Episode 5 – Dr Laurence Klotz

I’m Joseph Ischia

I’m Nathan Lawrentschuk.

Joseph: And we’re Talking Urology where we go to the source and chat to the world opinion leaders about their landmark papers. 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”.

Today we are talking testosterone and the importance of achieving very low levels in men being treated with ADT for their advanced prostate cancer.

Nathan: We are going to look at the paper by Laurie Klotz published in the Journal of Clinical Oncology April 2015, titled “Nadir Testosterone Within First Year of Androgen- Deprivation Therapy Predicts for Time to Castration-Resistant Progression: A Secondary Analysis of the PR-7 Trial of Intermittent Versus Continuous ADT”. And we asked Laurie if he would join us for the podcast.

Laurie:  It’s a good idea.

Joseph: I was asking around, does anyone have a good podcast for urology? I just want something I can listen to for 15 mins; learn something about urology while I’m driving in my car.

Joseph: All right, Laurie. Introduce your self for our listeners.

Laurie: I am a urologist, I do mainly oncology, I’m a Prof of Surgery at the University of Toronto, I work at the Sunnybrook Health Sciences Centre and I’ve had a long interest in many facets of prostate cancer from early to advanced disease.

Joseph:  One of the living legends of prostate cancer with us today.

Laurie:  Hardly.

Joseph: Historically, castrate testosterone levels have been set at 50 mg/dL (or 1.7 nmol/L). This was the lower detection limit of the first radioimmunoassay technique for measuring testosterone. However, the modern ultrasensitive testosterone measuring techniques, usually mass spectrometry, can now detect levels below 20 ng/dL or 0.7 nmol/L. We are using these numbers a lot so don’t get upset if we drop the units. So now that we can measure it, this raises the question, is lower better?

Laurie: So, 20 was historically the level that was achieved with surgical castration. There’s actually been one study published just recently that went further and looked at how patients did below 8, like that really ultra low range, – there was no benefit. In other words in that study once it was below 20 there was no further benefit to getting it lower.

Nathan: Usually we set the scene for the paper with some background, but in true Laurie-style, he had this covered for us. We asked him why he did this study.

Laurie: The idea that testosterone matters in men on ADT is not a new one, and the first paper that really described this was by Morote published in 2007; and it was a retrospective paper in 72 patients and it showed the patients whose testosterone (these were patient’s with metastatic disease) did not drop below 20 had a much worse outcome than those who had a testosterone higher than 50.

Joseph: That’s the paper by Juan Morote, Journal of Urology 2007. In fact it was 73 patients (close enough) with nonmetastatic prostate cancer treated with medical castration and found that if you maintained the testosterone below 32, you had a mean time to “androgen independent progression” of 137 months compared to 88 months if it broke through this threshold.

Laurie: I had a long interest in intermittent hormonal therapy which I believed in, still continue to believe in for the right patient; and I thought how could testosterone be so important if intermittent therapy looks so good. So I didn’t believe it, and the other thing that struck me was, this was pharma driven. So, I would hear about this Morote paper and the 2nd one by Perachino, which was a few, more patients but still retrospective and fairly small,

Nathan: BJUI 2010. 129 men with metastatic bone-only prostate cancer. Risk of death was directly correlated to the 6-month serum testosterone level with a statistically significant hazard ratio 1.32 for men whose testosterone was over 20.

Laurie: And then a third one by Bertaglia published more recently which was about 150 patients that all showed a benefit.

Joseph: Published in Clinical Genitourinary cancer, 2013. 153 patients, mixed M0 and M1. And they found that serum testosterone levels < 30 ng/mL were associated with a significantly lower risk of death with an adjusted HR, 0.45.

Laurie: But it was all retrospective, fairly small numbers and I just kept hearing about it at Pharma ad boards and I thought ‘I don’t think this is likely to be correct’.

Joseph: I too am suspicious of big Pharma, and back in 1995 I would often mull this over while watching new episodes of Seinfeld or ER. So what was Laurie doing?

Laurie: We launched back in 1995 the PR7 trial, which was a large pivotal trial of continuous versus intermittent hormonal therapy with a mortality end point almost 1500 patients, and that trial finally completed in about 2010 and was published in the journal in 2012. It showed absolutely no difference in overall survival between continuous and intermittent therapy in men with rising PSA after radiation or surgery plus radiation. We collected testosterone throughout that trial – particularly in the first year; every time patients came in for their injection they got a testosterone and PSA.  

Nathan: I asked Laurie how he knew that testosterone was going to be important when they were designing this trial back in 1995. This is 20 years ago when we thought that cancers were “hormone independent” because back then we thought we had the androgen receptor absolutely nailed with ADT.

