Episode 1 – Dr David Quinn

I’m Joseph Ischia
I’m Nathan Lawrentschuk

And we’re talking Urology where we discuss the key points of the landmark papers that guide your practice everyday. Our goal is to empower doctors to develop a deeper understanding of the literature to ensure we apply the right evidence to the right patient.

We are all about “bringing the literature to life”.

Joseph: Today we are looking at the landmark paper comparing intermittent vs continuous androgen deprivation in men with metastatic prostate cancer. It was published in the NEJM in 2013 by first author Maha Hussein and I remember when it was first presented at ASCO in 2012: it really stirred up some discussion in the pro-intermittant camps.

Nathan: Today we also have the opportunity to chat to one of the key authors on this paper, Prof David Quinn, to get his thoughts and insights.

David: I am an Associate Professor of the Keck School of Medicine at the University of Southern California. I am the medical Director of the Norris Cancer Hospital and Clinics and I am the organ site chair for advanced prostate cancer within the genitourinary cancer committee

Nathan: Today we will look at the key points of this paper so you are fully armed in your next MDM when trying to decide who is suitable for IAD and who is probably not.

Nathan: Let’s begin by looking at why was this paper done?

Joseph: Up until the 1990s, we had devoutly followed the findings of Nobel Laureate, Charles Huggins, by inhibiting men’s testosterone to treat their metastatic prostate cancer.

Nathan: It works very well, but inevitably- CRPC will develop [sad]. Furthermore, a large proportion of men will find the SEs quite debilitating. So in the late 80s and early 90s, a few Canadian urologists started looking at the possibility of IAD.

Joseph: Charles Huggins must have been rolling in his grave [shock], but they did have some very compelling pre-clinical data that IAD may be able to delay progression to CRPC in a mouse model of an androgen-dependent tumour [interesting]. The theory was that PCa is made up of different subgroups of prostate cancer cells competing for growth [fascinating]. They found in a mouse model that during ADT, that while the overall tumour burden decreases with death of the androgen sensitive cells, the proportion of stem cells increased 20 fold and the proportion of androgen insensitive stem cells increased 500 fold. And so IAD emerged as possible alternative where the regrowth of the androgen sensitive cells would suppress the growth of the CRPC cells with ultimate the benefits of delayed Castration resistance, as well as QoL improvements in the OFF phase,

Nathan: and possibly reduced cost [positive].

Joseph: So in 1993, Maha Hussein and SWOG started to plan a trial with the following co-primary objectives:
1. To determine whether survival on intermittent therapy was non-inferior to continuous therapy, and
2. To assess QoL three months after randomisation.

Nathan: The trial was an International, multicentre, randomised, controlled, phase III trial, which was non-blinded. Patients with newly-diagnosed prostate cancer with radiological evidence of metastasis. Median PSA was 42.

Joseph: This is important when we try to put this in to context wth the other IAD trials. These were M1 patients.

Nathan: All Patients received a 7-month induction course with an LHRH agonist and an anti-androgen and had to achieve a PSA levels ≤4 ng/mL to be included in the trial. And at the end of the 7 month induction course, patients were randomised to continue ADT in the CADT arm whereas those randomised to IADT discontinued ADT at completion of the induction course. Triggers for re-commencement of ADT in the IADT group were: a rise of PSA to baseline, or ≥20 ng/mL, or investigator discretion (PSA ≥10 ng/mL or symptomatic disease}.

Joseph: One of the most important aspects of this trial is this HR of 1.2 which was set as the upper limit to confirm non-inferiority.

Nathan: Why was that set as the limit?

Joseph: It had to do what was the expected survivla in the control continuous arm, and what would be considered a clinically significant decrease in survival.

David: We were looking at a survival of 3-31/2 years in our non experimental continuous arm; and we wanted to make sure that we were really within six months of that. That worked out to be around 20%. That was projected over a period of time. In addition, it wasn’t just a statistical calculation

Joseph: So we can see that it was determined that a decrease in median survival of 6 months in the group receiving IAD would be considered clinically unacceptable and we get a hazard ratio of 1.20 for death with IAD. So to paraphrase George Orwell, more than 1.2 – bad; less than 1.2 – good.

Nathan: A total of 3040 patients were enrolled, and at the end of the 7 month induction 1535 were suitable for randomisation.
• 765 randomised to CADT; and
• 770 randomised to IADT.

Joseph: Why such a drop out?

