25 novembre 2012

Auteurs : Y. Loriot, K. Fizazi, F. Saad, C. Sternberg, K. Miller, P. Mulders, K. Chi, M. Hirmand, B. Selby, J. De Bono
Référence : Prog Urol, 2012, 13, 22, 780


Objectives.– Enzalutamide-proposed INN (formerly MDV3100) inhibits androgen binding to AR, AR nuclear translocation, and association of AR with DNA. The AFFIRM trial (NCT00974311) demonstrated that enzalutamide increased survival by 4.8 months (P <0.0001, HR 0.63) vs placebo in metastatic castration-resistant prostate cancer patients post-docetaxel.

Methods.– In the double-blind, multinational Phase 3 AFFIRM study, patients were randomized 2:1 to enzalutamide 160 mg/day or placebo (stratified by baseline ECOG and mean pain score (BPI-SF question #3 [Q3]).Corticosteroids were allowed but not required. SRE was defined as radiation therapy or surgery to bone, pathological bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain. Pain was assessed using patient diaries, FACT-P, and BPI-SF. Pain palliation was based on mean of worst pain over 7 days and analgesic use in patients with disease-related pain.

Results.– Eight hundred patients were randomized to enzalutamide and 399 to placebo; 273 patients were recruited in France. At baseline, 8.5% had ECOG2 and 28% BPI-SF Q3 score4. 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 enzalutamide and 13.3 months (9.9, NYR) for placebo (HR 0.69, P =0.0001). Pain palliation (≥30% reduction in mean pain score at week 13 vs baseline without a30% increase in analgesic use), assessed by patient diaries, was achieved in 45% of enzalutamide patients and 7% of placebo patients (P =0.0079). In evaluable patients (i.e. both baseline and week 13 BPI-SF Q3 scores), 28% enzalutamide and 39% placebo patients (P =0.0018) had pain progression assessed by patient diaries (increase over baseline in mean pain score). Median time to pain progression (confirmed increase in FACT-P score for “I have pain”) was not yet reached with enzalutamide vs 13.8 months for placebo (P =0.0004, HR 0.56). There were mean reductions in pain severity (average of 4 severity items of the BPI-SF) and interference (average of 7 interference items of the BPI-SF) favouring enzalutamide (0.65; P <0.001, and 0.76; P <0.001, respectively).

Conclusion.– Enzalutamide significantly delayed the time to first SRE and had a consistently favourable and significant impact on measures of pain vs placebo.

Funding .– Medivation Inc. was the study sponsor.

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© 2012 
Publié par Elsevier Masson SAS.