An article published today in the New England Journal of Medicine and based on a re-visitation of data from the Prostate Cancer Prevention Trial (PCPT) suggests that finasteride may prevent as many as 30 percent of cases of low-risk prostate cancer without any increase in mortality.
The new paper by Thompson et al. looks at follow-up data from the original PCPT study at a median of 18 years after the initiation of therapy with either finasteride or a placebo.
Here is the quick summary of the updated findings:
- 18,880 eligible men were randomized to treatment with finasteride or a placebo.
- Prostate cancer was diagnosed in
- 989/9,423 men in the finasteride group (10.5 percent)
- 1,412/9,457 men in the placebo (control) group (14.9 percent) in the placebo group
- The relative risk for a diagnosis of prostate cancer in the finasteride group compared to the control group was 0.70.
- Of the men who were evaluated,
- 333 men (3.5 percent) in the finasteride group had cancer with a Gleason score of ≥ 7.
- 286 men (3.0 percent) in the conntrol group had cancer with Gleason score of ≥ 7.
- Of the men who died,
- 2,538 were in the finasteride group.
- 2,496 were in the control group.
- The 15-year survival rates were
- 78.0 percent for men in the finasteride group
- 78.2 percent for men in the control group.
- The unadjusted hazard ratio for death in the finasteride group was 1.02.
- For men with Gleason scores of ≤ 6, the 10-year survival rates were
- 83.0 percent in the finasteride group
- 80.9 percent in the control group
- For men with Gleason scores of ≥ 7, the 10-year survival rates were
- 73.0 percent in the finasteride group
- 73.6 percent in the control group
Thompson et al. conclude as follows:
Finasteride reduced the risk of prostate cancer by about one third. High-grade prostate cancer was more common in the finasteride group than in the placebo group, but after 18 years of follow-up, there was no significant between-group difference in the rates of overall survival or survival after the diagnosis of prostate cancer.
There are two excellent discussions of all the relevant issues related to these new data on “All Things Considered” on the NPR web site this afternoon. The first is an overview of the study results with commentary from Dr. Ian Thompson (the principal investigator for the PCPT). The second is an interview with Dr. Michael LeFevre, the vice chairman of the U.S. Preventive Services Task Force. Even Dr. LeFevre is willing to state that for those men who do want to undergo prostate cancer testing after an appropriate discussion with their doctor, these data do suggest that preventive therapy with finasteride is likely to reduce the risk of a diagnosis of prostate cancer with no apparent increase in risk for long-term mortality.
We will have more to say about these new data.
Filed under: Diagnosis, Management, Prevention, Risk | Tagged: finasteride, mortality, Prevention, risk, trial |
THE "NEW" PROSTATE CANCER INFOLINK 
Ian talked about this in one of our recent SWOG GU Committee meetings. It’s interesting news indeed. I was expecting to see something sooner. There is still concern, I think, for the higher rate of more aggressive tumors, but with OS being the same it makes you wonder if finasteride had any effect on those tumors as well.
STUDY SUPPORTS WHAT A LOT OF US THOUGHT AT THE TIME OF THE FDA HEARING
I’m really glad to see Dr. Thompson and his colleagues getting this vindication. I thought they did an excellent job explaining and supporting the reasons for the finding of a higher proportion of Gleason 8-10 disease in the finasteride group, but the advisory committee, buffaloed by Dr. Patrick Walsh and by aggressive chairmanship in my view, did not think the issues through clearly enough before voting, again as I saw it. (I watched the whole hearing via computer from my perspective as a patient with a once life-threatening case. I’m now at the 13.5-year point, and I have taken either finasteride or dutasteride continuously — and briefly both — for nearly 13 of those years as part of my intermittent triple androgen deprivation therapy with the 5-ARI continued as maintenance during the vacation periods.)
Apparently, as both sides more or less concurred at the hearing, finasteride did not have much effect on higher grade disease, especially Gleason 8-10 disease. Therefore, not much impact on lethality was expected, and this study bears this out with virtually identical figures for survival at 15 years.
I am no longer discouraged, as I’ve become more accustomed to ignorance where I once expected insight, to read a sentence like the following in the NPR commentary cited above: “It’s not clear why finasteride users who got higher-grade cancers didn’t die at higher rates.” Actually, it should be clear, though not conclusively proven: finasteride makes it easier to detect high-grade disease; therefore, more of the actual high-grade disease was detected in the finasteride group, while some was missed in the placebo group. This is a point that Dr. Thompson and his colleagues have thoroughly explained and emphasized repeatedly! Over time, the presumably very similar proportion of high-grade disease, which is mostly unaffected by finasteride as a stand-alone preventive agent, in both groups — the kind of disease that is usually the lethal variety — produced highly similar overall survival.
Just maybe the U.S. Preventive Services Task Force will prove to have been enough impressed to revisit their poorly analyzed recommendation to essentially oppose screening for prostate cancer.
