ASCO 2020: Updates in non-metastatic castration-resistant prostate cancer

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Published: 24 Jun 2020
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Prof Boris Hadaschik - University of Duisburg-Essen, Essen, Germany

Prof Boris Hadaschik (University of Duisburg-Essen, Essen, Germany) discusses the latest updates in non-metastatic castration-resistant prostate cancer (nmCRPC) that were presented at the ASCO 2020 virtual meeting.

He begins by outlining the final analyses from the SPARTAN, PROSPER and ARAMIS trials, which are investigating the use apalutamide, enzalutamide and daralutamide, respectively in patients with nmCRPC.

Prof Hadaschik states that these three trials all displayed an overall survival benefit, and discusses the validity of metastasis-free survival as a clinical endpoint.

He also comments on the toxicity profile of these three androgen receptor antagonists, and mentions that daralutamide seems to be the most tolerable for this patient population.

Prof Hadaschik concludes by explaining how these agents fit into the treatment paradigm for nmCRPC.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

2½ years ago the primary endpoint of both the SPARTAN and the PROSPER study was presented at ASCO GU and both these trials showed an extension in the novel endpoint of metastasis free survival by roughly two years. Then one year later also the ARAMIS study with darolutamide confirmed this mechanism of action, that early treatment in men with non-metastatic castration resistant prostate cancer really makes sense and prolongs metastasis free survival as compared to placebo.

So this novel endpoint of metastasis free survival, we were hoping that it would correlate with overall survival because it’s just an earlier endpoint for clinical trial design. So our patients had the opportunity to crossover earlier and we, in fact, had approvals based on this novel endpoint before it really has been validated to correlate with overall survival. So this year’s data that was presented at ASCO really was important data because now we were able to look at overall survival which, in the end, is the most important endpoint for patients besides quality of life.

In all three trials men with non-metastatic castration-resistant prostate cancer and a PSA doubling time below 10 months have been included. So in the last years we had a lot of discussions with regards to next generation imaging and especially the PSMA PET imaging. All these men had non-metastatic castration resistant disease based on conventional imaging because at the time when the trials were designed the PSMA PET imaging was not readily available. Certainly if you image these men with more modern agents such as PSMA PET you will find low volume metastases in the population and this M0 disease state is diminishing. We have been running an analysis in a retrospective multicentre setting where we showed that roughly 50% of the population do, in fact, have metastases but we were not able to define subgroups that did not benefit from systemic treatment in this patient population who are already castration resistant and have a short PSA doubling time. So I believe it’s really important that we focus on the short PSA doubling time because these men, anyhow whether you can see it with imaging or not yet, have a high risk of developing metastases and dying of their disease.

So now what has been presented at ASCO were the overall survival data and these were the final analyses. The follow-up times in the three trials are a little bit different because, as I told you before, the ARAMIS study was a runner-up, it reported one year later so its follow-up is shorter. But in the end, again, the mechanism of action and the clearly significant extension of overall survival was comparable in all three studies. So the SPARTAN study in the intention to treat analysis demonstrated a 22% reduction in the relative risk of death; PROSPER reported a 27% reduction in the relative risk of death as compared to placebo and ARAMIS, with a shorter follow-up, demonstrated even a 31% reduction in the relative risk of death. When you look at the absolute numbers then apalutamide seems to extend the median overall survival by 14 months, PROSPER is extending this timespan by 11 months and for darolutamide we don’t know the data because the medians have not been reached in either the placebo or the verum arm. But in the end, from a clinical perspective I’m very happy that all three drugs clearly extend the life of the patients and this despite having a crossover in all three trials and despite early reporting, as in the case of the ARAMIS study. In the SPARTAN cohort we did present an analysis where we accounted for those men that crossed over to apalutamide after the primary endpoint was reached and the data presented 2½ years ago at ASCO. If you account for these men that cross over then the extension of overall survival is even more than 20 months, it’s 21 months and then the hazard ratio goes down to 0.69. So this is great data and it’s fair to run this kind of analysis because in SPARTAN, for example, the amount of time that men were receiving apalutamide in the crossover population was over two years again. So this is a long time and people are doing fine with the drugs. It’s really important and great data because we now have validation that this early endpoint of metastasis free survival based on conventional imaging is really correlating with overall survival.
With regards to adverse effects, all three drugs basically did not impact quality of life as compared to placebo, very much in the data that has been presented before. If you look at overall scores like FACT-P then all three drugs, despite being added on top of ADT, they did not lead to really deterioration in quality of life of these asymptomatic elderly gentlemen.

