Developments in metastatic hormone-sensitive prostate cancer

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Published: 11 Jun 2021
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Prof Karim Fizazi, Prof Alicia Morgans, Prof Neeraj Agarwal and Prof Laura-Maria Krabbe

Prof Karim Fizazi (Institut Gustave Roussy, Villejuif, France), Prof Neeraj Agarwal (Huntsman Cancer Institute, University of Utah, Salt Lake City, USA.), Prof Alicia Morgans (Northwestern University Feinberg School of Medicine, Chicago, USA) and Prof Laura-Maria Krabbe (University of Muenster Medical Center, Muenster, Germany) discuss the developments in metastatic hormone-sensitive prostate cancer.

Initially, they talk about the SWOG S1216 study; A phase III randomised trial comparing androgen deprivation therapy (ADT) plus TAK-700 with ADT plus bicalutamide in patients with newly diagnosed metastatic hormone-sensitive prostate cancer.

Prof Fizazi then directs the discussion towards the first results of the PEACE-1 trial.

They then discuss results from the final analysis of TITAN. They discuss a post hoc analysis of ARCHES. They conclude by talking about 177Lu-PSMA-617 in relation to metastatic hormone-sensitive prostate cancer.

Analysis of the SWOG S1216 trial
First results of PEACE-1 trial
HRQoL and patient-reported outcomes at final analysis of the TITAN study
A post hoc analysis of ARCHES
177Lu-PSMA-617 in relation to metastatic hormone-sensitive prostate cancer

This programme has been supported by an unrestricted educational grant from Janssen.

KF:         Hello everybody, thank you to this ecancer event. We are here right after ASCO 2021 which I think I was great for GU in general and for prostate cancer specifically. Karim Fizazi, medical oncologist at the Institut Gustave Roussy in Villejuif in France, I’m delighted to be here together with colleagues and friends, to be honest. So I have Laura-Maria Krabbe from Germany, Alicia Morgans from the US and Neeraj Agerwal also from the US. So we are here today to try our best to summarise the data that were shown at the congress regarding treatment for men with metastatic castration-sensitive prostate cancer. It’s true that the field has changed dramatically in the last five or six years; sometimes we’re lost, to be honest, but it’s good, it means that we are improving patient outcomes. Of course it generates a lot of debate which again is very important. So let’s start with one of the papers which was shown at the congress, at the overall session, by you Neeraj and this is an academic phase III trial looking for the first time at Orteronel or TAK-700 in men with metastatic castration-sensitive disease. This was conducted by the co-operative group, the SWOG group, and this is the first time we see the data. So can you please remind us what was the design and what are the main data?

NA:         First of all, it’s such an honour and pleasure to be here with my esteemed and respected colleagues who I always look up to in my career. So thank you for the invitation. SWOG 1216 was an NCI-funded co-operative group where patients were accrued by SWOG, Alliance, ECOG and basically the co-operative group is funded by the National Cancer Institute. In this trial we hypothesised that a combination of ADT plus TAK-700, which is a specific CYP 17,20-lyase inhibitor and does not require prednisone at the doses it was used at in the trial, will improve overall survival compared to standard ADT plus bicalutamide in men with metastatic hormone-sensitive prostate cancer. So the trial enrolled around 1,300 patients, 1,279 men to be precise. The primary endpoint was overall survival and secondary endpoints were progression free survival and PSA responses. At the time of final analysis, at that time after a median follow-up of 57 months, the median overall survival was 81 months with TAK-700 versus 70 months with bicalutamide. However, an improvement of 11 months in the median overall survival did not meet the pre-specified criteria for statistical significance. Other endpoints also favoured TAK-700. So we were intrigued why it happened – it’s a very strong survival benefit for TAK-700 and the control arm actually did much better than expected. We estimated control arm survival would be 54 months, it was 70 months, so a 16 month improvement in the control arm and 11 months improvement in overall survival with TAK-700, all great news. But statistically it was not positive so we decided to do a post-hoc analysis. We found that the leuprolide subsequent therapies were received by 77% of patients on the SWOG 1216 control arm which may have resulted in an absolute median overall survival of 70 months which is, by the way, the highest ever reported for men on the ADT alone arm of all contemporary trials in mHSPC. If you compared the median overall survival of men on the SWOG 9346 trial, reported by Dr Maha Hussain in 2013 which basically included all patients with standard ADT only, the median overall survival on the standard ADT arm was 46 months. So compared to the SWOG 9346 trial which also, by the way, had a similar number of patients with extensive risk, so exactly the same number, the survival was 46 months. So basically survival of patients with hormone-sensitive prostate cancer has improved from 46 months to 70 months in the US. So we concluded by saying that the result of the 1216 portended great news for our patients with newly diagnosed metastatic hormone-sensitive prostate cancer and these results show that early intensification of ADT in metastatic hormone-sensitive prostate cancer in combination with access to life-prolonging therapy in metastatic CRPC is likely going to lead to an unprecedented overall survival benefit in our patients who are being diagnosed today. So this is how I would conclude my trial results.

