Two years after the FDA denied a request to expand the indication of finasteride and other 5Î±-reductase inhibitors to prevent prostate cancer, a major study has cast doubt on the concerns that prompted the denial: that the drug raised the risk of more lethal cancers.
Gerald L. Andriole Jr, MD
Robert K. Royce Distinguished Professor
Chief, Division of Urologic Surgery
Siteman Cancer Center
Washington University School of Medicine
St. Louis, MO
Two years after the FDA denied a request to expand the indication of finasteride and other 5α-reductase inhibitors to prevent prostate cancer, a major study has cast doubt on the concerns that prompted the denial: that the drug raised the risk of more lethal cancers. Results from an 18-year follow-up study1 of the National Cancer Institute’s landmark Prostate Cancer Prevention Trial (PCPT), which evaluated the drug’s safety and efficacy, found a slightly higher rate of high-grade cancers among the men taking finasteride but no difference in survival rates between treated men and those in the placebo arm, even among men with a high-grade cancer diagnosis (Figure).
The analysis showed that finasteride reduced the risk of low-grade prostate cancer by about one-third. Yet, the drug has seen little use in cancer prevention since the initial report, published in 2003, which found that it reduced the risk of prostate cancer by about 25%, but increased the risk of high-grade cancer by about the same amount. Those findings sparked debate over whether the drug caused more serious cancers or made it easier to detect them. In the latest analysis, Thompson et al collected data on the incidence of prostate cancer among PCPT participants and then searched the Social Security Death Index to assess survival status through October 2011.
Although this follow-up study may have allayed some concerns about finasteride, it remains unclear whether clinicians will now use the drug as a cancer prevention tool. Proponents of cancer prevention with finasteride and other 5α-reductase inhibitors are reassured by these findings but other considerations, such as the reduced emphasis on prostate-specific antigen (PSA) screening and the need for clinicians to use PSA differently in men receiving these agents, may result in little change in the use of these medications. These drugs remain approved and widely prescribed as treatments for benign prostatic enlargement, however, and use for that indication may well rise.
For more than a decade, Gerald L. Andriole Jr, MD, of Barnes-Jewish Hospital and the Siteman Cancer Center, has been conducting research into the optimal use of finasteride and other 5α-reductase inhibitors. In this interview with OncologyLive, Andriole discusses the implications of the latest finasteride findings.
OncologyLive: Does finasteride have a role in cancer prevention going forward?Andriole: I think it does, and I think it should be used selectively for this purpose. If a man is going to be screened with PSA, I think that 5α-reductase inhibitors will improve the overall effectiveness of screening for two reasons: They reduce the diagnosis of low-grade cancers that do not warrant treatment and they improve the ability of PSA to detect more aggressive cancer. Reducing the diagnosis of trivial cancers is important, as a major problem with screening is overtreatment of lowgrade cancers. This causes real harm to patients as they may experience side effects from treatment while getting no benefit from it.
Finasteride also makes PSA a better marker for aggressive cancers. For men taking [finasteride], PSA initially falls. If PSA subsequently rises above the nadir, then that is a strong signal that an aggressive cancer may be developing. The interpretation of PSA is different for men taking this drug. While urologists are sensitized to these nuances, many primary care providers and family doctors may not know that a rising PSA for men receiving finasteride, even if it is still under 4, is not normal and is a serious warning sign that an aggressive cancer may be developing. The potential for misinterpretation of PSA in this way was one of the reasons the FDA decided not to modify the label.
How should clinicians interpret the updated results of the PCPT?
Individuals who were concerned that finasteride use promoted aggressive prostate cancer should find reassurance from this analysis. The results show that the drug is safe if patients are closely monitored and PSA is interpreted correctly. But will that message get out to primary care physicians? I doubt it. Will they prescribe it for prostate cancer prevention? Probably not. It’s a complicated issue in which they hear that experts disagree, and there is a movement against widespread PSA screening at the moment anyway. This drug is most beneficial for men at higher risk of prostate cancer who should be getting screened. On the other hand, use of this drug for men with benign prostatic hyperplasia [BPH] could well increase.
How has finasteride’s use evolved over time?
Medical missionaries including students working in Haiti and the Dominican Republic in the 1970s identified villagers with disorders of sexual differentiation, including small testicles and no BPH. These men were born with a deficiency of the enzyme 5α reductase. Learning this, the academic and pharmaceutical communities realized they could potentially eliminate the development of BPH by inhibiting this enzyme with drugs. Two such agents have been approved: finasteride and a related drug, dutasteride, a dual 5α-reductase inhibitor. These drugs were initially approved for treatment of men with BPH. Later, as results of the PCPT trial and the REDUCE trial became known, there was hope they would be approved for prostate cancer prevention as well. For this use, the men who stand to benefit most from receiving these drugs are those at high risk of aggressive cancers, including men with a strong family history of prostate cancer and African-American men. Other tools, such as measurement of PSA at an early age—in the 40s for example—may also identify at a relatively young age which men are a high risk of prostate cancer.
What is the drug’s mechanism of action?
Finasteride inhibits the enzyme 5α reductase, which converts testosterone to dihydrotestosterone (DHT). DHT is a very potent hormone that causes the prostate and prostate cancers to grow. By reducing DHT, finasteride and dutasteride slow the growth of many prostate cancers and cause many prostate cancers to actually shrink in size.
Is it clear whether finasteride enhances detection of prostate cancer—particularly high-grade cancer— or causes it?
I think finasteride enhances detection of prostate cancer for two reasons. First, it makes PSA a better marker and second, it shrinks the prostate by approximately 25%, thereby making biopsies more accurate. A standard prostate biopsy consists of 12 cores, and the smaller the prostate the more complete is the assessment of whether cancer is present. In larger prostates, the cores can be so widely spaced that cancers are missed by the biopsy.
What are the principal adverse effects of finasteride?
There are sexual side effects, including higher rates of erectile dysfunction and reduced semen volume. I discuss this with my patients. I tell them that not everyone develops these side effects, but we will stop the medication if they do. These effects are usually not permanent.
Are there broader concerns about the entire class of 5α-reductase inhibitors?
I don’t think so. In the PCPT, 18,000 patients were randomized over the trial’s two arms and now have been followed for close to two decades. An even larger number of patients were studied in a Swedish analysis2 that assessed 5α-reductase inhibitor use in men with BPH. It found a decreased risk of lower grade cancers and no increase in the risk of higher grade cancers. Finally, a third trial, the REDUCE study3 of dutasteride, for which I was the principal investigator, confirmed the safety and efficacy of dutasteride for chemoprevention of prostate cancer in men at high risk. In the aggregate, these three studies, plus over 20 years of experience in using these drugs for men with BPH, are very reassuring.
How should we approach prostate cancer prevention?
We now have three major studies—REDUCE, PCPT, and the Swedish study—that evaluate the efficacy of cancer prevention. As data from these studies become more widely known, additional data come out, and the medical community comes to a consensus on the need for PSA screening, there will be more clarity and willingness to use these drugs for prevention.
Are we closer to finding a balance between intrusive and potentially harmful screening and successful early intervention?
I think the guidelines of multiple professional organizations are starting to reflect that. Doctors are becoming more aware of the nuances of prostate cancer detection and the consequences of overtreatment. We are also finding new biomarkers in addition to PSA that will help minimize detection and treatment of minimal cancers. Studies on these new biomarkers will be released soon.
PCPT indicates Prostate Cancer Prevention Trial. Thompson IM et al. N Engl J Med. 2013;369(7):603-610.