If you look now more closely at details then we have to acknowledge that the monitoring intervals in SPARTAN as compared to PROSPER and ARAMIS were a little bit different. So SPARTAN in the beginning reported AEs every four weeks while the other two trials reported AEs every sixteen weeks and this a little bit explains why the overall amount of adverse events in the placebo arms are a little bit different. They are roughly 80% in PROSPER and ARAMIS and 94% in SPARTAN. However, if you look at the serious adverse events then in all three trials in the placebo arm you do see roughly one in four men with an SAE. When you look at the verum arms, so apalutamide, enzalutamide and darolutamide, there you see an increase and this increase is in SPARTAN 46%, in PROSPER 40% and in ARAMIS it’s only 26% so ARAMIS seems to be a little bit better tolerated. However, because of the longer follow-up time both in SPARTAN and PROSPER we don’t know exactly how much exposure adjustment would level out these diverse effects because people just have been taking enzalutamide or apalutamide much longer than darolutamide.
However, if you look at AEs leading to treatment discontinuation it pops out, at least in my eyes, that in the ARAMIS study with darolutamide the amount of men that were quitting therapy because of AEs between placebo and the verum arm were similar at roughly 9%. In the other two studies you could see an increase in AEs leading to treatment discontinuation when you compared the two arms. So this is something we have to acknowledge. On the other hand, AEs leading to death, there is a similar amount of men dying in all three treatment arms with apalutamide, enzalutamide and darolutamide. I think there are maybe a little, little bit more deaths in the enzalutamide arm but these are not head-to-head comparisons and we cannot really do sound evaluations and compare the three drugs in the three different populations and different study centres that were included.

In the end our patients and we as providers, we are privileged that we have three compounds that clearly prolong overall survival. In the beginning we asked ourselves the question does it really make sense to treat men who are asymptomatic just because of their PSA dynamics and now non-metastatic CRPC. Now we can confirm the guideline recommendations that early treatment really makes sense in prostate cancer, we can prolong men’s lives by initiating therapy early. This is a very important result. The three compounds are all great and it really depends on the healthcare context, where your practice is based, which drug you can prescribe. For example, in my country I have the opportunity to use all three compounds and I’m happy to do so and to use all three of them.

These M0 CRPC men, they are still niche and this niche is diminishing because we do use a lot of next gen imaging, especially at hormone sensitive disease stages. With all three drugs, they are really well tolerated and certainly they are alerted or sensitised that apalutamide can lead to some rash which is easily being taken care of but with enzalutamide and the other two drugs do pay attention to cardiovascular events and collaboration with oncologists if needed. But darolutamide, the newest compound, I do have a little bit limited experience because I was only able to prescribe the drug from the beginning of May this year, it was not available before. But it looks very easily tolerated by the patients.
With all the discussions of next generation imaging it is important to always ask yourself whether imaging would make a difference. I personally believe that in these men with non-metastatic CRPC and a short PSA doubling time imaging in general does not really impact on my treatment decision. So if men are qualified for treatment with apalutamide, enzalutamide or darolutamide, I’m happy to prescribe it because I know it’s well tolerated and it prolongs overall survival. PET imaging should have been done earlier at the time of hormone sensitive biochemical recurrence or, in the case of my country, later on when we decide whether PSMA radioligand therapy is an opportunity for that patient.

So whenever you think of imaging ask yourself first does it make a difference or not. I believe that in nm-CRPC its value is limited because we now have three great drugs that I’m happy to prescribe.