Karim Fizazi, MD
An analysis of the phase III AFFIRM trial showed that enzalutamide (Xtandi) significantly delayed the time to first skeletal-related event (SRE) and significantly improved pain and quality of life (QOL) compared with placebo in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel.
Enzalutamide is an oral androgen receptor inhibitor that targets multiple steps on the androgen receptor pathway. Based on the results of the AFFIRM trial, the FDA recently approved enzalutamide to treat patients with mCRPC who were previously treated with docetaxel.
The AFFIRM trial included 1199 patients with progressive mCRPC who had received ≤2 regimens of docetaxel. Participants were randomized 1:1 to enzalutamide or placebo. Demographic characteristics were well balanced between the two treatment arms. Median age was 69 years. Median pain score was >4 in 28% of patients. Ninety percent had bone metastasis, and 43% had received bisphosphonates. Overall results of the AFFIRM study showed that enzalutamide prolonged survival and risk of death versus placebo. Median survival was 18.4 months with enzalutamide versus 13.6 months with placebo, representing a 37% reduction in risk of death.
At the 2012 ESMO Congress, Karim Fizazi, MD, Institut Gustav Roussy, Villejuif, France, reported a subanalysis of AFFIRM focused on the effect of enzalutamide versus placebo on SRE, pain, and QOL. The subanalysis showed that enzalutamide significantly delayed time to first SRE: a median of 16.7 months with enzalutamide versus 13.3 months with placebo, representing a 31% reduction in risk of SRE (P
The distribution of first SRE showed a generally favorable effect of enzalutamide, with fewer patients experiencing radiation to the bone (20% for enzalutamide versus 25% for placebo) and spinal cord compression (6% versus 8%), but about 4% in each group experiencing pathological fracture.
Pain was assessed by three methods: Brief Pain Inventory Short Form (BPI-SF, baseline and week 13); self-reported pain diaries at baseline and weekly, including analgesic use and worst pain for 7-day period; and Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire at baseline and week 13.
On the BPI-SF, enzalutamide reduced pain severity; patients taking enzalutamide improved pain scores by 7.5%, while those on placebo had worsening pain by 23% (P
Pain diaries showed pain progression in 28% taking enzalutamide versus 39% of placebo patients (P
= .0018). Palliation (ie, >30% reduction in mean pain score at week 13 versus baseline without a >30% increase in analgesic use) was achieved in 45% of the enzalutamide arm versus 7% of the placebo arm (P
Eleni Efstathiou, MD, PhD
On the FACT-P, the median for time to pain progression had not yet been reached in the enzalutamide arm versus 13.8 months in the placebo arm, representing a risk reduction of 44% (P
= .0004). The total QOL score on the FACT-P showed that QOL was dramatically improved in patients taking enzalutamide: 43% had improvement in QOL versus 18% in the placebo arm. Significant improvements were seen in all QOL domains for enzalutamide compared with placebo (P
<.001 for all except social/family, which was significant at P
Formal discussant of this trial, Eleni Efstathiou, MD, PhD, MD Anderson Cancer Center, Houston, Texas, commended the authors for including QOL and pain alleviation in their analysis of AFFIRM. However, she urged caution when considering the positive results of the subanalysis.
“Although enzalutamide clearly reduced the risk of SRE, improved QOL and functionality, and relieved pain and delayed pain progression, there is no evidence in this trial that severe pain is reduced. Enzalutamide ameliorated bone metastasis in symptomatic men with CRPC. However, we cannot declare victory, given that severe painrelated events may not be altered,” Efstathiou said. She added that better understanding of the mechanisms involved in bone metastasis could move the field forward.
Fizazi K, Scher HI, Saad F, et al. Impact of enzalutamide, an androgen receptor signaling inhibitor, on time to first skeletal related event (SRE) and pain in the phase 3 AFFIRM study. Presented at: 37th European Society for Medical Oncology Congress; September 28-October 2, 2012; Vienna, Austria. Abstract 896O.