For some 15+ years there have been subsets of patients and physicians who have believed strongly that adding a 5α-reductase inhibitor (5-ARI) like finasteride or dutasteride to an anti-androgen would quite certainly aid in the prevention of prostate cancer progression because such a regimen would reduce levels of dihydrotestosterone.
The so-called TARP trial was initiated in 2007 to test this hypothesis in men with non-metastatic castration-resistant prostate cancer (CRPC), and the trial was fully enrolled in 2009.
Men on first-line androgen deprivation therapy (ADT), i.e., receiving standard treatment with an LHRH agonist, were eligible to participate in this trial when they exhibited a rising PSA. Eligible patients were then randomized, in a double-blind trial, to one or other of two treatment regimens:
- Arm A: Additional treatment with an anti-androgen alone (i.e., bicalutamide 50 mg + a placebo) once daily for 18 months
- Arm B: Additional treatment with an anti-androgen + a 5-ARI (i.e., bicalutamide 50 mg + dutasteride 3.5 mg) once daily for 18 months
The patients who completed an initial 18 months on therapy could participate in a 2-year extension study. All central laboratory and study sites/monitors were blinded as to treatment category. The study’s primary end-point was time to disease progression (TDP) up to 42 months (defined as PSA progression from baseline or nadir, radiographic disease progression, death from prostate cancer, or receipt of rescue medication).
After 8 years we have a complete report of the study results (see Chu et al.):
- 127 patient were randomized to the trial.
- 65 men were randomized to Arm A.
- 62 men were randomized to Arm B.
- The estimated median TDPs were
- 425 days for men in Arm A
- 623 days for men in Arm B
- This difference in median TDP between the two study arms was not statistically significant (hazard ratio [HR] = 0.94; p = 0.79) — despite the 198-day difference in median TDPs.
- There were also no statistically significant differences between the treatment groups for any secondary efficacy end-points, including time to treatment failure or PSA response.
- In multivariate analysis, age, non-White race, higher baseline testosterone levels, and lower baseline PSA levels were associated with longer TDP.
- Adverse events were comparable between treatment groups.
The authors conclude that
In men with non-metastatic CRPC, adding dutasteride to bicalutamide did not significantly prolong TDP. Prospective data are provided concerning the common practice of using bicalutamide in this setting.
One might reasonably wonder how a 198-day difference — i.e., a 46.6 percent difference — in median TDP could not be statistically significant, … but it isn’t. Your sitemaster is not a statistician, but he suspects this has to do with the numbers of men in each arm of the trial (which is relatively low). You could reasonably ask why more patients weren’t enrolled into the trial. Your sitemaster suspects that it would probably have needed more than 1,500 patients to show a statistically significant difference in TDP … and that difference would still not necessarily have indicated a difference in median overall survival.
Is there a numerical difference in median TDP between the two study arms? Yes, there is. Do we know whether this difference is clinically meaningful after 8 years? No, we don’t. Can we tell you that there is absolutely no point in adding a 5-ARI to an anti-androgen and an LHRH agonist in the treatment of non-metastatic CRPC? No, we can’t. Can we tell you that you should add a 5-ARI to an anti-androgen and an LHRH agonist in the treatment of non-metastatic CRPC? Nope, we can’t tell you that either!
Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: 5-ARI, ADT2, ADT3, anti-androgen, castration-resistant, CRPC, non-metastatic, outcome, trial |
THE "NEW" PROSTATE CANCER INFOLINK 
At first blush … I think I would rather go half a year year without progression (20.76 months vs. 14.16 months).
Interesting.
When a 46% reduction in time to progression is not statistically significant, all one can conclude is that this is yet another poorly designed trial that tells us nothing other than the fact that we need better statisticians designing these trials.
If overall survival is the same in the arms the difference is insignificant. Same with disease-specific survival. I suppose the best person to ask is Dr. Chu? Oliver Sartor?
Unfortunately, statistics don’t really work like that, which is what the Sitemaster pointed out. Look at it this way … Based on the sample size used in this study, the range in progression time in the placebo group was 302 to 858 days with 95% confidence; the range in the group that got dutasteride was 369 to 730 days with 95% confidence. So the dutasteride group was well within the range of the placebo group. In fact, some in the placebo group were more likely to have longer progression times. All you can comfortably conclude is that based on this sample size, there was no difference. In fact, the odds are about 4 in 5 that the numbers are really the same. Could a difference show up with a larger study? Maybe. But considering the wide natural variance in men’s progression times, it isn’t likely.
Me, too, Jerry (and of course, Sitemaster has expected my post). The extra 6.5 months “as median” means many experienced much longer TDP, though granted many did not. I am surprised by the dutasteride/Avodart dosage of 3.5 mg when the medication is normally prescribed at only one 0.5 mg capsule per day. Makes one wonder if the “over-dosage” caused a different internal system reaction than if the normal dosage would have been prescribed in the trial. Having had excellent personal results with dutasteride as part of my over 18 years of continuing ADT/IAD, I naturally support its inclusion in ADT.
Some clarifications:
(1) It is actually somewhat unclear what the dose of dutasteride was that was used in this trial. In the abstract of the paper, it says 3.5 mg/day (which, as has been pointed out, is a very odd dose level). In the trial summary on Clinical Trials.gov it states 3.5 mg/d in one place and 0.5 mg/d in another. My suspicion is that the actual dose of dutasteride used in this trial was 0.5 mg/d. I will see if I can find out.
(2) The statisticians involved in the design of this trial were, in fact, extremely experienced. That doesn’t mean that anyone was willing to cover the costs of a trial that would have needed to enroll 1,500 patients and follow them for 15 years to see an overall survival benefit! Those who do the funding of large clinical trials have to make decisions about financial risks and benefits as well as clinical ones.
(3) Allen’s comments on the statistical strengths and weaknesses of this trial are precisely on target.
What makes this trial insignificant is its weak Phase IV design and a very high hazard ratio to go with an unfavorable P factor. It’s entirely possible the findings are chance. Mike you suggest 1,500 and I would suggest 15,000. In any case the findings could not be substantiated. The costs of a larger trial would also face the challenges on “Who” would pay for it.
