Canadian Consensus Conference: The FDA decision on the use of 5ARIs

In late 2010, the U.S. Food and Drug Administration’s (FDA) Oncologic Drug Advisory Committee (ODAC) recommended against prostate cancer chemoprevention labelling for the 5-alpha reductase inhibitors (5ARIs). The ODAC met on December 1, 2010 to hear presentations from GlaxoSmithKline (GSK) and Dr. Ian Thompson (Merck) regarding dutasteride and finasteride.1 GSK was seeking a prostate cancer risk reduction label. Merck was not seeking a risk-reduction label, but rather a change in their product monograph. The FDA presented new, unpublished analyses of the data from the Prostate Cancer Prevention Trial (PCPT) and the REduction by DUtasteride of prostate Cancer Events (REDUCE) trial, as well as risk-benefit analyses unadjusted for detection-bias.2–4 The FDA asked the voting panel to consider whether the “real world” risk-benefit ratio was favourable for: Finasteride in men >55 years old with a normal digital rectal examination (DRE) and prostate-specific antigen (PSA) <3 ng/mL Dutasteride in men with an elevated PSA and a negative biopsy In discussing the real world risks and benefits of these drugs, panel members expressed concern that some men would take the drug without adequate follow-up. ODAC voted against recommending dutasteride for the prostate cancer risk reduction indication because, in the view of the ODAC members, the risk for an increase in high-grade tumours outweighed the benefits of prostate cancer risk reduction, given the potential for widespread use of this agent in the United States. The ODAC recommended against prostate cancer chemoprevention labelling for 5ARIs (Table 1). Table 1. Results of the ODAC vote chemoprevention On June 9, 2011, the FDA notified health care professionals that the Warnings and Precautions section of the labels for 5ARIs was revised to include new safety information about the increased risk of high-grade prostate cancer. This risk appears to be low, but health care professionals should be aware of this safety information, and weigh the known benefits against the potential risks when deciding to start or continue treatment with 5ARIs in the approved indication for benign prostatic hyperplasia (BPH). To review the FDA’s decision from a Canadian perspective, the Canadian Urological Association (CUA), with direction from Dr. Laurence Klotz, assembled a team of experts and a meeting was convened on November 20, 2011 in Toronto, Ontario. The objectives of the meeting were as follows: To review the FDA’s decision regarding the use of 5ARIs in prostate cancer prevention, specifically with respect to the increase in high-grade cancer. To develop a Canadian consensus statement based on expert opinion and review of the evidence, on the use of 5ARIs in prostate cancer prevention and BPH.3–9 The deliverables proposed by the consensus panel chair and the CUA Office of Education are as follows: (a) To prepare a Canadian statement on the use of 5ARIs in prostate cancer prevention, which reflects a broad consensus of academic and community practitioners, and primary care physicians with an interest in prostate cancer; (b) To publish this statement as a peer-reviewed article in CUAJ; and (c) To produce a patient brochure, which reflects this Canadian consensus. Meeting participants were provided with all pertinent data, a description outlining the meeting objectives, expected outcomes and presentations and three position statements for voting (Appendices 1–4). After an introduction and review of the positions by Dr. Laurence Klotz, participants were asked to vote on the three positions prior to the initiation of discussion. After the initial vote, 7 presentations were made to the group: A summary of the ODAC hearing and the FDA position: Laurence Klotz and David Penson Personal take on the ODAC hearing as a participant: Howard Parnes Pathology issues/Gleason scoring system: Linda Sugar The CCO position on risk reduction of prostate cancer: Neil Fleshner The modelling of cytoreduction and PSA effects: Eric Klein The link between the FDA decision and the United States Preventive Services Task Force (USPSTF) screening decision: Laurence Klotz Implications for use of 5ARIs in surveillance: Tony Finelli Key findings 1. Preliminary vote Attendees were given a ballot containing three positions (Appendix 1–4) and were asked to vote secretly. Position 1: The FDA Position (3 votes) Position 2: The “Pro” Position (3 votes) Position 3: The Middle Ground (6 votes) Expert Presentations a) David Penson: A summary of the ODAC hearing Dr. Penson reviewed the ODAC decision and the data that were presented. His recommended use of 5ARIs moving forward is: Continue to use 5ARIs for BPH with the following proviso: – Explain possible increased risk of high-grade prostate cancer to patients and DOCUMENT in chart – Closely monitor PSA kinetics after starting therapy – Unclear if you need to send a letter to your patients currently on 5ARIs Only consider 5ARI use for chemoprevention for men at increased risk of prostate cancer who are motivated to pursue chemoprevention – Explain to patient that it is off-label use and highlight the possible risks of treatment and DOCUMENT in chart – Closely monitor PSA after starting therapy and contact patient if he misses follow-up PSA mean scores or appointments to reschedule b) Howard Parnes: A personal take on the ODAC hearing as a participant Dr. Parnes also provided a summary of the decision-making process by the ODAC panel. Of note: - ODAC met on 12/1/2010 to hear presentations by GSK and Merck regarding dutasteride and finasteride, respectively. GSK was seeking a risk-reduction label Merck was not seeking a risk-reduction label - Merck stated that the post-hoc analyses addressing the observed increase in high-grade prostate cancer “did not rise to the level of a label.” - ODAC took the position that mortality reduction is the goal of chemoprevention - Burden of prostate cancer was not considered by ODAC - No weight was given to the possible role of detection-bias - The addition of the “real world” setting did not leave much choice for the panel to vote in favour of dutas-teride as widespread use has significant public health implications. The crux of the controversy is whether the observed increase in high-grade cancer in the two trials was an artifact caused by several unavoidable biases associated with the use of 5ARIs, or represents a true increased risk. If the latter, it is unclear what the mechanism for the increase in high grade cancer is.

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