KF:         Thank you so much Neeraj. So on the one hand it’s a negative trial but it’s also informative of the current situation with probably better outcomes for patients as compared to what we used to see in the past. Alicia, what do you think about this data and what do you think is going to be the future for Orteronel in this space or in other spaces? Tell us what you think.

AM:        Sure, well thank you for asking and, of course, thank you for the invitation. I think that Orteronel unfortunately is not a drug that I anticipate will be moving forward in ongoing development. It actually, as we know, has been assessed in the metastatic CRPC setting and already has not been developed in that setting due to a separate trial. But I do think that Neeraj’s point about the control arm in this particular setting and the way that we have really shifted the survival curve for patients with metastatic prostate cancer in the last decade is probably what this is reflecting is phenomenal. As he said, that 16 month longer than predicted overall survival is just a testament to the work that has been done. I am really happy to see this data because patients who are in this setting who have metastatic hormone sensitive prostate cancer sitting in the clinic will say to you, ‘Well, what is my life expectancy?’ This is, of course, assuming that they get the treatments that we know that we want to give to them. Now we have a way to estimate that and that is one of the biggest benefits from this trial.

KF:         I fully agree. Just to put this into perspective, just two decades ago men in this setting with metastatic hormone-sensitive basically had about one year to live before progression and then a total of, say, three years just to live. We have made tremendous progress and this is what Neeraj’s trial basically confirms and shows very beautifully. Excellent. Laura-Maria, any other comment on this trial?

LMK:      I would obviously agree with what Neeraj and Alicia have said before and unfortunately also for me I don’t think that TAK-700 is going to move forward to where we can use it in practice in this setting. However, to the point of the control arm being so good, we have probably to discuss about what our endpoints for trials are going to be because if we have so many effective treatments out the back, maybe overall survival is not something that we can count on reaching in the future, that’s one thing. Secondly, I would want to congratulate Neeraj because this was a trial where for probably the first time ever a significant number of patients of minority ethnic groups were included and I thought that is the point where we are talking about for quite some time but this is the first time that we see a relevant proportion of minority patients included in this trial. So thank you so much, Neeraj, for contributing this to our whole prostate cancer community.

KF:         Thank you very much. So basically we all agree that we should now intensify treatment for men with metastatic castration-sensitive disease, at least to make it easy for those with de novo disease. There is still some debate here and there about patients relapsing. This is because we saw in the last five or six years a positive trial for docetaxel, for next generation hormonal therapy and also for local radiation therapy directed to the primary in men with oligometastatic disease. The big question is how best we should combine all these treatments on top of ADT and actually should we really combine these treatments? This is exactly the question the second trial that was shown at the overall session, PEACE1, is actually trying to address as a question. PEACE1 enrolled almost 1,200 men, this is also an academic trial collaboration between seven countries here in Europe. Those men received standard of care which consisted of ADT alone at the beginning of the trial and then we moved to ADT docetaxel when docetaxel was shown to improve overall survival during the second part of the trial. Most patients in the trial received actually ADT docetaxel and the randomisation, it’s a 2x2 design so the randomisation was for standard of care alone or standard of care plus abiraterone, standard of care plus radiation therapy or standard of care plus both abiraterone and radiation therapy. So currently with the current follow-up and the number of events that we have in the trial we were able to report data about radiographic progression free survival, which is one of the two co-primary endpoints of the trial, for the abiraterone question. For the radiation therapy question we will need a longer follow-up because we’re focussing mostly on men with oligometastatic disease or large volume disease, whatever you call this situation. But for now what we saw at ASCO was data regarding abiraterone on top of ADT plus docetaxel. So should we use two drugs only or should we move to three drugs? The answer when it comes to radiographic progression free survival is clearly in favour of adding abiraterone. The median rPFS was 2 years in the control arm with ADT plus docetaxel and it was 4½ years with the triplet treatment with abiraterone added on top of ADT plus docetaxel with a hazard ratio of 0.5 and a very highly significant p-value. We also looked at various means of assessing PFS – counting PSA or counting symptoms – and what we found was basically exactly the same thing and the same delta, a big difference – 2 years or 2½ years of absolute difference between the two arms. So there is no doubt that for PFS, even including or using a sharper, hard endpoint, there is benefit to adding abiraterone. The second good news that we saw in the trial was that during the first six months we don’t see much added toxicity from abiraterone. Actually neutropenic fever is the same – 5% in both arms. Some docetaxel side effects are actually even mitigated, perhaps thanks to the prednisone, and the toxicity of abiraterone is as expected with 12% hypertension versus 8%, nothing big. Of course we need to be cautious and see longer term data regarding toxicity. With this I’m happy to ask you the question because that’s much more important than probably even my own opinion. So are you prepared to change your practice based on this data? Should we wait for overall survival/quality of life data or do you think this is sufficient to change, at least for some patients? Maybe Alicia, if you don’t mind?