Just another note: Since this trial started, there have been several novel agents approved that too may be able to be used in this setting with likely better chance of showing better TDP in the same timeframes.
I’d still like to see the overall survival and disease-specific survival data.
Tony, there was nothing wrong with the design of the trial as far as I can see — perhaps you can specifically point to any faults you imagine to be there? The hazard ratio is not “high,” it’s 0.94 — close to 1 — which means “no effect.” The high p-value shows that the hazard ratio is not significantly different from 1, not that the “trial is insignificant.” It tells us that there is such a wide natural variance in times to progression, that any possible benefit of the dutasteride is tiny by comparison.
The endpoint they used — time to progression — was completely appropriate. They did include death as one of several kinds of evidence of progression, but no one seriously thinks that dutasteride is going to have a survival benefit with CRPC. However, it had been hoped that intensifying the first-line androgen blockade with bicalutamide and dutasteride could extend the time before the bigger guns were brought out.
While there are two excellent new FDA-approved hormonal medications — Zytiga and Xtandi — they are currently only approved for metastatic CRPC, and their cost for off-label use puts them well out of reach for most people in the situation of non-metastatic CRPC. There are some clinical trials in which patients might be able to obtain them, but for the most part options are limited. Other options may include estrogen patches and ketoconazole.
There were very few deaths, I was told, and thus no data on overall survival.
Jerry:
This trial was never designed to be able to generate overall survival data. To generate such data one would have required much, much longer follow-up, as previously noted. And so, yes, the number of deaths in this trial remain very low.
Can someone please clarify what is meant by “metastatic”? Specifically, is extracapsular extension to bilateral SVs and regional lymph nodes considered metastatic, or is that still considered “locally advanced”? Thanks.
Dear Len:
There are two forms of metastatic prostate cancer. The first is the historic form, in which there is clear, visible evidence on a bone scan or a CT scan of prostate cancer that has metastasized to bone or to soft tissues like the lungs or the liver. (This is stage M1 disease). The second is the so-called “micro-metastatic” form which may only be visible on specialized scans like the choline-11 PET/CT scan or some types of specialized MRI or which may be suspected because of elevated PSA levels or CTC levels (or the presence of cancer cells in bone marrow biopsies) even though there is no actual visible evidence of spread of the tumor. (This is stage M0 disease.)
In clinical trials, the research teams usually specific exactly what they mean by “metastatic” in the details of the study protocol and in the reports of the trial results. Most commonly they are referring to the former, historic, descriptor. However, regardless of whether we are discussing M1 or M0 disease categories of metastasis, metastasis means very specifically cancer that is no longer localized to the prostate itself, or to the immediate, nearby tissues (e.g., the seminal vesicles or the prostate bed), or to the pelvic lymph nodes.
Sitemaster, Thank you for this clear, concise explanation.
Good news (I think), but well disguised
Allen, Sitemaster, Tony and other friends who are not impressed with the findings here, I understand your reasons. However, as a long time patient on IADT3 who has been following this technology and succeeding with it from nearly the get go of my diagnosis, I think these results are pretty impressive. That said, I’m not going to be able to convince skeptics. Here are the key facts
The intriguing result we all find interesting is the time to disease progression (TDP):
“The estimated median TDPs were
425 days for men in Arm A
623 days for men in Arm B”
The problems are in that unimpressive hazard ratio of 0.94 and the high p value, suggesting a result due to chance, of 0.79, where we would like to see a p value of 0.05 or lower.
Here’s how I see it.
ADT3 — using a drug (an LHRH agonist here) or orchiectomy to eliminate testicular production of testosterone, plus an anti-androgen to block remaining testosterone from latching on to androgen receptor, plus a 5-alpha-reductase inhibitor drug (finasteride or Avodart) to sharply reduce conversion of remaining testosterone to DHT — a far more potent fuel for the cancer, was awkwardly implemented in this trial, and that created a lot of “noise”.
First, neither of the second or third drugs was added until men were already deemed to no longer respond to suppression of testicular testosterone. That means that the group is a considerably more challenging group of patients that a “hormone ‘naive’ ” group, meaning a group that has never had any hormonal therapy. Therefore, it is likely that a naive group would show more of an effect than was shown here, and those I consider experts in ADT, especially ADT3, prefer to start it in hormone naive patients, believing that it does better when the cancer has not built up momentum.
Second, “noise” is introduced in this small study right at the beginning as the test for adequate suppression of testicular testosterone was a testosterone level of less than 50 (an eligibility criterion). In sharp contrast, the experts in ADT I follow have been convinced since at least 2000 that testicular testosterone suppression is likely inadequate unless the level is less than 20. Thus, if a patient is on Lupron but his testosterone is, say, 35, those doctors would look for either flaws in delivery of the medication or unusually rapid clearance of the drug, and they would ensure corrective measures were taken, such as decreasing the dosing interval. The significance of this for the trial is that some of the patients deemed to have disease that progressed with adequate suppression almost certainly really were progressing — increasing PSAs — because of inadequate suppression, but would not have been progressing with adequate testosterone suppression. In other words, they were healthier, more favorable patients than the others, but it is unknown in what numbers they appeared in each arm of the study, hence the “noise.”
Third, more noise is introduced because the trialists evidently did not gather and track testosterone and DHT levels for their patients. The experts I follow do that so they can adjust dosing (and even drug choice) for the typically significant percentage of patients with inadequate testosterone suppression or unusually high DHT production despite adequate T suppression. (Dr. Myers himself is an example.) For example, for patients with very high DHT, the anti-androgen dose might be increased to 150, or even higher. The experts have stated repeatedly that about 10% of the patients coming to them on ADT have inadequate testosterone suppression. Dr. Myers has stated, as I recall it, that about 10% of patients on Avodart (dutasteride) do not respond well to it, but do respond when switched to finasteride. Moreover, eventually, many patients on anti-androgens develop androgen receptor (AR) mutations, which involves the AR morphing so that it can use the anti-androgen as fuel, and my impression is that a small percentage do this fairly early on, which could have affected patients in this trial. Again, without monitoring testosterone and DHT and making appropriate medical adjustments, the doctor and patient are flying blind in a fog. In a small study, a 10% flaw here, another 10% flaw there, and the AR mutation flaw could well create substantial noise. I believe this has happened in this trial. A considerably larger trial would have tended to even out noise effects, but the best approach would have been to have stopped the noise at the outset. The protocol could have been designed to do that; it was certainly being done by some experts in their clinical practices, and they were far from shy in talking about their approach.