A company called Nymox claims to be testing a drug that is injected into the prostate about once every 7 years for the treatment of BPH. They claim it is more effective than either of the oral treaments (including finasteride) for BPH, without any of the side effects They also claim to be testing it as a treament to prevent the growth of indolent prostate cancers.
I tried finasteride years ago for BPH, but hated the side effects. I hope Nymox is actually onto something (but I do have some reason to be sceptical … they have been working on this for years with no published papers or data).
Dear Doug:
We last reported on the potential of the Nymox product (NX-1207) in prostate cancer a little more than a year ago. Click here.
FDA SHOULD REOPEN CONSIDERATION OF 5-ALPHA REDUCTASE INHIBITOR (5-ARI) DRUGS (FINASTERIDE/PROSCAR, DUTASTERIDE/AVODART) FOR PREVENTION OF PROSTATE CANCER
I just finished reviewing the FDA’s “Quick Minutes” of the December 1, 2010 hearing by the Oncologic Drug Advisory Committee regarding the issue of 5-ARI drugs for prevention of prostate cancer. It is a short, 7-page document that captures only the highlights of the hearing. There were two decisions at issue for which the FDA was seeking the recommendation of the committee.
The first decision at issue was whether to revise labeling for finasteride to include added information in the “Clinical Studies” section of the information sheet that, in the FDA’s words, “could be interpreted to suggest that finasteride is safe and effective for the risk reduction of prostate cancer in otherwise healthy men age 55 or older.” The second decision at issue was whether to approve a new use for dutasteride (Avodart) “for reduction in the risk of prostate cancer in men at increased risk of developing disease, defined as those who have had a prior negative biopsy due to clinical concern and have an elevated serum prostate-specific antigen (PSA).”
The subject study led by Dr. Ian Thompson, published August 14, 2013 in the NEJM as described above, should satisfy one of the critical reservations of the ODAC committee voters who chose to turn down these issues by votes of 17 to 0 with 1 abstention for the first and 14 to 2 with 2 abstentions for the second. That critical reservation was that neither the Prostate Cancer Prevention Trial (PCPT, involving finasteride) nor the REduction by DUtasteride of prostate Cancer Events (REDUCE) Trial were of sufficient duration, with long-term follow-up needed. The subject study now provides much longer follow-up than was available at the time of the ODAC hearing.
The subject paper provides “up to 18 years follow-up” with projected Kaplan-Meier survival curves at 15 years, apparently, based on the study URL (haven’t had access to the full paper). (Participants were randomized between 1994-1997 for the PCPT, and survival status was assessed through October 31, 2011, allowing for a maximum of slightly under 18 and a minimum of 14 years of follow-up.) Based on the Quick Minutes, follow-up available to the committee was just 7 years. Thus, the subject paper more than doubles the follow-up available to the committee. It is worth noting the context of typical life span: a fairly typical age at diagnosis would be age 65, and adding 15 years would bring that age to 80. Thus, available follow-up data is documenting safety through at least what would be a fairly typical life span for an American man as of 2013!
Also key, of course, is the fact that survival data from this longer follow-up demonstrated equivalent survival for the two arms of the study, indicating that the higher proportion of high-grade disease in the finasteride arm did not cause poorer survival, which suggests strongly to me that the explanation of superior detection due to finasteride was the likely cause of the higher proportion of high-grade disease detection, which is the contention maintained for years by Dr. Thompson and colleagues.
Both the longer survival and the reassuring outcome, using a hard, objective, survival endpoint, should be persuasive at an ODAC hearing to revisit the key issues, at least regarding the follow-up and high-grade issues.
There were other concerns, such as potential overly wide use should the approved indications or labeling for finasteride and Avodart be expanded, with their cost impacts and potential health impacts regarding side effects, and use outside the indication requested for approval, with its cost impact. For instance, would there be wide and low-value use by men with no negative biopsy and/or no rising or elevated PSA? These other concerns would remain issues for discussion.
My view as a now savvy survivor, but with no enrolled medical education, is that wise use of 5-ARIs should be approved in the current prostate cancer management environment in the US, an environment where a large majority of men who are diagnosed with low-risk cases appropriate for active surveillance still forgo that wise option and instead choose treatment, with its large cost impact and likely burden of some side effects. For such men, finasteride and dutasteride would prevent a substantial proportion of low-risk cases that would otherwise lead to biopsies and often treatment.
Hi Jim … Much as you may want the FDA to do this, I very much doubt that it will happen. But it is perfectly acceptable for any physician to prescribe either of these drugs off label for this indication. Finasteride is available as a generic drug and is hardly expensive. Dutasteride will be available as a generic drug relatively soon too, I believe.
On the other hand, as Dr. Scardino is quoted as saying (on the New York Times “Well” blog today), the new data “could also pave the way for more research into prostate cancer prevention and treatments for men with early-stage prostate cancer.”
A full report on this topic has just been published on the Medscape web site with input fro Dr. Eric Klein of the Cleveland Clinic, who is considered to be an expert of prostate cancer prevention.