David: Well, I think we’d never really look at it before and obviously there was a paper published by Maha Hussain and others in 1996 in JCO that looked at nadir as a predictor of outcome and that was an important paper in itself because the patients that didn’t essentially go to less than 4 had a survival of about 1 year. The ones that got to be less than 0.2 had a survival of 72 months and then the others in the middle. So that was important but the drop out occurred was somewhat multifactorial, about 2/3 of the patients didn’t meet criteria of response, the other 1/3 dropped out for other reasons, they were lost to follow up they got sick from other things.

Nathan: Median follow-up period was 9.8 years. Median duration of protocol therapy after randomisation was 19 months in the IADT- versus 17 months in the CADT group which means they were changed to CAD and then followed.

Joseph: Remembering that the trial period does not include the 7 month lead in this means that after 2 years men will progress or become castration resistant which seems about right I these high risk men.
Nathan: Patients in the IADT group received ADT for a median 47% of time before going to off protocol- meaning on to CAD and then CRPC. At 15 months, 78% of men in the IADT group had resumed ADT.

Joseph: That is another great stat that around of a fifth of men never regain their testosterone.

Nathan: The primary endpoint of the trial and the key finding was the median survival after randomisation. [most important point] This was 5.8 years in the CADT group versus 5.1 years in the IADT group, representing a 10% relative increase in the risk of death with IADT (HR for death with IADT was 1.10; 90% CI, 0.99 to 1.23).

David: This study did not meet it’s end point so in other words, intermittent therapy for a prostate cancer survival endpoint or an overall survival endpoint was not met. So intermittent is not, not inferior. You can turn that around and say it’s inferior but we don’t have power to prove that statistically.

Joseph: The hypothesis that the HR for death would be less than 1.20 was not rejected because the upper limit of the 90% CI was 1.23, extending beyond the pre-determined non-inferiority threshold of 1.20. Importantly, a 20% increase in the risk of death could not be ruled out with 90% confidence.

Nathan: But the second important point is that because the lower limit of the CI (0.99) did not exclude 1.00, it could not be stated that IADT was significantly inferior to CADT.
Joseph: well where does that leave us?

David: When the New England Journal accepted the paper, they did some interesting things editorially. I think that their statement in the abstract was really their feeling of how the data might be interpreted rather than what the SWOG investigators felt, we didn’t disagree with that interpretation but I think there is an issue here. If you’re an abstract reader you may not get it

Nathan: When you look at the raw numbers, there were almost 10% more deaths in the IAD arm compared to the CAD (445 compared to 483 in the IADT arm), and if you did die, it was more likely to be due to prostate cancer. Overall, 73% of deaths in the CADT group and 80% of deaths in the IADT group were related to prostate cancer.

Joseph: However, given that nearly the entire confidence interval tends to favor continuous therapy, the result suggests that intermittent therapy may compromise survival. The lack of a significant difference between the groups does not imply similar survival.

Nathan: Let’s have a closer look at some unplanned subset analysis. The investigators divided the men in to those with Extensive vs minimal disease. Minimal- spine, pelvic bones, or lymph nodes. Extensive- ribs, long bones, or visceral organs. Counterintuitively, while not statistically signficant, there was no difference in survival in the men with extensive mets (4.9 vs 4.4 years) but a larger survival in the men with minimal mets (5.4 vs 6.9 yrs).

Joseph: Why is that?

David: There is not a significant difference in the more extensive group. So, do they in fact have intrinsic castration resistance to a point where they have sufficient clones that are resistant to initial hormone therapy to some degree so that the relative exposure to hormones with intermittent doesn’t actually make a big difference. Where as, if you look at the limited group are they maybe more hormone sensitive? Therefore, it’s more important to block their testosterone optimally to get that to happen.

Joseph: But hold on a minute. Aren’t these the exact patients that were the subject of CHAARTED and STAMPEDE trials of upfront chemotherapy. So where does that leave us? Do we need to do this trial again?

David: I think that ship has sailed.

Joseph: What ship?

David: We’ve now moved on from that, so that group that are the extensive were what Chris Sweeney and the ECOG and SWOG teams put together in the chartered study and gave them 6 cycles of Docetaxel produced a big survival advantage. The good risk patients we’re now looking at doing more extensive suppression of the androgen receptor pathway earlier so in the US we have the SWOG 1216 study where we are giving a Tarinol which is an androgen bio-sensis inhibitor versus Vercludomine. In Australia we have the Enzamet study which is Enzalutamide.

Nathan: What a great point. Upfront chemo has been a massive change in our management of men with hormone sensitive metastatic prostate cancer. By the time we are deciding whether they are suitable for IAD vs CAD they are a lot further down the track. Does chemo change their disease?

Joseph: I don’t know but I don’t think we are going to see the trial done again.