If substantial noise occurred, then the scatter of results around the “best fit line” would be amplified considerably, and that would erode the confidence level, despite the striking difference in the median time to disease progression. One could argue that this trial was not dealing with extra dosing of the anti-androgen or adjusting the frequency of LHRH-agonist treatment, etc., but I will argue that it should have been! Some of us are not eager to have oncologists who use a one-size-fits-all, paint-by-numbers approach. Since this trial did not make appropriate, reasonable adjustments for patient circumstances, to me the results mainly prove that inadequate ADT leads to inadequate results (the high hazard ratio and probability of a chance result), which is not news. At least, not news to some of us!
All this said, I’m glad that Dr. Oliver Sartor and his colleagues executed this trial, using their best judgement with an approach that was not yet credible to them. That’s always a dicey proposition, and I thank them for trying. Despite the flaws, that difference in the median time to progression will hopefully capture the attention of patients and doctors!
Dear Jim:
As I have told you before, no one is saying that there aren’t some men (you apparently included) who appear to respond extremely well to ADT3 and IADT3.
However, as you appear to concede, that doesn’t mean it is a viable therapeutic approach for the majority of patients. What you are saying is that if you narrow the eligibility criteria (a lot) you might see much better results in trials of ADT3 and IADT3 in men who have lower testosterone levels when they become castrate resistant. That may well be true. However, the definition of castration resistance is a rising PSA in a man with a serum T level < 50 ng/dl.
Regardless of your opinions, they do not invalidate the results of this trial. And Allen, Tony, and I aren't "disguising" anything. I find that comment personally offensive. The information we provided is factually accurate. The information you are providing is speculative.
I would also point our that you are extremely selective in your definition of an "expert" in the treatment of late stage prostate cancer. There are a lot more experts in the treatment of late stage prostate cancer than the few who support your perspective — Dr. Sartor and his colleagues explicitly included.
It is actually very easy to design trials that are likely to produce positive results in very highly selected groups of patients. Carrying those trials out in a meaningful manner and paying for them is a whole other issue. None of the experts you refer to have ever done that successfully with respect to ADT3 or IADT3.
In a recent study there was some debate about taking drugs like Avodart in the off period of hormone therapy because it might speed up resistance. Can we learn anything from this study with regards to this? Or is this apples and oranges?
Anecdotal I know, but I know a lot of guys like Jim doing the IHT and ADT3 thing and seemingly responding well. I just wish that someday a drug or therapy would be introduced that would trump all these different ways we combat advanced prostate cancer. It seems there are so many ways to patch the leaking lifeboat. Each guy has different size rafts, different size holes, different bodies of waters, and several different sets of tools to stop the water from gushing in. I’d prefer to have the one tool (or combination of tools) to stop the water permanently. (OK, I’ll admit it…I just saw the movie, “Unbroken”.)
Hi Sitemaster, and others who may have been offended when I meant no offense. My phrase “well disguised” was meant to refer to the results — not your comments or those of other contributors. I seem to be constantly short of time, but I will try to find some to elaborate on that, specifically on the impact of a few inadequately managed cases (the inadequate suppression and blocking issues, etc.) on the p value.
Regarding expertise, I regard Dr. Sartor in the foremost rank in addressing very advanced cases, but not so much when it comes to ADT with drugs approved for all prostate cancer patients. As a patient with a particular experience over 15 years, I believe there are experts in ADT; I believe this perceptive set of doctors, who communicate a lot with each other, came across a highly effective way of treating a large proportion of prostate cancer patients and have refined that over the years. My hunch is that the proportion who will benefit is a large majority, when properly managed, but with some exclusions, such as those with very low testosterone at the outset and men with small cell and endometrial prostate cancer. I’ll see if I can add some points to support that in coming days.
Dear Jim:
By defining “experts in the use of ADT” as physicians who believe in the value of intermittent ADT, ADT3, and intermittent ADT3 in “a large proportion of prostate cancer patients” (i.e., those who you agree with), you are demonstrating a very clear form of bias, which you then use to justify what you admit to be a “hunch”.
All that I am saying is that if we are ever going to resolve this issue, then it has to be based on at least one large, high quality, randomized, double-blind trial — probably in men with TxN+M0 disease, with time to clear evidence of metastatic disease as a primary endpoint. Nothing else is ever going to successfully change practice. All the speculation in the world is meaningless by comparison. So go and get your group of “experts” together and tell them that you need them to stop standing on their principles and work with others to get a real clinical trial done that is designed to test a well-defined hypothesis in a large enough, and well-stratified group of patients. It’s not as though this isn’t an interesting clinical question!
You have made the “points” that you believe in over and over again. Repeating them actually doesn’t help anyone any more. We need actual clinical data from a trial you and your experts consider to be viable — and which others who may be more skeptical are willing to work with them to test. I promise you that I for one would encourage enrollment in such a trial, but absent such a trial there is increasingly limited clinical justification for ADT3 or IADT3 in the majority of patients.
Jim,
Reading your posts and your desperation to make a “silk purse of of a sow’s ear,” it occurs to me that you never learned how to assess medical evidence. I hear this a lot in my support groups — how do we deal with conflicting data from various studies? Researchers have agreed that there are “levels of evidence” — we are increasingly confident in higher level studies. At the top (level 1) are prospective, randomized, controlled trials like Sartor’s or the recent one by Klotz — still better if they are confirmed by several such studies.
Level 2 studies consist of cohort studies among a well-defined population, or case-control studies where a post hoc attempt is made to match the patients to similar people, or just a large number of case reports. Sometimes these are compared to historical controls. Because there is no randomization, there is always the potential for selection bias.
