5ARIs: An Ounce of Prevention vs A Pound of Cure

It has been said that "an ounce of prevention is worth a pound of cure".  However, the FDA holds the ounce of prevention to a higher standard than the pound of cure and posits that any side effects are intolerable in prevention since there's no guarantee that one will succumb to the potential condition that one is attempting to prevent.  Therefore, their Oncologic Drugs Advisory Committee just voted 17-0 with one member abstaining to reject finasteride as a chemoprophylaxis against prostate cancer.  They also voted 14-2 with two members abstaining against the use of dutasteride for the same proposed indication.

The background and premise certainly was tantalizing back in July 2003 when the Prostate Cancer Prevention Trial (PCPT) was published evaluating the 7yr effect of finasteride 5mg daily vs placebo randomized to 9,060 men w/PSA 3.0ng/mL.  In this particular population, the risk of low grade prostate cancer was reduced by 24.8% (absolute reduction from 24.4% on placebo down to 18.4% on finasteride) but at the cost of increase risk of high grade tumors (Gleason >7) from 22.2% on placebo to 37.0% on finasteride.  To add insult to injury, sexual side effects, eg loss of libido, erectiledysfunction, reduced ejaculate volume & gynecomastia, were more common in those randomized to finasteride (while lower urinary tract symptoms were more common in those randomized to placebo).  Several papers published since this original study have concluded that the increase in high grade tumors was a statistical anomaly and not likely the cause of finasteride.

Earlier this April, the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial was published evaluating the 4yrs effect of dutasteride 0.5mg daily vs placebo randomized to 6,729 men w/PSA 2.5-10 s/p negative biopsy.  The authors concluded that there was a 22.8% relative risk reduction in prostate cancer, similar to that of finasteride.  But likewise, there was a statistically significant increase in high grade tumors (Gleason >8), decrease/loss of libido, erectile dysfunction, decreased semen volume, gynecomastia as well as heart failure! 

In their wisdom, the advisory panel recommended the ongoing use of 5 alpha reductase inhibitors to treat lower urinary tract symptoms (where benefit exceeded risk) but against use to prevent prostate cancer (where risk exceeded benefit).  Sometimes that ounce of prevention just isn't worth it.