AM:        Sure. Really I want to also commend you and Neeraj for a fantastic discussion, not quite a debate exactly but a wonderful discussion, at ASCO between the two of you and then Silke Gillessen and Lisa Horvath on this particular topic. Because I think that there will be a lot of answers that may be nuanced not just between clinicians but also, as Neeraj mentioned, between patients who will or who will not be interested in really intensifying. The debate regarding progression, particularly because this is radiographic progression which in many cases is symptomatic at least in terms of anxiety, if not in pain, I do think that there will be patients who are interested in trying to access abiraterone after initial treatment with ADT and docetaxel. I also think that this will be different depending on where you live and certainly even within the US there are regions and groups that want to do more and others that really want to see that final overall survival data before immediately jumping in to another treatment. Of course this is going to vary around the world and depend on financial toxicity as well which can limit people’s access to therapies. So at this point in time this is a conversation that I will have with patients and I look forward to hearing how different patients will fall out on different sides. I also look forward to the survival data and the biologic data that is going to help us understand whether there may be subgroups within here, within this cohort, that may benefit more or less. But very eager to hear what others have to say.

KF:         Thank you very much Alicia. Laura-Maria, what do you think?

LMK:      Thank you so much. Congratulations, this is a fantastic trial and obviously to me the biggest message is how underscored the added value of abiraterone is in this setting. Because obviously the TITAN population was a little bit more specific because it was only high risk, all de novo, as in your trial. Then from STAMPEDE we also have long-term data how big the effect of the addition of abiraterone is in basically a whole variety of patients. This study adds to this. With regards to will I use the triplet, I’m quote-unquote in a little bit of a pickle because for your trial, and that’s very understandable, you changed your standard of care after the coming out of the CHAARTED trial to ADT plus docetaxel. However, the current reality in at least my country where fortunately we have many options available is that the standard of care is usually ADT plus a new hormonal agent, so abiraterone, apalutamide or enzalutamide which was currently approved here too. So for me the question is does then the addition to that standard of care with docetaxel derive a benefit and unfortunately, and that’s just part of the design, this trial cannot answer this. Will I still talk to patients about the triplet? Yes, I will because I think there are certain patients – very young, very risky disease etc. – where I probably or you guys too have the feeling for a long time that the triplet might benefit these patients. But overall the added value of abiraterone in such a variety of patients is underscored again and again, including your trial here, and it’s a little bit sad almost that the approval in de novo high risk disease of abiraterone will probably not change here, despite us knowing that it could benefit so many more patients.

KF:         Thank you. Neeraj, you have the last word regarding this question of triplet versus doublet – what do you think?

NA:         I agree with everything that was said just now by my dear friends Alicia and Laura-Maria, you’ve said it so nicely, so put together. I just want to add here one thing. In my view the castrate resistant metastatic disease phase is the symptomatic phase of prostate cancer or metastatic prostate cancer. I try my best always to delay that phase of the disease and anything I can get hold onto which will allow me to do it for my patients I will look forward to. So if this combination is available in my clinic I will discuss this combination with my patients; I will present the data like I do. In my clinic patients make the decision, my job is to help them make a decision. If patients want to get this triplet as a treatment I will be very happy to offer it. So that’s my take number one. Number two is it will be a nice segue to what we are going to discuss next – we need biomarkers to stratify patients who are at the highest risk of disease progression and death. I think this triplet combination and others coming up soon, hopefully in the next one or two years, will allow us to give something beyond monotherapies and doublet therapies to those patients who are at the highest risk of disease progression and death. So I think we need to find biomarkers to identify those patients. Thank you.

KF:         Absolutely, thank you so much. Okay, let’s move to another phase III trial, TITAN. We saw the data already for the primary endpoints and obviously this is another positive trial for overall survival. But here at ASCO we saw the very first data for quality of life, I believe. Alicia, can you summarise them to us and tell us what you think?

