Darbepoetin alfa (Aranesp) failed to significantly reduce the need for blood transfusions in patients with active cancer not being treated with chemotherapy or radiotherapy and was associated with decreased overall survival compared to placebo, according to results from a phase III trial reported at the 2007 Annual Meeting of the American Association for Cancer Research (14-18 April, 2007; Los Angeles, USA).

Darbepoetin alfa is a synthetic form of erythropoietin, a hormone that signals the formation of new red blood cells from within the bone marrow. It is currently approved for the treatment of chemotherapy-induced anaemia in patients with nonmyeloid cancers. Anaemia can result from either chemotherapy or the cancer itself, and reduces quality of life and overall cancer survival, so the trial was carried out to assess whether treatment could reduce anaemia, as measured by a reduction in the need for blood transfusions, in patients not on chemotherapy.

The study randomised 985 patients with active cancer and no chemotherapy or radiotherapy within four weeks of screening, to darbepoetin alfa (6.75mcg/kg) or placebo every four weeks. The most common cancers were non-small cell lung, breast and prostate cancer, with 82% of patients in disease stages III or IV.

Results showed that that although the number of transfusions was lower in the active treatment group from weeks 5 to 17 of therapy, this was not statistically significant (hazard ratio 0.85; p=0.32). The adverse event rate was similar with darbepoetin alfa as with placebo. However, the overall number of deaths was significantly higher with active treatment (136 deaths vs 94 deaths with placebo; HR 1.29; p=0.006). This difference in survival remained during post-hoc analysis adjusting for a range of factors, including stage of disease, prior chemotherapy and radiotherapy.

Reporting the findings, lead investigator John Glaspy, professor at the University of California, Los Angeles School of Medicine, USA, said: “While the study was not specifically designed to study survival rates, our results indicate a statistically significant decrease in patients given the drug versus those who were given placebo.” He added: “Since erythropoietic agents are sometimes used to treat anaemia and reduce transfusion risk in patients not on chemotherapy, these results are of concern to the research and clinical cancer communities. For now, we have to conclude that these agents may reduce survival in patients not on chemotherapy.”

One confounding aspect of the results was the different reactions among patients in the darbepoetin group, he noted. Patients with kidney, prostate, or stomach cancers, non-Hodgkin’s lymphoma, or multiple myeloma appeared to have worse survival outcomes with darbepoetin. However, the opposite was seen in patients with breast, colon, ovarian, or cervical cancer. Many of these patients also achieved higher hemoglobin counts (although still within the study’s safety parameters). Survival rates were higher for patients in either group who did not need to receive blood transfusions.

When the researchers notified Amgen of their preliminary results, the company issued a warning to doctors and informed the Food and Drug Administration (FDA) of the results. In March, the manufacturer and FDA agreed to a ‘black box’ warning for doctors about the drug’s safety in this setting.

“The findings will pose a puzzle to cancer researchers, as the mechanisms behind the observed decrease in patient survival are not clear,” concluded Professor Glaspy. He suggested that possible reasons included effects on delivery of oxygen to tumour cells, increased risk of blood clots and the possibility that erythropoietin receptors may occur on tumour cells. “We need to resolve these data in light of evidence that darbepoetin offers benefits for patients with certain types of cancer when used within chemotherapy. There are no obvious reasons for this discrepancy.”

Written by: Susan Mayor PhD Freelance medical journalist