Epoetin alfa and darbepoetin alfa go head to head.

Since July 2002, when the US Food and Drug Administration approved the use of darbepoetin alfa for treatment of chemotherapy-associated anemia in patients with nonmyeloid malignancies, American oncologists have had two recombinant erythropoietic agents from which to choose when trying to ameliorate anemia in patients suffering from cancer. Darbepoetin alfa and epoetin alfa share the same native protein sequence, but the molecules have distinct glycosylation patterns, resulting in a threetimes longer serum half-life and a modestly reduced erythropoietin receptor affinity for darbepoetin compared with its predecessor, epoetin. Darbepoetin is currently marketed by its manufacturer as having “increased potency and longer half-life” compared with epoetin, which purportedly “allows for less-frequent dosing than the previous standard of care.” However, until recently, there have been few reports of clinical trials directly comparing darbepoetin alfa and epoetin alfa administered in the doses and schedules that are now commonly used in clinical oncology practice. Most of the larger published comparative analyses to date have been retrospective, have been limited to historical controls, or were pilot studies using multiple dose levels of darbepoetin. This issue features an important prospective study by Glaspy et al comparing two doses and schedules of these erythropoietic agents frequently used in oncology clinics (once weekly subcutaneous epoetin alfa initiated at a fixed dose of 40,000 U v darbepoetin alfa administered subcutaneously once every 2 weeks, beginning at a fixed dose of 200 g). Both treatment groups were permitted a 50% dose escalation at week 5 for nonresponse, which was defined as failure to achieve a hemoglobin increment of at least 1 g/dL above the baseline measurement. This study, as with other community-based erythropoietin treatment protocols organized by Glaspy et al, is remarkable first of all for its size, and the authors are to be congratulated for completing accrual so rapidly. To our knowledge, the present trial is the largest randomized study of erythropoietic agents in cancer-associated anemia; 1,209 patients received protocol therapy. The study was sponsored by the manufacturer of darbepoetin (Amgen, Inc, Thousand Oaks, CA), and the report includes an industry coauthor. The outcome in terms of the primary end point, which was the proportion of patients who required RBC transfusion, was similar between treatment groups, with 21% of patients in the darbepoetin arm receiving transfusion between week 5 and the end of study (27% from beginning to end) compared with 16% of patients in the epoetin group (22% from beginning to end). For comparison, the historical control transfusion rate for a similar group of placebo-treated patients with a comparable degree of chemotherapy-associated anemia is approximately 40% to 45%. The investigators’ predefined cutoff for declaring inferiority of one regimen was an absolute proportional difference in transfusion rate of 11.5%; because the upper limit of the CI of the 5% observed difference (ie, 16% for epoetin v 21% darbepoetin) favoring epoetin was 10.8%, the authors conclude that these two regimens are equivalent from the standpoint of a noninferiority analysis. Equivalence is a formal statistical term, and equivalent should not be seen as semantically equal to identical. In fact, in some respects, the results of this study could be interpreted as suggesting that weekly epoetin might be slightly superior to every-2-week darbepoetin, at least in the doses chosen for the trial. The transfusion end point, although not quite meeting the predefined inferiority cutoff, did favor weekly epoetin, whereas the CIs for the proportion of patients transfused narrowly missed refuting the noninferiority hypothesis. The mean hemoglobin increment from baseline, especially around week 9, was superior for the epoetintreated group, albeit again not statistically significant. From week 5 until the end of the study, more patients on the epoetin arm were within the stated goal hemoglobin range of 11 to 13 g/dL (see Fig 3 of the report). Additionally, the rate of increase of hemoglobin seems to have been slightly greater with the weekly epoetin regimen, which is a scheduling phenomenon that has been observed in a few other studies, including those comparing various darbepoetin doses and schedules with each other (increasing the drug dose seems to be more effective at augmenting hemoglobin rapidly than does increasing the dosing frequency). One might argue about whether a rapid increase in hemoglobin is always a good thing; after all, the package inserts for recombinant erythropoietins were modified in 2004 to warn about an excessive rate of hemoglobin increase because of concerns about a possible association between rapid increase of hemoglobin and risk of thromboembolic events raised by several studies. However, if a patient has severe anemia and is in danger of needing a transfusion soon, a rapid hemoglobin increase is likely to be beneficial. In contrast, the trend in the study in terms of quality-of-life (QOL) changes favored darbepoetin. QOL has proven to be a rather variable, complex, and inconsistent factor in past analyses of erythropoietic agents, so it is difficult to know just what to make of this finding. The study was not double blinded, which could influence QOL comparisons, but it is also possible that the advantage of receiving an injection less frequently is a component of QOL. If so, that could favor every-2-week darbepoetin, as used in the study by Glaspy et al. Overall, all of the differences (transfusions, hemoglobin, and QOL) between groups were small, so JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 15 MAY 2