Joseph: Let’s take a look at some of the other findings of the trial. Another take home message was that there were no significant between-group differences in the number of grade 3 or 4 treatment-related adverse events, including cardiovascular events.

Nathan: But really the study was not powered to detect a difference in these events. Mark Fui and Mathis Grossman, who published a detailed commentary in the Asian Journal of Andrology in 2013 also raised this point. The study was not powered to detect between-group differences in serious androgen deprivation therapy-associated adverse events between groups such as minimal trauma fractures or cardiovascular events.

Nathan: Patients assigned to intermittent therapy reported significantly (p<0.001) less impotence and significantly better mental health, but these differences did not persist beyond 3 months.

Joseph: Not unexpected considering after this time point there was mixture of men ON and OFF treatment. And those of you who love QoL data there is more to come.

David: So, just to be clear; the quality of life data is the subject of a very extensive paper and we submitted 2 papers to the New England at the same time and were asked to condense them. So you’ve got the abstract, abstract version of the quality of life, so we are preparing that paper for submission soon.

Joseph: Let’s talk about some of the limitations of the study. One of the possible limitations that may affected its statistical power is that the median survival in the CADT arm was 5.8 years instead of the expected 3.5 years.

David: The fact that the patients lived almost twice as long as we expected them to is a good thing for patients. The predominant accrual occurred at tertiary referral centres, mainly MCI designated centres; when you look at survival over the years the patients that have gone into trials have a better survival slightly, but significantly at those big centres they do better and at those big centres they’re offered other therapies after they fail initial hormone therapy. So, there may be more treatment options for castration resistance disease.

Nathan: And this is something that comes up in other papers and is the topic for a whole other discussion, this tertiary referral centre benefit.

Joseph: Three meta-analyses leading up to this trial had found no difference in OS between the two strategies in MO or M1 patients or a mixture, and that IADT was associated with some better QoL outcomes. How does this study fit with the other trials and meta-anlyses on IAD vs CAD which have almost all shown that IAD is not inferior to CAD.

David: The best study is the Canadian study, the JPR7 in NCI and C study which SWOG was involved in. Thea Hagana was our lead on that and we accrued very well to it. There are differences in the groups. The JPR7 study smaller, you did not have a qualification period to go on so if you had rising PSA and no evidence of metastasis ….

Nathan: Well that would be a significant difference then because they may have not excluded a number of people that you lost.

David: Yeah so the population didn’t have to get through that 7 month gate, and I’m not suggesting they should have designed it that way; but from that perspective the fact that you don’t see a difference is important. If you step back a little way, in the M0 group, so we’re not talking castration resistant disease we’re talking patients that are hormone naive or hormone sensitive, by whatever criteria; the benefit for giving them androgen deprivation is questionable possibly accepting patients that have a rapid doubling time. And so I think that the implications there are, I sort of asked the question “should I give this patient hormone therapy first” and then if I do I can say – look we can do intermittent to control your PSA which is a useful marker at that stage, but becomes less so as the disease progresses; we can use your PSA, we can control you and we can give you a better quality of life without compromising. When you become metastatic the situation changes and we have you on continuos therapy if we are trying to optimally control your prostate cancer.

Joseph: There are enough differences there to keep you busy through an MDM.

Nathan: This really highlights the importance of well conducted randomised trials to answer the questions we want answers for rather than relying on clumping together lesser data.

Joseph: There does seem to be a big difference in the efficacy of drugs in a lot of trials, such as the bone targetted therapies, between M0 and M1 disease. Is M0 really that different?

David: I think M0 disease is a moving bus for a number of reasons. We have seen in Australia better the advent of better scanning with PSMA scans which is very interesting, we have not seen that in the US, but the PSMA scan here the carbon 11 scans with acetate and choline in the US which have limited availability; allow you to detect a lot more metastasis. Stepping back a bit, if you screen people in that M0 group, you just to a an old style bone scan and a CT, 30% of them have METS. If you do a sodium fluoride PET bone scan which is a better bone scan, 30% more you find 30% more METS better sensitivity. Then there is an upping of sensitivity with various advanced MRI and other imaging techniques.

Nathan: In Australia we have enthusiastically embraced PSMA-PET. It has lead to a true stage migration with almost no data on its effective role in men with prostate cancer compared to standard imaging techniques.

David: I think it’s an interesting technology, I mean I think our challenge now is to embed it into clinical trails, and it’s something that we have not done in clinical trials well enough and it’s lead to us being impeded in trying to apply that technology; and at the end of the day we have to do some sort of cost benefit analysis to make sure that we’re really doing what we think we’re doing.

Joseph: I think this is an enormous issue. It’s almost like we are getting a bit of a reputation as urologists for whole-heartedly adopting new technologies before the evidence is in!

