WHITE OAK, MD-The Oncologic Drugs Advisory Committee to the US Food and Drug Administration voted in two separate actions during an occasionally testy meeting on the FDA campus here against recommending use of the 5 alpha-reductase inhibitors finasteride and dutasteride to prevent prostate cancer in healthy men.
While the FDA does not have to take ODAC's recommendations, it often does. The Prostate Cancer Roundtable, a group of not-for-profit organizations dedicated to reducing the toll of prostate cancer, had expressed hope that ODAC would recommend dutasteride for prostate cancer chemoprevention in men at higher than average risk for the disease.
First Action
In the first action, ODAC members were asked to make a determination on whether the finasteride risk/benefit profile was favorable for reduction in the risk of prostate cancer in men age 55 or older with a normal digital rectal examination and a prostate specific antigen (PSA) level of 3.0 ng/mL or under.
The finasteride sponsor, Merck & Co., Inc., was not asking for a new indication but a revision in the label that could have been interpreted to support its use for prostate cancer chemoprevention. Out of 18 members, there were 17 no's and one abstention.
Second Action
In the second action, ODAC members were asked to decide whether the dutasteride risk/benefit profile was favorable for reduction in the risk of prostate cancer in men at increased risk of developing the disease, defined as those who had had a prior negative biopsy due to clinical concern and had an elevated serum PSA.
In this action, the sponsor, GlaxoSmithKline, sought a new indication for prostate cancer chemoprevention through a supplemental New Drug Application (NDA). Fourteen ODAC members voted no, two voted yes, and two abstained.
ODAC member Margaret Tempero, MD, Deputy Director of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, in explaining her decision about why she voted yes, said, "I was persuaded by the opportunity to minimize procedures in this higher-risk population."
ODAC Chair Wyndham Wilson, MD, PhD, who voted no on both actions, said, "My attitude is, you do no harm." Dr. Wilson, Chief of the NCI's Lymphoma Therapeutics Section in the Metabolism Branch of the Center for Cancer Research, said that when a drug is going to be used as chemoprevention in men who do not have cancer, the onus is on the drug to be completely safe and show benefit.
"We're asking you for your clinical judgment on risk/benefit," said Richard Pazdur, MD, Director of FDA's Office of Oncology Drug Products, Office of New Drugs, Center for Drug Evaluation and Research, in addressing ODAC members. Speaking to the committee firmly and directly, Dr. Pazdur said, "Is there a positive risk-benefit relationship here? That's why we brought both of these applications to the committee. This is not an argument with the sponsor."
Dr. Pazdur added, "This is not an oncology drug that is only going to be prescribed by board-certified medical oncologists." He noted that while ODAC often meets to consider approving a drug for a relatively narrow group of patients with metastatic cancer who have few treatment options, this meeting was totally different because it concerned chemoprevention in a broad population of men without cancer.
For people who don't have cancer, "Your level of certainty has to be heightened," stressed Dr. Pazdur. "We're talking about potentially hundreds of thousands of people. This is where the rubber meets the road, so to speak."
Sit Down!'
Dr. Pazdur-who had been quiet during the morning presentations-appeared to become somewhat frustrated at one point in the afternoon. Dr. Pazdur cautioned two invited speakers-who were standing up to deliver their remarks-that they were not there to engage the sponsors of the two drugs in combative conversation, but rather to give their best clinical judgment on the two questions before ODAC so that ODAC members could vote in an informed manner.
Raising his voice, Dr. Pazdur called for two chairs to be brought and asked both speakers to sit down and not talk unless they were recognized by the ODAC chair or himself. The two speakers were well-known prostate cancer specialists Peter T. Scardino, MD, Head of the Prostate Cancer Program, Chairman of the Department of Surgery, and the David H. Koch Chair at Memorial Sloan-Kettering Cancer Center, and Patrick C. Walsh, MD, University Distinguished Service Professor of Urology at the Brady Urological Institute at Johns Hopkins Medical Institutions.
It's a Little Frightening, to be Honest'
During the wide-ranging discussion, several ODAC committee members expressed concern about the possibility of widespread chemoprevention prescriptions being written by varied practitioners for these drugs, and about patients possibly influenced by direct-to-consumer advertising. "It's a little frightening, to be honest," said temporary voting member Inger Rosner, MD, LTC, US Army Medical Corps, Urologic Oncologist at Walter Reed Army Medical Center's Urology Service.
In its background information on chemoprevention with finasteride and dutasteride, the FDA noted that if the drugs were to be approved for prostate cancer chemoprevention, they would be widely used "for the risk reduction of prostate cancer in healthy men who may never have or may never require treatment for prostate cancer. Currently unrecognized safety signals may become evident when these drugs are used in larger populations and for longer time periods."
Potential Red Flags
Members of ODAC not only heard reports on randomized clinical trials that showed benefits of finasteride and dutasteride in reducing the risk of being diagnosed with prostate cancer, but they also heard about potential red flags raised by these trials.
The randomized seven-year Prostate Cancer Prevention Trial (PCPT), which included more than 18,000 men age 55 or older without prostate cancer, found that men on the finasteride arm had a 26% lower risk of being diagnosed with prostate cancer when compared with the placebo arm. In this trial, the reduction in risk was limited to Gleason score 6 or lower prostate cancers.