Laurie: There was a lot of interest in testosterone kinetics, for e.g.. During the off treatment interval and how long does it take to reach a testosterone nadir. So my goal was to disprove the Morote data that testosterone really mattered. The other part of it in my thinking was, we know now (we didn’t know then) you have intracrine synthesis of androgens through the backdoor pathway, prostate cancer cells figure out how to make their own androgens, why should the serum level be so important?

Nathan: And that is the $64 million question. This study looked at the 696 men in the continuous arm of the PR-7 trial. Men were included if they had had at least 3 serum testosterones in the first year which left 626 evaluable men with PSA recurrence after radiation (+/- surgery) for their prostate cancer with M0 disease.

Joseph: And this is a point I want to pick up on for just a moment. We have the two big intermittent vs. continuous ADT trials with apparent different results. The PR-7 trial with first author Juanita Crook enrolled men with M0 disease and found no difference in overall survival; the SWOG trail with Maha Hussain enrolled men with M1 disease and found that intermittent therapy was almost certainly inferior to continuous.

Laurie: But I think in non metastatic disease the data is pretty clear that these things have a long off treatment interval, in many cases had a long survival, you reduce side effects of treatment which are very relevant in these patients, it cut costs; it makes a lot of sense. In metastatic disease, you have to be very selective. If you select a guy who doesn’t have such extensive disease, the PSA has a complete response to undetectable levels, one try of stopping therapy to me is worth while and many of these patients will have a very long off treatment interval. And if they don’t, then you put them back on continuous, and I don’t think there’s any harm done.

Nathan: The primary hypothesis was that a higher nadir testosterone value in the first year of ADT would correlate with a reduced time to development of castration-resistant prostate cancer and lower cause- specific survival. 

Joseph: Laurie did just say he expected survival not to be correlated with testosterone, but history is written by the victor. Anyway, as already mentioned, 626 men were included and nadir, median, and maximum testosterone levels were measured during the first year of therapy.

Nathan: That’s right- nadir is the lowest the testosterone ever got to, but because this could have been just a one off, they also looked at median to get a kind of average, and also maximum to capture all the breakthroughs or miniflares to determine if these were significant events. But if we just focus on the nadir testosterone, a level of <0.7 (or <20) was achieved in 78% of men. A further 21% achieved the intermediate range of 0.7 to 1.7, and only 1% never got below 1.7.

Joseph: During the study, 226 men developed CRPC while receiving continuous ADT for a median of 8 years. Median time to CRPC was 10 years. Around 20% of men died of prostate cancer with up to 10 years follow-up (so the median survival is going to be more than double the SWOG trial).

Nathan: Patients who did not achieve nadir testosterone < 0.7 had a significantly higher risk of developing CRPC. If you nadired in the intermediate range (0.7 to 1.7) the HR was 1.62, if you never reached below 1.7, the HR was 1.9. Benefits in delays of progressing to CRPC were also seen with lower median and maximum testosterone levels. And nadir testosterone > 1.7 had a shorter time from CRPC to death compared with groups with better testosterone suppression.

Joseph: And testosterone levels had similar effects on CSS. Patients with first-year nadir testosterone consistently > 0.7 had significantly higher risks of dying as a result of disease. In fact, compared to men whose testosterone suppressed to <0.7, the HR for cancer specific death in men with testosterone levels 0.7 to 1.7 was 2.08, and those with > 1.7 , the HR was 2.93.

Laurie:  So this just the effect of level of testosterone in men on the continuous arm; and to my complete amazement we absolutely vindicated the results of those earlier trials. The hazard ratio for time to progression for the patients who’s median PSA was above 50 or 1.7 was about 2 times greater than the ones where it was fully suppressed below 20. The patients in the intermediate range had intermediate time to progression and it was a very robust find, it was strongest for our time to progression. But it also was there for prostate cancer mortality

Nathan: And for comparison, an analysis of the relationship between serum testosterone in the first 8 months of ADT was performed in the intermittent ADT cohort. A similar correlation was found between time to CRPC and median testosterone level. There were no correlations between minimum and maximum serum testosterone levels and time to CRPC or CSS in men in the intermittent arm.

Laurie: We looked also at the intermittent arm, and all the trends were in the same direction but the data was not as clean, which is kind of to be expected because these are guys who are going off treatment, the testosterone is coming up, there’s various off treatment intervals, so there’s a lot more variables at work it terms of time to progression.

Joseph: So what does it all mean?

Nathan: A recent review found that up to 12.5% of patients do not reach the 1.7 (i.e. 50) serum testosterone target, and up to 37.5% do not attain levels 0.7 (i.e. 20). Why is it so important to achieve a testosterone < 0.7?