Level 3 studies consist of observational studies, questionnaires, case reports, ideas, editorials, and expert opinions. And below that, we have animal studies and lab studies.
The point is that we rely on higher levels of evidence. They are more expensive and take more time to come by, but once we get them, we can put aside the lower levels of evidence.
There may be “increasingly limited clinical justification for ADT3 or IADT3 in the majority of patients”, but it would surely be valuable information to know why several guys like Jim have been very successful with this approach. 15 years is a very long time to be on IHT. We should be asking Jim to fill out all sorts of forms and learning from his experience.
What is it with these subsets of patients that seemingly makes this a very effective form of therapy. I’m hoping the common thread is that all of these men’s name begin with the letter “J”.
Jerry:
Just as there are men with very aggressive forms of disease that we don’t seem to be able to do much about at all, there are men with very different types of prostate cancer whose cancer appear to respond well to all sorts of odd therapy combinations that other men won’t respond to for long at all. If we knew why, we could do something rationale about it … but we don’t know why … and although Jim’s 15 years may seem to be a long response time, I would point out that he is far from unique, and that there are other men who have responded well to much simpler forms of ADT for 15+ years. (Alas, not all their names begin with a J, however.)
Regarding The Need for Evidence From a Trial of ADT3/IADT3 – We Tried – May Be Academic Now
Hi Sitemaster,
I’m responding to your response to me of June 16, 2015 at 9:13 am with the following key text: “… All that I am saying is that if we are ever going to resolve this issue, then it has to be based on at least one large, high quality, randomized, double-blind trial — probably in men with TxN+M0 disease, with time to clear evidence of metastatic disease as a primary endpoint. Nothing else is ever going to successfully change practice. All the speculation in the world is meaningless by comparison. So go and get your group of “experts” together and tell them that you need them to stop standing on their principles and work with others to get a real clinical trial done that is designed to test a well-defined hypothesis in a large enough, and well-stratified group of patients. It’s not as though this isn’t an interesting clinical question! … We need actual clinical data from a trial you and your experts consider to be viable — and which others who may be more skeptical are willing to work with them to test. I promise you that I for one would encourage enrollment in such a trial, but absent such a trial there is increasingly limited clinical justification for ADT3 or IADT3 in the majority of patients.”
My response: I’ll readily admit to that bias you mention (dramatic personal experience does grease the skids toward over generalization), and I’ll agree that it may be blinding me to appreciating reality, though I believe that is not the case. However, it’s tough for any of us to see beyond our blinders if they exist, and that applies to the research community that is not interested in a trial as well as to me, and to you of course. I’ll acknowledge that I may be wrong. However, I do try hard to stick to facts and logic, and I hope my earlier post reflected that.
Regarding trials of ADT3, I recall an audience question relevant to such possible trials that was directed to Dr. Sartor at the International Conference on Prostate Cancer 2006 (produced by Dr. Charles (Snuffy) Myers’s Foundation for Cancer Research & Education, with Us Too as the co-producer, a rare year in which PCRI was not a major player in the nearly annual conference series that is essentially to benefit patients). Dr. Sartor had been a fairly regular presenter at these conferences and was well aware that he was among doctors who were prominent advocates of ADT3 in contrast to his own position; he was unconvinced of the worth of ADT3. At previous conferences led by by Dr. Stephen Strum, MD, another prominent pioneer of ADT3, Dr. Sartor had been a key presenter — helping summarize Saturday’s talks in 2000 with Dr. Strum, including Dr. Strum’s talk in which he reported his practice’s stunning ADT3 results versus ADT2, and Dr. Sartor had also been a presenter at the conference. At this more recent conference in 2006, there had been plenty of attention to ADT3. Dr. Mark Scholz, MD, one of the leading pioneers of ADT3, had given a talk listed in the agenda as “Triple Hormonal Blockade With Proscar Maintenance.” The role of Proscar (finasteride) had been highlighted and Avodart (dutasteride) also addressed. Dr. Charles “Snufffy” Myers, MD, a prominent proponent of ADT3 who had been on that therapy himself as part of treatment for his own challenging case, had spoken on “second line” ADT. Moreover, Drs. Sartor and Myers were and are good friends, Dr. Sartor having worked under Dr. Myers’ direction when they were together at the NCI for several years. This sets the stage for the audience question to Dr. Sartor on ADT3.
For those interested, the question, though difficult to hear as the DVD recording system did not pick up the audience microphone well, starts at the 44th second of the 18th minute of the second hour (1:18:44) of Dr. Sartor’s talk (Disc FCRE06-110) on “Novel Approaches to Bone Metastases.” Dr. Sartor’s answer is quite audible. Here is the verbatim exchange which I transcribed last night from the DVD:
Question: “There is a difference between you and Snuffy regarding triple hormonal blockade. I understand that at the big university centers triple blockade has not gotten much resonance. Is that your impression, or could you go into that?”
Dr. Sartor’s answer: “Sure. We have to separate data from opinion, and I think the opinions on triple blockade cover the gamut. The data on triple blockade is fairly limited. There are no controlled trials, so you have to make conclusions regarding single arm data. Now the thing that makes that particularly challenging is that if you look at prostate cancer patients, they’ve evolved pretty dramatically over the years. And it used to be that hormonal therapy in a metastatic disease patient would work for about 9 months, and there were good studies that indicated that about 9 months was what you got. Well there are now studies in the PSA rise population, post radical — this is data out of Memorial Sloan Kettering — that the average response to hormones in that setting –- and this in a wide variety of hormones, either Lupron, Zoladex or various combinations — that the average response to therapy is 10.7 years. So it’s hard to evaluate data in the absence of controls. And so that’s the reason why there is a diversity of opinion. By the way, whenever you find diversity of opinion, what it means is the data allows more than one interpretation. And things are not subject to a great deal of discussion or disagreement if it’s clear. I mean everyone believes that Taxotere prolongs survival because we have two randomized trials that show it. That’s beyond the discussion point. Now we’re trying to figure out what do we add to Taxotere? What do we do when Taxotere fails? But the debate moves as the data moves, and that’s the reason there is more debate than you anticipate.” (time: 1:21:10)
The date of the question and answer was October 22, 2006. A half-year later in May the TARP trial had been registered on ClinicalTrials.gov, with enrollment actually starting in April, with Dr. Sartor playing an important role. As you may have guessed, I was the one who asked that audience question, so I have been eagerly awaiting results of this trial. Clearly I was not its father, but I may have contributed to the gleam in the eye of Dr. Sartor. I have tried on numerous occasions to motivate other researchers to put ADT3 to the test, but outside of possibly influencing the TARP trial I have seen no signs of success for anyone trying to get such a trial started. Drs. Strum and Scholz also tried, actually submitting a protocol to at least one prospective sponsor prior to 2000 by my recollection, but their trial was not accepted. (I have a copy buried somewhere in my files.) So it’s not as if we proponents have not tried to motivate a trial of ADT3/IADT3. There clearly has been resistance in the medical and pharmaceutical community, and sources of some of that resistance are likely economically but not patient friendly. I appreciate Glaxosmithkline for funding this study, which involved its product Avodart (dutasteride).
