The Risks and Benefits of 5α-Reductase Inhibitors

Authors : Marc R. Theoret, M.D., Yang-Min Ning, M.D., Ph.D., Jenny J. Zhang, Ph.D., Robert Justice, M.D., Patricia Keegan, M.D., and Richard Pazdur, M.D.
The use of 5α-reductase inhibitors for prevention of prostate cancer continues to be widely discussed within the scientific and medical communities. Much of this discussion has been fueled by the findings of two large randomized, placebo-controlled trials — the Prostate Cancer Prevention Trial (PCPT) with finasteride and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial . Together, these trials showed an overall relative reduction of 23 to 25% in prostate-cancer diagnoses, a seemingly significant benefit from drugs aimed at preventing one of the most common cancers in men. However, the observed reduction resulted from a decreased incidence of only low-grade prostate cancer (Gleason score, ≤6). In fact, in both trials, there was an absolute increase in the incidence of high-grade prostate cancers in the chemoprevention group.
Evaluating the potential chemopreventive benefits of 5α-reductase inhibitors and assessing the potential increased risk for high-grade prostate cancers have been central issues for the Food and Drug Administration (FDA). There has been much hope for an FDA-approved chemopreventive agent for prostate cancer, and there is clearly ongoing off-label use of 5α-reductase inhibitors for this indication. The FDA has been actively evaluating the relevant data and held a meeting of its Oncologic Drugs Advisory Committee to address this topic in December 2010.

Both chemoprevention trials were conducted in men who were at risk for prostate cancer but did not have diagnosed prostate cancer at study entry. The FDA’s analysis of the trials confirmed that there was a relative reduction of approximately 25% in the overall incidence of prostate cancer and a significantly increased incidence of high-grade prostate cancers. During the FDA review of the REDUCE trial, we requested that biopsy specimens be reassessed, according to the modified Gleason scale, by an independent pathologist who was unaware of the earlier scores. The central pathologist for PCPT performed this reassessment. The use of modified Gleason scores is consistent with current recommendations for prostate-cancer grading and the grading system used in PCPT; modified Gleason scores were not originally reported in the REDUCE trial.
The reassessment revealed no reduction in the incidence of tumors with modified Gleason scores between 7 and 10 — a finding that was consistent with the published data. However, an absolute increase of 0.5% in the incidence of tumors with modified Gleason scores of 8 to 10 (relative risk, 2.06; 95% confidence interval [CI], 1.13 to 3.75) was observed with dutasteride treatment. This increase is similar to the absolute increase of 0.7% in the incidence of such tumors observed with finasteride treatment (relative risk, 1.70; 95% CI, 1.23 to 2.34) .These results suggest that one additional man would receive a diagnosis of high-grade prostate cancer (modified Gleason score, 8 to 10) for every 150 to 200 men treated long-term with a 5α-reductase inhibitor.

It has been suggested that detection bias, attributable to the fact that 5α-reductase inhibitors reduce serum levels of prostate-specific antigen (PSA) and prostate volume, led to an increase in detection of high-grade prostate cancer in the finasteride group of the PCPT. Indeed, the sensitivity of an elevated PSA level (a PSA level above 4 ng per milliliter in the placebo group or, in the finasteride group, above the adjusted value designed to correct for a finasteride-induced PSA reduction of approximately 50%) for the detection of prostate cancer, including high-grade tumors, was increased in the finasteride group of the PCPT. The observation that the increased risk of high-grade tumors (modified Gleason score, 8 to 10) with finasteride or dutasteride persisted in analyses of scheduled biopsies independent of PSA results argues against PSA-related detection bias as the cause of the observed increase in the incidence of high-grade tumors. Approximately 56% of all prostate cancers in the PCPT and 90% of those in the REDUCE trial were diagnosed by means of scheduled biopsies.
As for detection bias due to 5α-reductase inhibitors’ reduction of prostate volume by approximately 20%, it is possible that core needle biopsies may uncover more cancers, including high-grade tumors, in smaller prostates because of increased sampling density. Proponents of this hypothesis accounted for the intergroup difference in prostate volume either by statistically adjusting for prostate volume at the time of biopsy (using logistic-regression analysis or the Peters–Belson method) or by circumventing any potential for sampling bias by extrapolating from the Gleason scores for a subgroup of patients who had had prostatectomies to patients without prostatectomy data (weighted imputation estimation). These analyses resulted in estimates of the relative risk of high-grade prostate cancer (Gleason score, 7 to 10) in the finasteride group ranging from no increase to a relative decrease of 27%. Since conventional criteria define “high-grade” as a Gleason score of 8 to 10 and 75% of the increase in tumors with modified Gleason scores of 7 to 10 observed in the finasteride group involved tumors with a score between 8 and 10, the FDA repeated the same analyses, statistically adjusting for prostate volume and using a modified Gleason score of 8 to 10 as the definition of a high-grade tumor. The results of those analyses do not support the contention that increased sampling density is responsible for the increased incidence of high-grade tumors in the finasteride group (see table for opposing risk estimations for tumors with a modified Gleason score of 7 to 10 and those with a score of 8 to 10). Although questions concerning detection bias remain, none of the post hoc exploratory analyses provide convincing evidence that the increased incidence of high-grade disease observed in both trials can be dismissed.
Analyses of these trials indicate that the reduction in prostate-cancer risk with both drugs was limited to tumors with a modified Gleason score of 6 or lower. Prospectively collected data in REDUCE showed that 80% of such tumors met the Epstein pathological criteria for “very-low-risk” disease, which indicates that a reduction in their incidence is unlikely to be clinically significant. An analysis of biopsies performed in response to an elevated PSA level or an abnormal digital rectal examination, as would be done in clinical practice, revealed a smaller reduction in the relative risk of prostate cancer (14%; 95% CI, 4 to 23%) than that reported for all cancers in men receiving finasteride. Therefore, the trade-off inherent in using a 5α-reductase inhibitor for prostate-cancer prevention is the acceptance of one additional high-grade cancer in order to avert three to four potentially clinically relevant lower-grade cancers.