Sitemaster, thanks as always for your comments. I’ll admit to some pessimism about another FDA review too, but from a merits standpoint, it should happen.
I just looked at that well-done report at the Medscape site. I was amused, in a jaded way, that the head of the US Preventive Services Task Force is still trotting out their old line.
“For men who choose regular prostate-cancer screening, the use of finasteride meaningfully reduces the risk of prostate cancer and thus the morbidity associated with the disease,” Dr. LeFevre writes.
The drug may reduce the harm of screening, he concludes.
“Of course, another way to reduce the harm of screening is to choose not to be screened,” he adds.”
He failed to state that choosing not to be screened also eliminates vital advance warning for men with high-risk disease (like me). That strikes me as grossly irresponsible! He needs to reverse course and apologize to the community of patients with serious prostate cancer!
Although Dr. Thompson has done an excellent job presenting this update, some additional analysis is needed.
Although there was a 30% reduction in detection and no increase in mortality so far from the men diagnosed with higher grade cancers, I still think there is a problem. First, in the PLCO screening trial, the overall cancer detection rate was about 7.5% — but in the PCPT trial control group, it was about 14.5%. The group getting the drug dropped down to about 10% but even so it means that almost twice as many men were diagnosed compared to a routine screening program. The reason was that a biopsy was part of the end of study protocol. So taking the drug greatly reduced the incidence of a positive biopsy, but even taking the drug still resulted in many more cancers that would normally be detected in a screened population. The added increase in cancer was primarily those that would never be life threatening. Had biopsies not been mandated, the reduction in cancers detected by taking the drug is likely to have been much lower. Although survival was not affected, the authors acknowledge that mortality could have been higher by 27%, so it is not conclusive that safety was not affected. We also know nothing about the quality of life or the treatments incurred by the men with higher grade cancer as that would offset some of the potential benefit of a lower detections rate. In the end, I doubt the FDA will give approval for this indication despite these results and still there is reason to be concerned about the net benefit vs. harms.
PC DETECTION RATE ISSUE: PLCO AT 7.5% VS. PCPT CONTROL AT ABOUT 14.5%
Hi Dr. Chodak, and thanks so much for joining this discussion. You raised the subject point in your post of 8/16 11:06 am. I’m looking for an explanation why the PCPT rate of prostate cancer detection is about double the overall rate in the PLCO trial.
Here is one significant difference, and I’m trying to grasp how much of the difference in rates this might explain. In the PCPT control group, men received annual PSA tests and DRE exams. In contrast, while there were annual PSA tests and DRE exams in the PLCO screening arm for a number of years, but in the control group (usual care) there was only 40% screening in the first year, which increased to 52% in the sixth year, with DRE screening in the control group ranging from 41% to 46%.
It seems logical that more intense screening in the PCPT would explain some of the higher detection rate.
Jim:
You appear to have missed one of Dr. Chodak’s key points … that in the PCPT every patient in the trial (unless he actively refused) underwent a prostate biopsy at the end of the 7-year period on drug or on placebo. This was true regardless of whether the patient had any indication of need for a biopsy based on his PSA level or his DRE data. I had completely forgotten this.
Still struggling with this. I see that your thought at 5:24 pm, echoing Dr. Chodak’s earlier observation, fits here, and I’ll put my understanding of this in a second paragraph below. But would add a second reason for explaining more diagnosed cases in the PCPT than in the PLCO:
(1) annual PSAs and DREs in the PCPT but not in the PLCO, at least for the control (usual care) group;
(2) a mandated end of trial biopsy in PCPT but not in PLCO?
Both (1) and (2) would seem to add opportunities to diagnose the disease, seemingly adding to the likelihood of more diagnoses in the PCPT simply due to the trial protocol.
Looking at another aspect, Dr. Chodak wrote: “Had biopsies not been mandated, the reduction in cancers detected by taking the drug is likely to have been much lower.” This is the biopsies “for cause” versus “mandated” issue, I believe, and I’m taking the main point here to be that in a real world/non-trial clinical situation many of those detections would not have occurred, both in the finasteride and in the control group. I believe this was looked at during the FDA hearing, with a table and analysis, but I do not recall the detail. It might have been Dr. Walsh who emphasized this point. Perhaps the idea was to look just at the “for cause” biopsies to see how diagnosis proportions between the groups looked on that basis, as “for cause” corresponds to the real world situation. If someone has that information at hand, it might shed some light on all of this. I believe it is in the FDA full transcript and document record of the hearing.
I’m taking the significance of this “for cause” conjecture to be that, if the conjecture is sound, the impact of taking finasteride on avoiding unnecessary treatment in real world conditions would be reduced.
This Swedish study also seems to say that finasteride does not cause an increase of Gleason 8-10 cancers (the third fairly recent study).
Not sure why Drs. Walsh and Moyad continue to insist that 5ARIs cause high-grade cancer.