All this said, the question whether ADT3/IADT3 is effective is fading, at least somewhat, in prominence as newer, more potent drugs come closer to availability to the hormone sensitive/non-metastatic population of prostate cancer patients. Dr. Myers has said he has already moved toward some of these drugs for such patients, including off-label use as I recall his remarks, such as degarelix plus Xtandi. (My recollection of this example may be faulty here; I have not checked documents.) I’m not sure about the role of 5-ARI drugs (finasteride, dutasteride) to support such advanced combos. There is reason to suppose that the 5-ARI drug would be superfluous and therefore not beneficial with such combos, but that remains to be demonstrated.
Jim:
Thank you for continuing to make the point that Dr. Sartor and I have been making for most of the past decade or more. There are absolutely no compelling Level 1 or Level 2 data from any form of randomized trial that support a survival benefit for ADT3. Drs Strum and Scholz might have got their original trial concept approved back in (I think) about 2002 if they had actually involved people like Dr. Sartor in the development of the trial concept.
Again, I have never said ADT3/IADT3 may not work for some men. … All I am saying is that there is no evidence at all that it is an appropriate treatment strategy for most men with progressive prostate cancer, and no one can tell us clearly how to select appropriate patients in whom it might be reasonably expected to work better than ADT1 or ADT2.
Levels of Evidence and Evidence for ADT3/IADT3
Hi Allen,
I’m responding to your response to me of June 16 at 12:59 pm regarding evidence and medical decision making.
I am very glad that you are contributing regularly to the New Prostate Infolink blogs and have learned a lot from your excellent articles. That said, there are a couple of very important aspects of clinical trials that you may want to consider and take on board. I am very short of time this weekend (and most days since my wife’s stroke), but here is a thought challenge that leads into the first point, and I’ll try to follow-up in a few days: What do these men and their associated accomplishments have to do with your discussion: Ignaz Semmelweis and childbed fever; Louis Pasteur and rabies, anthrax, and the germ theory of disease; Robert Koch and tuberculosis and cholera; Edward Jenner and smallpox; and Walter Reed, Carlos Finlay, and colleagues versus yellow fever?
The Answer to the Question Posed in Post of June 21
All of these doctors listed in the June 21 post are associated with major breakthroughs in medicine, but NONE of these doctors based their breakthroughs on the kind of Phase III, randomized and placebo controlled, double-blind, large clinical trial that is now considered to be essential proof for medical effectiveness! How fortunate that they were not ultimately disregarded by the medical world! (However, there was fierce resistance at the time in the medical community to what each was doing and their conclusions. Sound familiar?)
Indeed, in our modern medical world many physicians will not accept a medical strategy unless it is supported by clear and favorable results under such a Phase III, randomized, etc. trial. Indeed, an unfortunate corollary is that many physicians will accept results from such a trial even if the trial is seriously flawed. (The medical community’s reaction to the egregiously and all too obviously premature and flawed results of the ERSPC and PLCO trials regarding screening for prostate cancer as originally reported in the New England Journal of Medicine is a most pertinent case in point!)
As someone who in 2000, for my own life-threatening case, had to evaluate the quality of evidence behind ADT3 in the absence of the kind of trial we would all like to see, I have come to realize that such trials should not be an essential, “sine qua non” requirement for use of a medical strategy. As desirable as such trials are, in certain circumstances I am convinced it is reasonable to lean on other evidence and our own ability to think our way through that evidence to maneuver around some of the evidence pitfalls that well-done Phase III trials help protect us against. I have had the good fortune to become familiar with much of that “other evidence” from doctors who pioneered ADT3/IADT3. While there is variation in the quality of their evidence (some excellent, some a bit shaky), what they have done as a group strikes me as similar to the evidence supporting the wonderful breakthroughs in medicine mentioned in that June 21 post that appears above.
This post is a prelude to a fresh look at the TARP study, which gives up most interesting evidence when the full paper is analyzed.
That said, while I feel even more confident after the TARP paper in advocating well-done ADT3, especially well-done intermittent ADT3 for appropriate patients, I acknowledge Sitemaster’s sound judgement that even advocates are not in a position to be conclusive about the worth of ADT3/IADT3 in the absence of a well-done Phase III clinical trial. I’ll close with a paradox related to successful implementation of a proving trial: the doctors who are in the best position to run such a trial cannot because they have seen such convincing success of ADT3/IADT3 that it would be unethical for them to put their patients into a placebo arm; in contrast, the doctors who have not gained experience in well-done ADT3/IADT3, and therefore do not face the ethical problem, seem to have substantial problems in achieving well-done ADT3/IADT3, as evidenced in the TARP study. I’m not criticizing the TARP trialists as cancer doctors; they impress me as fine physicians. It’s just that their experience has not extended to well-done ADT3.
A FRESH LOOK AT THE TARP STUDY RESULTS REGARDING ADT3
The complete paper by Chu, Sartor and colleagues offers intriguing indications that ADT3 was more much successful than the abstract suggested, especially more successful than suggested in the lines of the abstract that “There was no statistically significant difference in TDP [Time to Disease Progression] in 127 men treated with bicalutamide/dutasteride (n-62) compared with bicalutamide/placebo (n-65) (hazard ratio (HR) = 0.94 …” and that “There was no statistically significant difference between the treatment groups for any secondary efficacy end-points, including time to treatment failure or PSA response.”