Paradoxically, men on the finasteride arm had a 1.3% absolute increase and a 26% relative increase in high-grade prostate cancer (Gleason score 7-10), of which 75% of the increase was in Gleason 8-10 cancers.
REDUCE Trial
In the randomized, placebo-controlled, international, four-year REDUCE trial of 8,000 men at increased risk of prostate cancer, men on dutasteride had a 23% lower risk of being diagnosed with prostate cancer than men in the placebo arm. The risk reduction was limited to a decrease in Gleason score 6 or 5 prostate cancers, with no decrease in Gleason score 7-10 cancers. There was a marked increase in Gleason score 8-10 prostate cancers with dutasteride (16 vs. 32 using current Gleason scoring criteria).
In presenting the FDA's concerns about finasteride for prostate cancer chemoprevention, based on PCPT results, Marc Theoret, MD, Medical Officer in FDA's Division of Biologic Oncology Products, cited the increased risk for Gleason 7-10 tumors; risk reduction limited to Gleason score 6 or below tumors; and whether the results could be considered generalizable to the US population of men.
For example, scheduled end-of-study prostate biopsies to detect prostate cancer are not consistent with clinical practice. He also noted that while African American men have a much higher incidence of and mortality due to prostate cancer than white men do, less than 4% of men in this trial were black.
Dr. Theoret also pointed out that the most common adverse events from finasteride use can be very troubling to patients: erectile dysfunction; loss of libido; and gynecomastia.
Yang-Min Ning, MD, PhD, Medical Officer in FDA's Division of Drug Oncology Products, presented the FDA's concerns about dutasteride for chemoprevention. He said the 23% risk reduction in the REDUCE trial was almost entirely limited to Gleason Score 6 or under tumors, and that only a minority-some 20%-of these tumors "may be clinically important."
He asked, "Is this risk reduction clinically meaningful for prevention?" Only 2% of enrolled men in REDUCE were African American, which he cited as another concern; no risk reduction was detected in black men in the study.
Dr. Ning said the increase in high-grade tumors in REDUCE was another concern. He estimated that if approximately 200 men were treated with dutasteride for four years, there would be one increase in high-grade Gleason score 8-10 prostate cancer. On the other hand, he estimated that approximately 60 men would need to be treated with dutasteride for four years to reduce one possibly clinically meaningful prostate cancer.
The Crux...
To date there are very little data on what happens to men who develop high-grade prostate cancers while taking finasteride or dutasteride. "The crux for this part of the argument is what happened to these men [with high-grade tumors] afterward?" said ODAC member and OT Clinical Advisory Editor Mikkael Sekeres, MD, MS, Director of the Leukemia Program, Cleveland Clinic Taussig Cancer Institute, and Chair of the Hematology/Oncology Pharmacy & Therapeutics Committee.
"Within the context of approving a drug like this, we have to assume they're going to have the natural history of other high-grade tumors; we cannot assume they're indolent," said Dr. Wilson. He added, "All we can do is go with what we have." Dr. Scardino pointed out that Gleason scoring, along with PSA, has been one of the most powerful prognostic factors in prostate cancer.
"GSK is not proposing that dutasteride be used for every man over 50 with a rising PSA," cautioned Anne M. Phillips, MD, Vice President and Medicine Development Leader for Oncology Research and Development at GlaxoSmithKline. But, she said, today "Men are getting aggressive surgeries that might be avoided."
She pointed out that dutasteride has a long history of use for symptomatic benign prostatic hyperplasia [BPH]-since 2001-with a good safety profile.
"Why has the medical community not embraced widespread chemoprevention with finasteride or dutasteride?" asked Dr. Scardino. Because, he said, the studies that explain away the apparent increase in high-grade cancers with 5 alpha-reductase inhibitors are complicated; it seems excessive to have every 55-year-old man take a pill every day for 20 years to reduce the chances of being diagnosed with prostate cancer from 16.7% to 12.5%; and because physicians and patients worry about costs and side effects.
On the other hand, he said, these drugs are generally safe and their side effect profile well understood; Dr. Scardino suggested that they could be given to a subset of men (20% to 40%) at increased risk of prostate cancer as determined by serum PSA levels (greater than 1.3 or 2.0 at age 55-60) "with almost as much benefit as treating all men this age."
Dr. Scardino also noted that the limitations of PSA (low specificity, variability over time and between assays, a poor ability to distinguish indolent from aggressive cancers) "has led to over detection of cancers that pose little threat to health or life."
Dr. Walsh urged ODAC members not to recommend 5 alpha-reductase inhibitors for chemoprevention of prostate cancer. "For the patient who is worried about dying from prostate cancer, treatment with a 5 alpha-reductase inhibitor is the last thing he should do," said Dr. Walsh. "It does not prevent the disease but gives him the false sense of security that it does and in doing so may delay the diagnosis until he has aggressive disease that may not be curable."
GlaxoSmithKline's Dr. Phillips expressed disappointment with the ODAC vote on dutasteride in a statement given to the news media following the meeting. "We are disappointed by the Oncologic Drugs Advisory Committee's conclusions and will work to address any questions as the FDA completes its review of the supplemental New Drug Application," she said.