Nathan: Another issue is the the trigger to restart ADT. In ths trial it was a PSA of 20 or reaching the baseline PSA level. I think 20 is a lot higher than most of would now use and better trigger is probably 10. Therefore, the possibility of allowing high burden disease to exist was quite high and may have allowed disease to progress more significantly.

Joseph: One issue I want to discuss briefly is the issue in the IAD group of the recovering testosterone during the OFF period. This issue is very important when we consider the data coming through regarding the importance of very low testosterone (Klotz PR-7 trial).

David: The big question we have now is, and this cuts to a a current discussion we are having about testosterone levels and how we measure them and what they mean; is that we don’t have that data. So, one of the things is that your recovery from having stopped androgen deprivation can vary on a whole lot of factors, I mean some guys are back in the normal range 1 month later. More typically men take 6-7 months to recover and some never recover even after a short period of hormone therapy.

Joseph: This issue is important because IAD is not like the pre-clinical models which demonstrated a significant delay in CRPC. In the mouse model, tumours were transferred from castrate mice, chopped up and transferred into fully androgen-intact mice- and then allowed to grow back up- ideal conditions for the androgen sensitive cells to regrow quickly. However, men on IAD spend a considerable amount of time with T in the range from 50 to 500 where the the T is low enough to suppress the androgen sensitive cells but may drive the androgen insensitive cells.

Nathan: Good point. It’s like a worst case scenario during the early recovery phase.

Joseph: So, David, who do you think is suitable for IAD:

David: If I have a young guy who has asymptomatic disease at presentation, and this is just my bias; who is saying ‘I’m in the prime of my life, my quality of life and sexual experience is very important to me, I have an active and willing partner’ then that’s the sort of person. Now, there are propel that I select out as not being suitable for that and it may be a personal bias, so for example; I have men that are not in continuos relationships and if they’re out sort of seeking relationships and going onto hormone therapy and they think that intermittent is going to help them, then that’s a kind of separate non medical discussion I have with them because their performance anxiety is going to be considerable. So the lifestyle factor’s are very important, and I think a very hard end clinical study like this where we sweated over the stats 25 years ago can actually inform that and let’s me discuss with my average patient what the risk benefit is between maybe a decrement and survival from prostate cancer versus quality of life. I think I can meld that perhaps from a heterosexual couple, what in America they would call a conventional relationship to a same sex couple to a single guy to other permeations of the patient that I have in front of me.

Joseph: I asked David what is one of the most common questions you get asked about the paper.

David: I think that one of the issues for example when we go to our patient advocates and they’ve looked at this, the patient advocates asked us to review this paper with them. The real discussion was ‘what does this mean for the patient” and “what does it mean for the physician”? I think what it means is we can say look, we can do intermittent therapy but you give up some months, maybe depending on what group you are in up to a year and a half of survival, but your quality of life will be better. So it’s a buy off. It’s interesting with most of my patients are in heterosexual relationships, their wife or significant other is there and they’ll be a discussion where the man is “I’ll do intermittent thanks, I’ll go for quality of life” but the wife is saying “you’ve gotta be kidding, if you think you’re checking out early just that we can have a little bit more sex, that’s not what I signed up for”.

Joseph: Firstly, This study failed to show that IADT therapy was non-inferior to continuous therapy with respect to survival and the trial falied to show that CAD was superior to IADT.

Nathan: So it is not non-inferior and it is not superior: you could say that it was statistically inconclusive. But off the record, the deck seems heavily stacked towards CAD in men with metastatic hormone sensitive prostate cancer.

Joseph: This is important because I think in men with lower burden disease there does seem to be some evidence that IAD is not detrimental in men with early or true M0 disease.

David: I think intermittent suppression is not as good for controlling of prostate cancer. So, if individual patients and physicians want to do intermittent, I’m absolutely fine with that. But it’s a question where you give up something for that.

Nathan: Secondly, this study does not support the hypothesis from preclinical data that IADT delays the emergence of castration-resistant disease.

Joseph: And this is really case for pause as it may be issues with differences in the testosterone recovery phase in men compared to the preclinical rat model.

Joseph: Thirdly, And now for stating the bleedingly obvious: men in the first OFF period experience improved erectile function and mental health.

Nathan: what this trial does do is inform about patient characteristics predicting suitability for either CADT or IADT. Treatment needs to be individualised based on potential benefits and risks with intermittent versus CADT.

Joseph: And David’s take home message:

David: So what I’de say to urologists and patients is, look at the study – don’t just read the abstract – we’ll get you some more data on the quality of life soon, and you get to have that balanced discussion.

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