There are several reasons for this fresh encouragement:
– The two arms were clearly not equal in risk, with the dutasteride arm having notably higher risk patients consistently across a set of measures. (This outcome probably was aggravated by randomization by center for this multi-center study; I’m thinking this would not have been a problem if the study had been much larger.) This inequality means we should give added emphasis to the success achieved in the ADT3/dutasteride arm as that arm contained higher risk patients from the outset.
– The kind of ADT3 employed (first the LHRH-agonist/orchiectomy only, followed by the full triple combination after the LHRH-agonist/orchiectomy was no longer suppressing PSA) was bound to be less effective than the kind of ADT3 regularly used by the doctors who pioneered use of and now advocate ADT3/IADT3 (all three elements of ADT3 used at the outset).
– The threshold for “castrate resistance” used in this trial was a testosterone level of <50 ng/dL, which is widely used in research, but is considered far too high by the pioneers of ADT3, who want a testosterone of about 20 ng/dL, hopefully less, before they will consider the patient truly resistant (and that is in the context of adequate DHT suppression). The pioneering doctors will use corrective maneuvers, such as shortening the LHRH-agonist administration interval, to get the testosterone below 20. Once that happens, many patients no longer appear resistant. Apparently corrective maneuvers were not permitted or used in the trial, though I would like this confirmed. In fact, a large proportion of patients in the trial had “testosterone breakthrough”, which here meant the testosterone increased to 50 ng/dL sometime during the trial. That appears to my now savvy layman’s eyes as clear evidence that the LHRH-agonist was not being effectively employed. In the second column of page 8 of the electronic copy of the paper, we learn that about twice as many men in the dutasteride/ADT3 group experienced that breakthrough, which, while understandable due to the role of dutasteride under sub-optimal management, clearly was an artificial, avoidable disadvantage to the opportunity for the dutasteride/ADT3 group to prove successful. (Incidentally, the study uses swaps units, e.g., ng/dL and nmol/L, for the same measurement at different points in the text, which needs to be understood to avoid confusion.)
– The pioneers of ADT3 have regularly tailored management of ADT3 to their patients, based mainly on a few kinds of tests, rather than using the one-size-fits-all approach employed in the TARP trial. It is a virtual certainty that such tailoring maneuvers, if they were to have been accommodated in the protocol for the TARP trial, would have enhanced the “signal to noise” ratio in the data, making results clearer, and, I’m convinced, increasing effectiveness in the dutasteride/ADT3 arm.
– Result statistics were mainly based on a snapshot of the study at 42 months, per protocol, but the indication of substantial success for the dutasteride (ADT3) group was seen mainly and quite evidently from months 4.5 through month 20.5 (sixteen months). This success averaged about 10 percentage points from about month 10 through about month 20.5, a duration of approximately 10.5 months. These figures compare to smaller typical successes of just several months in trials leading to FDA approvals of new drugs.
– Supportive tactics routinely used by the doctors who pioneered ADT3 were not used in the trial. I consider it probable that the results would have been even better if such tactics had been used. Along this line, there is no evidence that patients were counseled about countermeasures typically used by the pioneering doctors and their patients against typical side effects. Such measures make ADT more tolerable for patients. In this trial, it is likely there would have been fewer drop outs in both arms if such tactics had been employed, and that would have made inferential statistics more likely to be useful.
– Despite early suggestion that the trial was fully enrolled, in fact the trial experienced enrollment problems and was “under powered” in statistical parlance, which, combined with confounding patient characteristics, patient drop-out problems and the small size of the trial, would have made achieving statistical significance very difficult even if the results figures were collected during the time of success of ADT3 in the trial rather than at the 42 month point. Therefore, “non-parametric” statistics (such as simple percentages and trends), which are included in the complete paper, are arguably a superior kind of evidence to the “inferential statistics” reported in the abstract of the TARP trial. These non-parametric statistics arguably indicate the ADT3/dutasteride group’s results were clearly superior.
– There are a number of additional problems with the statistics used (such as measuring the ITT – Intent-To-Treat – numbers despite substantial drop outs in a small and underpowered study), which I hope to address in a future post. (I would welcome help if a savvy statistician has access to the complete TARP study.) Cumulatively, the problems mentioned in this post and additional problems placed a heavy load on the statistical tools employed, arguably too heavy a load for meaningful results such as statistical significance.
– I am also concerned about what appears to be a lack of attention to some well-known potential problems with ADT, such as the very real prospect of loss of bone density in the absence of appropriate countermeasures in both arms of this trial. and lack of liver function testing after introducing bicalutamide in both arms of this trial. I have tried to contact the lead author by phone and email about this and other points (such as whether there were any professional statisticians involved – apparently not), but so far without response. Similarly, I’m curious why the protocol did not provide for intermittent therapy if a specified PSA nadir were achieved; perhaps that would have overly complicated the protocol.
– While, arguably, an attention grabbing measure of success for ADT3/dutasteride was achieved in the TARP trial, the degree of success is markedly lower than the success reported by a number of non-trial data sets from clinical practices that have extensive followings in survivor circles. Perhaps the most readily available comparisons are from the Strum/Scholz/Lam and colleagues publications, including several papers in highly respected peer-reviewed journals. One of their informal publications covers ADT3 versus ADT2 results. Graphs of some of these results are in the book “A Primer on Prostate Cancer – The Empowered Patient’s Guide, Figures 59, and 60 in the original edition. For instance, Figure 60, for men having had prior radiation or surgery for prostate cancer, shows a median vacation period from ADT2 (without finasteride) of 24 months versus a vacation of at least 60 months with the median not reached (meaning fewer than 50% having had to go back to therapy at that point) with follow-up only through the 60 month point for the ADT3 group (versus about 78 months for the ADT2 group). Note that what is being measured is the length of VACATION from therapy, a much happier situation than the failure of ADT that is being measured at just the 42 month point in the TARP study. If real, as I believe it is, that is a pretty stark difference!
