain, March 2015; XTD15017IE.
Approval code: XTD15016IE
Full prescribing information and references available from Astellas Pharma Co. Ltd. Telephone: (01) 4671555.
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