Enzalutamide improved overall survival (OS) and radiographic progression-free survival (rPFS) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC) in the randomised, double-blind, placebo-controlled, multinational, phase III PREVAIL study. The study findings were presented as abstract LBA1 in the Welcome and General Session entitled “Integrating Androgen Axis Therapy Across the Disease Spectrum” of the 2014 Genitourinary Cancer Symposium in San Francisco, USA (30 January-1 February). The lead author in the abstract is Dr Tomasz Beer, Deputy Director of the Knight Cancer Institute at Oregon Health & Science University, Portland.
Previously enzalutamide, an orally administered androgen receptor inhibitor, showed improved OS in men with mCRPC who had received prior docetaxel. The PREVAIL study examined whether enzalutamide could prolong OS and rPFS (co-primary endpoints and analysed for the intent-to-treat population) in asymptomatic or mildly symptomatic chemotherapy-naive patients with mCRPC.
The study results
Patients were stratified by site and randomised 1:1 to enzalutamide or placebo. A total of 1,717 men were randomised (1,715 treated) between September 2010 and September 2012. The interim analysis at 539 deaths showed a statistically significant benefit of enzalutamide over placebo with a 30% reduction in risk of death (OS, p < 0.0001) and an 81% reduction in risk of radiographic progression or death (rPFS, p < 0.0001).
At the time of the analysis, 28% of enzalutamide patients and 35% of placebo patients had died. Estimated median OS was 32.4 months in the enzalutamide arm vs. 30.2 months in the placebo arm. Median rPFS was not yet reached in the enzalutamide arm vs. 3.9 months in the placebo arm.
Overall response rate was 59% with enzalutamide (20% complete responses, 39% partial responses) vs. 5% in the placebo group (p < 0.0001).
Enzalutamide treatment delayed the need for chemotherapy by a median of 17 months. Median time to chemotherapy was 28 months in the enzalutamide group vs. 10.8 months in the placebo arm (p < 0.0001).
Enzalutamide was well tolerated with the most common side effects being fatigue, constipation, and back and joint pain (mostly grade 1), as well as common side effects of hormone therapy (e.g. weight gain and hot flashes). Grade 3 or higher adverse events were reported in 43% of the enzalutamide group vs. 37% of the placebo group. Seizure events were reported in two patients. Six percent of patients in both arms discontinued treatment due to adverse events.
At an interim analysis in October 2013, the Independent Data Monitoring Committee considered the benefit-risk ratio to favour enzalutamide and recommended stopping the study and crossing placebo patients to enzalutamide.
Enzalutamide is currently approved for mCRPC progressing on docetaxel. Further studies are needed to compare head-to-head in randomised trials enzalutamide with abiraterone in the pre-chemotherapy disease setting and to study sequencing and combinations of newer agents.
The study was sponsored by Medivation and Astellas.
Full disclosures of the abstract authors:
Tomasz M. Beer: Research Funding - Astellas Pharma; Cougar Biotechnology; Janssen Biotech; Medivation
Andrew J. Armstrong: Consultant or Advisory Role - Bayer; Dendreon; Janssen Biotech; Medivation/Astellas; Sanofi; Honoraria - Dendreon; Sanofi; Research Funding - Active Biotech; Dendreon; Janssen Biotech; Medivation; Sanofi
Cora N. Sternberg: Consultant or Advisory Role - Amgen; Astellas Pharma; Johnson & Johnson; Sanofi; Research Funding - Medivation/Astellas
Celestia S. Higano: Consultant or Advisory Role - Algeta; Amgen; Astellas Pharma; Bayer; BHR Pharma; Dendreon; Endo Pharmaceuticals; Ferring; Genentech; Johnson & Johnson; Medivation; Millennium; Novartis; Oncology Trials Insights; Pfizer; Teva; Research Funding - Aragon Pharmaceuticals; Dendreon; Exelixis; ImClone Systems; Johnson & Johnson; Medivation; Millennium; Oncogenex; Teva
Peter Iversen: Consultant or Advisory Role - Astellas Pharma; Janssen; Medivation; Research Funding - Astellas Pharma; Janssen; Medivation
Yohann Loriot: Research Funding - Astellas Pharma
Dana E. Rathkopf: Research Funding - Astellas Pharma; Medivation
Suman Bhattacharya: Employment or Leadership Position – Medivation; Stock Ownership - Medivation
Joan Carles: Research Funding - Astellas Pharma; Medivation
Johann S. De Bono: Consultant or Advisory Role - Astellas Pharma; AstraZeneca; Medivation; Sanofi; Research Funding - Astellas Pharma; Medivation
Christopher P. Evans: Consultant or Advisory Role – Medivation; Stock Ownership – Medivation; Research Funding - Astellas Pharma; Medivation
Anthony M. Joshua: Research Funding - Astellas Pharma; Medivation
Choung-Soo Kim: Research Funding - Astellas Pharma; Medivation
Go Kimura: Honoraria - Astellas Pharma; Research Funding - Astellas Pharma; Medivation
Paul N. Mainwaring: Consultant or Advisory Role - Janssen; Novartis; Honoraria - Janssen; Novartis; Roche; Research Funding - Astellas Pharma; Medivation
Harry H. Mansbach: Employment or Leadership Position – Medivation; Stock Ownership - Medivation
Kurt Miller: Consultant or Advisory Role - Amgen; Astellas Pharma; Bayer; Bristol-Myers Squibb; Dendreon; Ferring; GlaxoSmithKline; Janssen-Cilag; Merck; Novartis; Pfizer; Roche; Research Funding - Astellas Pharma; Medivation; Novartis
Sarah B. Noonberg: Employment or Leadership Position – Medivation; Stock Ownership - Medivation
Peter M. Venner: Consultant or Advisory Role - Astellas Pharma; Research Funding - Astellas Pharma; Medivation
Bertrand Tombal: Consultant or Advisory Role - Amgen; Astellas Pharma; Bayer; Ferring; Janssen; Medivation; Honoraria - Amgen; Bayer; Ferring; Research Funding - Astellas Pharma; Medivation
Reference
Beer TM, Armstrong AJ, Sternberg C, et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. J Clin Oncol 32, 2014 (suppl 4; abstr LBA1^).