I hope to elaborate on some of these points in subsequent posts and welcome discussion. It obviously helps to have access to the complete paper.
I realize my comments may appear to diminish the effort and dedication of the trialists, but I hope that will not be the case. They took on an unfamiliar therapy about which they had doubts, and they overcame enough difficulties to deliver some useful results. Moreover, trials are challenging to plan and run, and hindsight is always much clearer than foresight. The trialists have my profound thanks!
Dear Jim:
I want to return to the question you raised on June 21, which read:
“What do these men and their associated accomplishments have to do with your discussion: Ignaz Semmelweis and childbed fever; Louis Pasteur and rabies, anthrax, and the germ theory of disease; Robert Koch and tuberculosis and cholera; Edward Jenner and smallpox; and Walter Reed, Carlos Finlay, and colleagues versus yellow fever?’
I have to tell you that in my opinion the answer is “Almost nothing.”
The individuals you reference above all carried out preliminary studies that lead to the complete prevention or the actual cure of highly prevalent infectious diseases affecting tens of millions of people at a period in time when we hadn’t even recognized the value of randomized clinical trials.
By comparison, Drs Strum, Scholz, and others have carried out some small studies that have been suggestive of a possibility, but they haven’t been able to prove it, and even if they could there is absolutely no evidence that their hypothesis could either cure or prevent metastatic prostate cancer. I understand why you are fervent about this hypothesis … It appears to be supported by the course of your disease … but that still doesn’t make it a good idea for everyone.
One thing they have in common is they all did their work in the 19th century. Thank God, we have learned a thing or two since then about how to prove things scientifically. Your call to ignore the last two centuries of progress in that area is reactionary, to say the least. As the Sitemaster said, medical experiments that are not proved by randomized clinical trials must be regarded as hypothesis-generating only, and therefore provisional. Most hypotheses turn out to be incorrect, and there is no shame to that. If we didn’t have failures, we wouldn’t have successes either. Jim, if you want to hang onto a disproven theory, you are certainly free to do so, but there is no rational basis for doing so beyond an emotional attachment.
“Doesn’t Make It a Good Idea for Everyone” — I concur
Thanks for your response.
I’m actually in agreement with you that ADT3, and especially IADT3 is not a good idea, at least in the long run, for everyone, and I’m fairly confident that those doctors who have pioneered this strategy would agree too, though I believe they feel well-done ADT3 will benefit a large proportion of patients. I’ll also agree that its merits have not been proven, though to me we have the gun surrounded by a lot of smoke and have dug out the bullet, to use a detective analogy.
My impression is that the docs who advocate this strategy are convinced it is superior to two-agent blockade (LHRH agonist/orchiectomy plus an antiandrogen — typically bicalutamide), and absolutely superior in a great proportion of cases to just the LHRH agonist or orchiectomy. My strong impression is that they also are convinced that drugs recently approved, especially Zytiga and Xtandi but also Firmagon, are superior to the old options; however, due to the relative inexpensiveness of the older drugs, I suspect that they still are using these drugs where they are effective for many patients, especially those who are not in the approved groups for the new drugs or are poorly insured.
These doctors have described some of the limitations of ADT3/IADT3, and I’ll try to hit the key points as I understand them from an IADT3 veteran’s/now savvy layman’s perspective.
One tiny group — well under 1% of all prostate cancer patients — that is apparently not often benefited by ADT3 consists of patients with the most dangerous sub-types of prostate cancer, specifically small cell prostate cancer, endometrial cell prostate cancer, and perhaps expansion of these groups that has been described within the past year on this site (Dr. Eric Small per my hazy recollection). Apparently no type of ADT with older drugs (and orchiectomy) works well for these patient.
Another considerably larger group is men who try well-done ADT3 but are unable to get their PSA nadir below 5%. The ADT3 docs typically will modify the strategy at that point, perhaps still including ADT3, but relying more on other agents for cancer control. For instance, before FDA approval of the new drugs, my impression is that they would swap in ketoconazole for the much less potent antiandrogen bicalutamide or other older antiandrogens (flutamide, nilutamide). Now, in 2015, if faced with this rather strong evidence (PSA nadir of 0.05 or higher) of the “failure” of well-done ADT3, I’m thinking they would opt for drugs approved in the castration-resistant setting. There are likely some statistics on the size of this group from the Strum/Scholz/Lam research, but I have not refreshed my memory. All of the patients in Figures 59 and 60 in the Primer, mentioned in my previous post, had succeeded not only in getting their PSA to < 0.05 but also in keeping it there for a year, so the success reflected in these figures is after removing those patients who could not achieve that nadir of < 0.05. Maybe someone else can help with a supported estimate of the size of that group that cannot achieve the desired nadir. For approximately the past decade, some of these doctors at least have changed their success criteria and have not looked for an extended time below 0.05, with passing that nadir threshold enough evidence of success to trigger the intermittent vacation period. At least one of the doctors wanted his patients to achieve a nadir of < 0.01, and if not, he changed tactics, but now he strongly prefers to use the new drugs if practical in the patient's circumstances.
Also, coupled with what to me is a most impressive level of success for ADT3/IADT3, there is also considerable variation in the length of vacation time from ADT3 among patients who are successful in achieving the desired nadirs. For instance, that is evident in Figures 59 and 60 of the Primer. While the median for all ADT3 patients in Figure 59 (all achieving and maintaining the < 0.05 nadir for greater than a year before starting the vacation A) looks to me to be about 38 months — quite impressive, the graph shows that 25% had to go back on ADT3 by about month 20 (about 32 months for men who had previously had surgery or radiation in Figure 60). That said, the trigger for going back on therapy, notching a data point in the graph, was a PSA rising to just 2.5. Informal research by Robert Leibowitz, MD, has convinced many of us that many men have strangely fluctuating PSAs during the vacation period, and that it is reasonable to wait until the PSA reaches about 10, depending on the pattern and rate of increase, before going on vacation. Such a relaxed trigger (data end point) would have almost surely considerably improved the success reflected in Figures 59 and 60. My own trigger point during the first two cycles was about 10, but my tactic was to use low-dose (50 mg) thalidomide plus vitamin B6 to extend my vacation period when my PSA first reached about 10. (I used a somewhat different tactic during my third cycle, with my fourth ending at the end of month 18 as support for a curative attempt using radiation (looking good with a current PSA of < 0.02 about 15 months past the end of supportive ADT3).
