Nearly twenty years after the Prostate Cancer Prevention Trial (PCPT) enrolled its first participant, the drama surrounding finasteride use in prostate cancer prevention continues to unfold.
Finasteride, a 5-alpha reductase inhibitor, was once touted as a potential public health tool — a means of preventing prostate cancer. Results from the PCPT, a large-scale study that randomized more than 18,000 healthy men to receive either finasteride or placebo, suggested that finasteride use reduced the risk of being diagnosed with prostate cancer by nearly a third.
Subsequent analyses, however, cast a shadow over this promising finding. Among men who did get diagnosed with prostate cancer, the proportion with high-grade (Gleason 7-10) cancer was significantly greater in the finasteride study arm as compared to the control arm (relative risk 1.17, p=0.05). With that in mind, the notion of using finasteride to prevent prostate cancer fell into disfavor. The US Food and Drug Administration even mandated that a warning be added to the labels of 5-alpha reductase inhibitors to indicate a possible increased risk of high-grade prostate cancer.
But what ended up happening to the men from the study? In the long run, how did the use of finasteride affect their survival — if at all?
In this week’s NEJM, Thompson et al. report the results of a Long Term Follow-up study designed to analyze survival outcomes for PCPT participants. This study ran from 2005 to 2009 and encompassed 18 years of follow-up data. Survival was calculated from the date of diagnosis to either a censor date or the date of death from any cause.
The follow-up analysis found no difference in long-term survival between the two groups. This was true for the overall study population (15-year survival was identical at 78%) as well as the subset of men diagnosed with prostate cancer (finasteride vs placebo: HR 1.01, p=0.90; after adjusting for grade, age at diagnosis, race, and family history: HR 0.93, p=0.45). It remained true when comparing patients with high-grade disease: there was still no detectable survival difference between the two groups (ten-year survival of 73.6% on placebo versus 73% on finasteride; HR 0.94, p=0.68).
The authors recommend careful interpretation of this last finding, noting that “[t]he wide confidence interval for the hazard ratio means that we cannot rule out a 30% decreased risk to a 27% increased risk of death in the placebo group, as compared with the finasteride group.”
Combined with the findings of previous analyses, the results of the PCPT suggest that finasteride use does not change survival but can significantly reduce the risk of prostate cancer diagnosis. Specifically, finasteride offers a 43% reduction in the risk of being diagnosed with a low-grade (Gleason 2-6) cancer. Given the physical, emotional, and financial burdens associated with managing these cancers once they are detected, it seems preventing a diagnosis in the first place would offer profound value.
In an accompanying editorial, Dr. Michael LeFevre, Co-Vice Chair of the U.S. Preventive Services Task Force (USPSTF) and Professor at the University of Missouri Medical School, writes: “For men who choose regular prostate cancer screening, the use of finasteride meaningfully reduces the risk of prostate cancer and thus the morbidity associated with treatment of the disease. Whether the use of the drug has either a positive or a negative effect on prostate-cancer-specific mortality remains unknown, but either way the effect is probably very small and does not result in any difference in life expectancy. Men who are aware of and understand the benefits, risks, and uncertainties associated with the use of finasteride for prevention may make a rational decision to take the drug to reduce the harm of screening.”
NEJM deputy editor Dr. Dan Longo states: “Screening men for prostate cancer using PSA levels is not strongly supported by the available data; however, for men who insist upon being screened, it appears that finasteride can reduce the incidence of low grade cancers substantially thereby preventing the harms associated with treating non-life-threatening disease. Finasteride is also useful in the management of the obstructive symptoms of benign prostatic hyperplasia.”
As the role of prevention continues to evolve — in the management of prostate cancer and in the health care system more broadly — and as effective tools for preventive care are identified, we may find ourselves reevaluating accepted standards of care and treatment guidelines. As far as prostate cancer prevention is concerned, finasteride may not offer the happy ending we had once hoped for, but it seems safe to say the story is far from over.
How do you currently counsel your patients regarding prostate cancer prevention, screening, and management? How do you approach the use of finasteride? Will the findings of this follow-up study change your practice?