The conclusion drawn by the advisory committee in December was that finasteride and dutasteride do not have a favorable risk–benefit profile for the proposed use of chemoprevention of prostate cancer in healthy men. The FDA agrees with this assessment. The effects of finasteride or dutasteride on the incidence of metastatic prostate cancer and prostate-cancer–specific morbidity and mortality have not been evaluated.
Strategies for reducing cancer risk expose people who do not have and may never develop cancer to a drug and its potential adverse effects. In these circumstances, a high level of certainty about benefits and risks of intervention is warranted. The labels of approved 5α-reductase inhibitors, which are currently indicated for the treatment of symptomatic benign prostatic hyperplasia and male-pattern hair loss, have been modified to include the observation of high-grade prostate cancers in the relevant trials. In addition, health care professionals prescribing 5α-reductase inhibitors to men who opt for PSA screening should be aware that these agents reduce PSA values and that any increase in the PSA level above the lowest value obtained may signal the presence of prostate cancer, even if the value remains in the normal range for men not taking such an agent.

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Regulatory Action on Rosiglitazone

There have been ongoing concerns about the safety of the diabetes drugs containing rosiglitazone (Avandia, Avandaryl, and Avandamet) — a thiazolidinedione antidiabetic agent indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

In 2007, a meta-analysis of controlled clinical trials found increases in the risk of myocardial infarction and a near-significant increased risk of death from cardiovascular causes when rosiglitazone was compared with placebo or with standard diabetes drugs. Following an advisory committee meeting held in July 2007, the U.S. Food and Drug Administration (FDA) added information about the possibility of ischemic cardiovascular risk to the drug’s existing boxed warning. At the same time, the FDA also required the sponsors to conduct a head-to-head cardiovascular safety trial of rosiglitazone versus pioglitazone — the other antidiabetic drug in this class available in the United States. After new data became available, the FDA held a second advisory committee meeting on rosiglitazone safety on July 13 and 14, 2010. On September 23, 2010, the FDA announced regulatory actions stemming from these deliberations.

The FDA is restricting access to rosiglitazone by requiring the drug sponsor to submit a Risk Evaluation and Mitigation Strategy, or REMS. Under the Food and Drug Administration Amendments Act of 2007, the FDA can require a drug sponsor to issue a REMS to impose certain restrictions so that the benefits of a drug continue to outweigh its risks. When the REMS for rosiglitazone is implemented, the drug will be available to patients not already taking it only if they are unable to achieve glycemic control using other medications and, in consultation with their health care professional, decide not to take pioglitazone for medical reasons. Current users of rosiglitazone will be able to continue using the medication if they appear to be benefiting from it and they acknowledge that they understand these risks. Doctors will have to attest to and document their patients’ eligibility; patients will have to review statements describing the cardiovascular safety concerns. The agency anticipates that the REMS will limit use of rosiglitazone significantly.

The FDA is taking this step on the basis of its assessment of all available data on the cardiovascular ischemic risk of rosiglitazone. At the recent advisory committee meeting, FDA scientists and external experts presented new signals of risk from observational studies and meta-analyses. Each of these data sources has its limitations, including the potential for bias in observational studies and the fact that pooling the results of the studies that were not designed to assess cardiovascular risk can lead to invalid conclusions. But there was no reliable evidence to refute these cardiovascular safety concerns.

After considering the data, 18 members of the advisory committee found significant cause for concern about an increase in ischemic cardiovascular events with rosiglitazone relative to other non-thiazolidinedione antidiabetic agents, whereas 6 committee members did not. Twenty-one members believed that the cardiovascular risk with rosiglitazone was significant as compared with pioglitazone. Three members did not reach this conclusion. This 21-to-3 vote also reflected recognition that available evidence on pioglitazone, including the results of a well-designed trial in high-risk patients, does not show a signal of a cardiovascular ischemic risk.