Another group where no old style ADT (meaning prior to recently approved drugs), including ADT3, works very well is men with metastatic disease detectable with older technology (such as palpation, CT scan, technetium bone scan), especially widespread metastatic disease; my impression is that it was rare for metastatic patients to be able to use intermittent ADT, so they were on continuous ADT without vacation, typically enjoying at least a year of success but often not more than 2 years. While I suspect that ADT3 works better than ADT2, with ADT2 working better than single blockade, the doctors who use ADT3 a lot would reportedly often switch away from that strategy fairly early because PSAs were rising for their metastatic patients despite testosterone levels below 20 ng/dl and DHT that was also well suppressed, such as below 5 ng/dl. Now, with the recent medications approved for men with metastatic disease, those newer agents would probably be used up front instead of traditional ADT3 unless cost were a prohibitive factor, as it might be for an uninsured or poorly insured patient. (The old drugs have dropped a lot in cost.)
A final group I am aware of that does not do well with ADT includes those men who experience an intolerable level of one or more side-effects due to the ADT, even after appropriate and well-managed countermeasures and corrective maneuvers, which are of key importance. My impression is that this group is rather small, but I am aware of some of us who apparently drew the short stick and were in this group. I am aware of quite a number of patients who have stopped ADT due to side effects in situations where appropriate countermeasures had never been employed; sadly, they likely could have done a lot better!
So this is a qualified agreement with you, Sitemaster, one that applies to quite a number of patients. All things considered, however, to me, it makes great sense for many of us to try ADT3, hopefully under the guidance of a physician who understands the ins and outs of that strategy.
ADT3 (Dutasteride Arm) Succeeded Despite Consisting of Patients with Substantially Riskier Case Features
This is an expansion of the first dashed paragraph in my post of July 19, 2015 at 5:11 pm, titled “A FRESH LOOK AT THE TARP STUDY RESULTS REGARDING ADT3”.
The first paragraph stated: “– The two arms were clearly not equal in risk, with the dutasteride arm having notably higher risk patients consistently across a set of measures. (This outcome probably was aggravated by randomization by center for this multi-center study; I’m thinking this would not have been a problem if the study had been much larger.) This inequality means we should give added emphasis to the success achieved in the ADT3/dutasteride arm as that arm contained higher risk patients from the outset.”
The trialists/study authors recognized this issue, describing it as follows in Section 3 Results, p. 5 of the electronic version: “The bicalutamide/dutasteride group had a slightly higher proportion of subjects with baseline Gleason score >7, T3 stage disease, baseline PSA P 10 ng/mL, focal abnormality at the baseline digital rectal examination, higher body mass index, time from PCa diagnosis to treatment initiation P 10 years and subjects P 80 years old (Table 2).” While some of the differences were arguably slight, in percentage terms they look fairly large to me, as indicated below. Moreover, this was a fairly daunting COMBINATION of adverse risk features all in the ADT3/”bicalutamide/dutasteride” group with no offsetting features.
The authors added an additional adverse factor and recognized the significance of this problem in the Discussion as follows (note the Canadian influence on the spelling in this mainly US/Canadian trial): “… More subjects with baseline characteristics that favour disease progression were randomised to the bicalutamide/dutasteride group, including a greater proportion of men with stage T3 disease, baseline Gleason score >7, baseline PSA level P 10 ng/mL and abnormal baseline DRE; furthermore, a higher proportion of men in the bicalutamide/placebo group had undergone a prior prostatectomy or radiation therapy. Retrospectively, therefore, it may not be surprising that the combination did not show a statistically significant beneficial effect over bicalutamide alone.” (Keep in mind that all patients were on an LHRH-agonist or had had an orchiectomy as well, making this ADT3 and not ADT2.) (Prior prostatectomy or radiation therapy is significant probably because it debulks the cancer. Results reported for IADT3 in “A Primer on Prostate Cancer” by Strum and Pogliano, Figures 59 and 60 of the original edition, are consistent with idea of a debulking effect; the median vacation period for all patients, regardless of such prior RP or RT therapy, was about 38 months compared to the majority of RP/RT recurring patient doing better than 50% success (“median off-phase not yet reached”) at the 60 month point, at that time the full extent of follow-up.)
Here are some of the key facts:
— Gleason of >7: 37% in the “bicalutamide/dutasteride” (ADT3) group versus 30% in the bicalutamide group (in other words, 23% more with higher PSA in the ADT3 group)
— Stage T3/T4 (and not T2/T1): 32% in the “bicalutamide/dutasteride” (ADT3) group versus 24% in the bicalutamide group (in other words, 33% more with higher PSA in the ADT3 group)
— Baseline PSA of 10 or higher: 18% in the “bicalutamide/dutasteride” (ADT3) group versus 12% in the bicalutamide group (in other words, 50% more with higher PSA in the ADT3 group)
— Digital Rectal Exam finding of “focal abnormality” at baseline: 14% in the “bicalutamide/dutasteride” (ADT3) group versus 8% in the bicalutamide group (in other words, 75% more with higher PSA in the ADT3 group)
Testosterone breakthrough (a testosterone of 50 or higher at any of the scheduled testing points during the trial despite intended suppression, indicating that the therapy was not implemented successfully in a patient, even with that soft definition of success, in contrast to a level of 20 or higher commonly used by doctors who do a lot of ADT3 therapy): 20% in the “bicalutamide/dutasteride” (ADT3) group versus 16% in the bicalutamide group. Not only are 25% more men experiencing breakthrough in the ADT3 group, but the fact that both groups are experiencing a noticeable level of breakthrough introduces “noise” into the analysis and is an artificial factor making achievement of statistical significance more difficult.
Again, despite this confluence of substantial handicaps, the ADT3 group was still able to achieve a level of superiority that impresses me.