Laurie: So, the reason probably is that, despite all these survival mechanisms that kick in, prostate cancer cells are heterogeneous in terms of their response to different levels of testosterone and there’s pre-clinical evidence to support this. For example, some variance of LNCaP, which is an androgen receptor containing cell line, are maximally stimulated and others are maximally suppressed at the same level of testosterone. So, there’s pre-clinical evidence for it, and if you can imagine a three cell type model just to make it simple – you have stem cells that are not androgen sensitive at all they don’t express the receptor, you have typical hormone sensitive epithelial cells that die whatever the testosterone goes down to, and then you have a third compartment of partially sensitive partially resistant cells that only die if the testosterone goes below 20. So the basic concept is, if you hit the cells hard during the on treatment interval, you kill off both those compartments – the partially sensitive and the sensitive cells, and then the stem cells re-populate with androgen sensitive cells. Where as, if you don’t drive the testosterone low, then the partially sensitive cells survive and they re-populate with a more androgen resistant phenotype

Nathan:  If IAD relies on repopulating the cancer with androgen sensitive cells, should we be replacing testosterone in the OFF phase?

Laurie: I don’t believe in that for a few reasons, although I could be wrong. And what you say makes sense but first of all, I’m not convinced exogenous testosterone is the same as endogenous in terms of being as innocuous. In our study, the majority of patients recovered testosterone to at least 50% of base line by 6 months and that should be enough if you believe at any level the saturation hypothesis that the energy receptors centre relatively low levels of testosterone. Most patients will be in that range by 6 months, so I don’t give testosterone.… the limited experience….No-one that I know of has ever done any significant series in exactly the scenario we are describing. People have talked about it but, giving testosterone to a patient with advanced prostate cancer, mostly they don’t so well.

Joseph: This is very significant if these men are at a higher rate of progression to CRPC and prostate cancer specific death. Acknowledging that this was not an intervention study, can we extrapolate that if a man is failing to suppress his testosterone, should we change to another LHRH agonist or to antagonist?

Laurie: I think you can. If you’re a purist you would say – the study has not shown that lowering testosterone improves the outcome. But I think that’s a reasonable inference under the circumstance to say – guys did better with low testosterone and because different people respond differently to different LHRH agonists and antagonists, what I think is correct is to do the testosterone whenever you do the PSA, if it’s consistently above 20 or 0.7 nnmol, you should switch LHRH agonist, try a different one or try an antagonist and try and get the testosterone down. Most patients will respond to a change.

Nathan:  Why will they respond with the change?

Laurie: There may be many reasons why the testosterone isn’t suppressed, so it might be absorption, some patients may not just absorb the depot, and just to illustrate this, I have one patient who got a Zoladex and went out to his car and decided to have a look. So he lifted up the bandage and saw the pellet had extruded onto his abdomen. So he picked it up and thought because he knew it was worth like $1000 and thought ‘what the heck am I going to do with this?’ popped in his mouth and ate it! So, he is not going to get good testosterone suppression from that dose of Zoladex. That probably goes on more often than we think, so some of the drug is wasted or just doesn’t get absorbed or doesn’t go into the right spot.

Joseph: Why should the testosterone level matter in men receiving continuous therapy, if intermittent therapy achieves the same prostate cancer survival (in nonmetastatic disease)?

Laurie: Well that’s kind of the point I think I made earlier that – the fact that the low testosterone is important doesn’t mean it has to be sustained. It’s important to get cell kill during the treatment period, then you stop the treatment and it’s okay to have the testosterone come up, so you’re right on the face of it that it’s a conundrum but if you drill deeper there’s a very plausible explanation why both those things can be true.

Joseph: Well this has been fun and I think the evidence for suppressing the testosterone to less than 20 is quite convincing. I now do a testosterone with every PSA for the first year of ADT and at least once per year after that if the PSA is stable. Laurie has been great and he even gave us a little chestnut to go home with.

Laurie: So, what’s the message? The message is – you should track testosterone and it should be suppressed – the patient will do better. The only thing that predicted for failure to suppress was young age. So it makes sense that gonado-pituitary axis is more robust in younger men, harder to suppress, but in fact although the men who had higher testosterone on treatment were younger, they actually did worse even in terms of time from progression to death – they had a shorter time if the testosterone was higher. You might think you had room to manipulate the testosterone further if it’s higher they might do better – they didn’t

Joseph: We’ve been Talking Urology with Laurie Klotz. You can contact us with questions, corrections, or updates at talkingurology@gmail.com. And as usual, all negative feedback can be sent to the person who invented the assembly technique of the Swiss lithoclast master. Never fails to stump us.

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