The rosiglitazone controversy is remarkable because there are strongly held, differing positions on how the agency should respond to emerging safety data, both inside the FDA and in the biomedical community. The 2010 advisory committee was split in advising the agency about what to do. Moving from the least to most restrictive options, 3 members voted to allow continued marketing with no changes to the label; 7 voted that the FDA should adjust the label to account for the new concerns but take no additional action; 10 members voted for the FDA to both increase warnings and limit access to rosiglitazone; and 12 voted that the medication should be removed from the market altogether. The FDA decided to increase warnings and limit access to rosiglitazone substantially.

The FDA anticipates questions on whether the agency has gone too far, or not far enough.

Some may note the limitations of available data and argue that the FDA should provide more information to clinicians but not impose additional restrictions. The FDA’s response is that a label change alone does not provide adequate assurance that use of rosiglitazone will be limited to appropriate patients. New label warnings are not always read. The significant questions about the drug’s cardiovascular safety justify stronger measures to support good clinical decision making and protect patients.

Others may argue that rosiglitazone should be removed from the market because there is no predefined patient population for whom it is known that it will be more advantageous than pioglitazone. Our response starts with the fact that rosiglitazone does have benefits in glycemic control. These benefits include reductions in short-term complications of hyperglycemia. There is also a broad range of evidence supporting glycemic control as a reliable surrogate marker for decreasing the rate of progression of the microvascular complications of diabetes, including retinopathy and kidney disease.

Against these benefits, we must assess the evidence of rosiglitazone’s cardiovascular risks. This evidence is concerning, but it is not definitive. There are patients with severe type 2 diabetes whose disease may not be controlled on other medications and either may not tolerate pioglitazone or, in consultation with their health care professional, decide not to take pioglitazone for other medical reasons. If well informed, these patients may be willing to accept the concern about cardiovascular safety in exchange for the known benefits of glycemic control. The FDA recently announced that the agency is investigating further signals of a possible increase in the risk of bladder cancer with long-term use of pioglitazone. Although the absolute risk to all patients appears to be small, some patients with a history of bladder cancer, in consultation with their doctors, may decide not to take pioglitazone. When there are just two drugs in a class, and many outstanding uncertainties, maintaining some flexibility may have value for patient care.

The FDA will continue to review emerging data on rosiglitazone. The agency is requiring an independent readjudication of end points at the patient level of an important trial of rosiglitazone’s safety — the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes, or RECORD, trial. As published, RECORD demonstrated the noninferiority of rosiglitazone when compared with sulfonylureas and metformin with respect to a composite end point of multiple cardiovascular events and death, but it did not rule out an elevated risk of myocardial infarction. However, during the course of the FDA’s review of the RECORD study, serious questions arose about potential bias in identification of cardiovascular events arising from the study’s open-label design. The FDA is requiring the readjudication of end points to provide additional clarity about the findings.

Other actions taken by the agency include the discontinuation of the trial known as TIDE (Thiazolidinedione Intervention with Vitamin D Evaluation) — the head-to-head cardiovascular safety trial of rosiglitazone versus pioglitazone. Given the current state of the evidence and the FDA’s recent actions, participants would need to be informed of significant concerns that rosiglitazone may cause more cardiovascular disease than pioglitazone, the restrictions on the use of rosiglitazone that will be imposed through the REMS, and that it is unlikely that, outside the study, the patient would receive rosiglitazone. According to recent recommendations from an Institute of Medicine committee, such an informed consent process might be justified if the study’s outcome could realistically yield a significant benefit to public health. At this point, however, the FDA does not consider TIDE such a study. It is possible that additional data, including information from the readjudication of RECORD, could support additional clinical trials of rosiglitazone safety.

How can the FDA prevent such uncertainty about a major risk from happening again? In 2008, the FDA issued draft guidance on the assessment of cardiovascular risk for new antidiabetic drugs. In this guidance, the FDA proposed upper boundaries for the risk of major cardiovascular events in a meta-analysis or a noninferiority study that compares the new drug with standard therapy. The FDA also recommends that the data for these comparisons come from longer-term trials — that is, trials of at least 2 years’ duration. Guidance represents the FDA’s current thinking on how to meet a specific requirement — in this case, demonstration of the safety of a new drug for this indication. Drug sponsors are free to use other methods to show safety, but such methods need to be equally robust. The expectation of longer-term evidence on the cardiovascular risks of new antidiabetic drugs will assure that such evaluations are routinely conducted and that longer-term data on multiple safety parameters are also available.

The case of rosiglitazone underscores the need for a robust evidence base to demonstrate the safety of medicines administered long-term. The FDA is committed to advancing the science of drug safety evaluation, during both drug development and in the postmarketing period.