As such, the agency stands by its current recommendations for the use of Stalevo (entacapone/carbidopa/levodopa) and Comtan (entacapone; brand name is Comtess elsewhere) to ease motor problems in Parkinson’s disease.
The FDA review was conducted after the findings of a Phase 3 trial, called STRIDE‐PD (NCT00099268), suggested that the entacapone component of Stalevo could raise a person’s risk of prostate cancer. The trial primarily aimed to test whether whether Stalevo or Sinemet (carbidopa/levodopa, by Merck) was more effective in lowering the likelihood of motor complications.
Notified of this concern, the FDA alerted the public in March 2010, the agency said in a release of its decision.
It also required Novartis — which markets both Stalevo and Comtan, and was the sponsor of STRIDE‐PD — to further investigate by comparing entacapone along with a conventional Parkinson’s regimen of dopamine decarboxylase inhibitor/levodopa (DDCI/LD) to treatment with DDCI/LD and either a dopamine agonist or a monoamine oxidase B (MAO-B) inhibitor. (DDCIs and MAO-B suppress the breakdown of levodopa and dopamine, respectively.)
Novartis’ study observed 11,396 male Parkinson’s patients in Finland, 1,141 of whom were using entacapone. Among all patients, 359 prostate cancer cases were reported over an average follow-up of 4.6 years, and 89 cancer-related deaths over 4.7 years. No significant difference in cancer development or death was seen between treatment groups.
Entacapone’s use in combination with DDCI/levodopa was also not linked to a greater risk of prostate cancer or mortality among patients using this combination for more than one year, the FDA found.
However, the agency noted limits to this observational study: Stalevo was available in Finland for a short time given the long latency of prostate cancer, men with advanced Parkinson’s are likely not examined regularly for this cancer, and little information existed as to patients’ family history of prostate cancer and prior screenings.
In parallel, the FDA conducted an independent study using data from the U.S. Department of Veterans Affairs health care system.
A total of 17,666 U.S. male veterans with Parkinson’s were included, all treated with Sinemet. Of these, 5,257 patients used entacapone as an add-on treatment, while the remaining 12,409 had as an add-on therapy a dopamine agonist or a MAO-B inhibitor (the study’s control group).
Twenty-three prostate cancer cases were reported among men on entacapone and 97 among those serving as controls over a follow-up period of 3.1 and 4.0 years, respectively. As with the study in Finland, treatment with entacapone did not lead to findings of a greater cancer risk, even analyzing patients using entacapone for more than two years.
The low overall incidence rate of of “1.8 cases of prostate cancer per 1,000 person-years compared to the age-adjusted rate of 1.3 per 1,000 U.S. males in the general population may reflect a possible bias in cancer ascertainment after Parkinson’s disease was diagnosed,” the FDA stated. (Person-years is a measure of both the number of people in the study and the amount of time each spends in the study. In other words, 1,000 person-years pertains to data gathered by following 1,000 people for one year.)
This rate could also partly be a consequence of lower rates of prostate cancer screening in the U.S., particularly among men with chronic conditions, it added, calling this a study limitation.
FDA officials advise healthcare professionals to follow standard prostate cancer screening recommendations. Patient and caregivers should stay on treatment as prescribed, and address questions or concerns with their doctors.
Comtess is marketed by Orion Pharma of Finland.