AM:        Of course. Just to acknowledge that this is the data for metastatic hormone sensitive disease – ADT plus apalutamide versus ADT plus placebo. This is the longer term follow-up, so about 44 months of median follow-up here. It was very important that what was demonstrated in terms of quality of life is that patients continued to feel well. Patients on the combination arm did not report worse quality of life overall, they did not have more pain. Interestingly, there was actually similar quality of life and pain control, it seemed, in both arms. Importantly, I would say, patients actually completed their quality of life metrics and this was done at a high rate even with this much longer term follow-up which is important. Also the patients as well as the investigators should be commended on encouraging patients to do that. There did seem to be a little bit more fatigue in the patients who were treated with the placebo rather than apalutamide but in general this patient population maintained a good quality of life. That is what we all want and, as Neeraj said, if our goal is really to prevent the symptomatic portion of the disease process, which really in many cases comes at metastatic CRPC, this drug was able to do that.

KF:         Absolutely, thank you so much. Laura-Maria, we also saw data from another phase III trial, ARCHES which is assessing enzalutamide, another positive trial, at least by rPFS. We saw an analysis for men with low burden disease, oligometastatic disease, can you tell us what was reported and what you think about the data please?

LMK:      Yes, thank you so much. This was a post hoc analysis of ARCHES, as you already said. In ARCHES, again, enzalutamide plus ADT was tested against ADT alone in patients with metastatic hormone-sensitive prostate cancer. Because this was an all-comer population, so there were patients that had a small amount of metastases or many, they could be newly diagnosed but also have a recurrence, the question obviously is is the effect of the addition of enzalutamide different with regards to tumour burden? So in this post hoc analysis it was looked if the presence of one metastasis, two or less, three or less, four or less, five or less or more than six would be different with regards to the effect size of the addition of enzalutamide. We saw that throughout those groups, so different tumour burden as in number of metastases, it was the same effect size almost for the addition of enzalutamide for the endpoints radiographic progression free survival, which is the primary endpoint of this trial, time to PSA progression, time to castration resistance and also time to initiation of new antineoplastic chemotherapy. So in the clinic we ask ourselves often, ‘This patient has a low burden of disease, how much is his benefit from giving an intensified combined therapy from the beginning?’ and this post hoc data would encourage us to use this in all levels of tumour burden.

KF:         Absolutely and actually this is supported by another analysis with the other NHT treatments showing pretty much most of the same degree of efficacy in low burden versus high burden disease. So this is important. Of course you need to balance the toxicity, the cost and all these things but they work. So we are about to finish but let me ask you maybe one final question with maybe a brief answer from you guys. We also saw one big thing at this ASCO which was, for the first time, positive data with Lutetium PSMA which actually was invented in your country, Laura-Maria, so congrats for that. Basically this treatment is now moving, at least in trials, in this metastatic castration sensitive space the trial has started. So tell me what you think about the potential and the rationale of this treatment. Actually, do you think eventually the trial will be positive? Let’s start with Neeraj, just a brief answer – do you think it’s worth it, testing Lutetium PSMA in mCSPC?

NA:         I think it’s worth it. There are always going to be patients who need more intense therapy than what we have right now. Yes, we have optimised, we have improved survival of patients with mCSPC, we have not cured any of them. So I think we will continue to work with newer drugs and novel agents and Lutetium, to me, is one of those agents.

KF:         Okay, thank you. Alicia, do you agree?

AM:        I completely agree. I think that the way that these mechanisms can work synergistically, I hope you’ll have ADT plus, I believe, the investigators’ choice of an AR-targeted agent plus Lutetium versus ADT/AR-targeted agent alone in the trial that I think you’re referring to. I think that will be attacking from multiple different angles and I really do think that that will give us the benefit we need, besides the fact that we’ve moved Lutetium from a very heavily pre-treated population, as was presented in VISION, into an earlier setting where everything seems to do better.

KF:         Okay, thank you so much. Laura-Maria, last word about PSMA Lutetium in this space from a German lady - what do you think?

LMK:      Thank you. Obviously it’s good that we now have a trial that reflects the experiences that we have had here with this drug already for a longer time because we had off label access to it. I’m also intrigued to see what it can do in the earlier disease spaces because it’s a new mode of action that we have not in our armamentarium beforehand. Also I think that PSMA is expressed in the overwhelming majority of prostate cancer cells so having that to target the effect size that that can reach in combination with other drugs is hopefully very good.

KF:         Excellent, thank you very much. I think it’s time to stop this event but I would really like to thank you for participating and I really hope to see you again at the next congress, maybe physically, maybe after the summer we’ll see. But thank you very much, I really enjoyed it. Thank you.