Impact of Enzalutamide, An Androgen Receptor Signaling Inhibitor, on Time to First Skeletal Related Event (SRE) and Pain in the Phase 3 Affirm Study

ABSTRACT Background Enzalutamide-proposed INN (ENZA, MDV3100) inhibits androgen binding to AR, AR nuclear translocation, and AR association with DNA. The AFFIRM trial (NCT00974311) demonstrated that ENZA increased survival by 4.8 mo (P Methods In the double-blind, multinational Phase 3 AFFIRM study pts were randomized 2:1 to ENZA 160 mg/d or placebo. Corticosteroids were allowed but not required. Patients were stratified by baseline ECOG and mean pain score (BPI-SF question #3 [Q3]). SRE was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. Pain was assessed using pt diaries, FACT-P, and BPI-SF. Pain palliation was based on mean of worst pain over 7 days and analgesic use in pts with disease-related pain. Results 800 pts were randomized to ENZA and 399 to placebo. At baseline 8.5% had ECOG =2 and 28% BPI-SF Q3 score ≥4. The study was halted following a planned interim analysis at 520 deaths. Median time to first SRE was 16.7 months (14.6, 19.1) for ENZA and 13.3 months (9.9, NYR) for placebo (HR 0.69, P = 0.0001). Pain palliation assessed by pt diaries (≥ 30% reduction in mean pain score at wk 13 vs baseline without a ≥ 30% increase in analgesic use) was achieved by 45% ENZA pts compared to 7% placebo pts (P = 0.0079). In evaluable pts (both baseline and week 13 BPI-SF Q3 scores), 28% ENZA and 39% placebo pts (P = 0.0018) had pain progression assessed by pt diaries (increase over baseline in mean pain score). Median time to pain progression (confirmed increase in FACT-P score of “I have pain”) was not yet reached vs 13.8 mo for ENZA and placebo (P = 0.0004, HR 0.56). There was a mean reduction in pain severity (average of 4 severity items of the BPI-SF) of 0.65 favoring ENZA (P Conclusions In the AFFIRM phase 3 trial, enzalutamide significantly delayed the time to first SRE and had a consistently favorable and significant impact on measures of pain vs placebo. Disclosure H.I. Scher: Consult/Advis: Amgen, Aragon, BMS, Dendreon, Exelixis, Janssen, Medivation, Millennium, Novartis, Ortho Biotech Oncol RD Research Fund (employer): Aragon, BMS, Exelixis, Medivation, Ortho Biotech Oncol RD Consulting fee or honorarium: Astellas, Medivation, Johnson & Johnson; Board membership: Medivation, Astellas, Johnson & Johnson. C.N. Sternberg: Consultancy fee or honorarium: Johnson & Johnson, Astellas, Amgen, Sanofi-Aventis. K. Miller: Consulting fee or honorarium: Medivation, Astellas, Novartis, Amgen, BMS, AZ, Roche; Payment for lectures including service on speakers bureaus: Novartis, Amgen, BMS. P. Mulders: Consultancy: Astellas, GSK, AZ, Pfizer; Payment for lectures including services on speaker bureaus: PRIME. M. Hirmand: Employement: Medivation; Stock/stock options: Medivation. J.S. de Bono: Consultancy: Medivation, Astellas. All other authors have declared no conflicts of interest.