Comparing real world evidence to phase III data on apalutamide for nmCRPC

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Published: 19 Sep 2020
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Prof Heather Payne and Prof Stéphane Oudard

Prof Heather Payne and Prof Stéphane Oudard discuss the use of apalutamide in the treatment of nmCRPC based on abstracts presented at the virtual ESMO 2020.

Prof Payne gives a description of nmCRPC and the need for a new treatment approach for this type of cancer. She also compared the benefits and drawbacks of a real world study in testing the efficacy of apalutamide to the phase III SPARTAN clinical trial.

Prof Oudard explained the aims of the SPARTAN phase III trial and the rationale behind using time on the treatment as a proxy for time to disease progression. Reasons behind age dependent early discontinuation of the drug, and health related quality of life proceeding this treatment, were also highlighted.

Both the participants discussed the outcomes of the real life named patient program (NPP) study and the SPARTAN phase III trial and the possible impact these results can have on the clinical treatment of non-metastatic castration resistant prostate cancer (nmCRPC).

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

Prof Heather Payne – University College London Hospitals, London, UK
Prof Stéphane Oudard – Georges-Pompidou Hospital, Paris, France

HP: Hello and a very warm welcome to this ecancer virtual discussion on apalutamide and its use in non-metastatic castration resistant prostate cancer. My name is Heather Payne, I’m a clinical oncologist at University College London Hospitals and I would like to introduce my colleague, in fact.

SO: Hello, my name is Stéphane Oudard, I am a Professor of Oncology and chief of the Oncology Clinical Translational Research Unit at Georges-Pompidou Hospital in Paris, France.

HP: Thank you so much. I’m really looking forward to our discussion today. We have opinions from both sides of the channel, it would appear. So, non-metastatic castration resistant prostate cancer, this is a relatively new term in prostate cancer and it describes a situation for men with a rising PSA despite castrate levels of testosterone from ongoing ADT or orchidectomy who have normal conventional imaging, so no metastasis on bone scan and CT scan. I think that we would all agree that for this group of men, and especially for those with a PSA doubling time of less than ten months, we have known that they are at a significantly increased risk of metastasis and death. Until recently there were no approved treatments for this situation which was incredibly frustrating for us as doctors but even more so for our patients who would have to wait to either get symptoms or have repeated scans to find metastasis, at which point they could have one of the many drugs for metastatic CRPC.

So non-metastatic CRPC, an unmet need but recently we’ve had data from three studies showing an improvement in both progression free and overall survival which I think is changing our practice considerably. Today we’re going to be thinking about apalutamide and talking about two abstracts which are being presented at virtual ESMO. The first is looking at apalutamide for non-metastatic CRPC and comparing data from a real-world named patient programme to that of a phase III randomised controlled study, the SPARTAN trial. We all know that randomised controlled trials are the robust reference standard in which we have new drugs available but real-world evidence is becoming more important to see how the data that we get with clinical studies translates to our everyday practice. Stéphane, what do you think? Do you think real-world data, are we going to be seeing this more in the future?

SO: First of all I think that there is the SPARTAN study which is a phase III trial, placebo-controlled study evaluating the addition of apalutamide or placebo to ongoing androgen deprivation studies. It was reported and published in The New England Journal of Medicine – more than 1,200 patients randomised two to one to apalutamide or placebo plus ADT. Just to remind you that those patients were stratified by PSA doubling time, use of bone sparing agents and nodal disease at study entry. As you say, the primary endpoint for this study, MFS, was positive, outstanding I would say, in favour of apalutamide plus ADT. Now we have this real life study looking at in daily practice in real life whether or not patients do benefit from apalutamide with ADT.

HP: Absolutely and I think some of these real world studies give us a little bit more information because they include groups of patients that perhaps wouldn’t be eligible for a clinical trial but obviously there is a lack of quality control in real-world evidence and there’s no regular radiology review and it can be susceptible to bias.

SO: That’s true. In real life you are not obliged to perform a CT scan, bone scan, every three months for instance like in the SPARTAN study. So that’s why in this named patient programme they compared time on apalutamide instead of time to progression to see in real life for how long the patient was on apalutamide until progression. So it’s interesting to have this endpoint to see if the patient can be maintained on treatment for a long period of time without toxicity and with efficacy.

HP: Do you think that’s a good proxy for time to progression? Do you think that was a reasonable endpoint to be looking at in this comparison?

SO: I think in real life you need to use not time to progression because from one investigator to another you may perform CT scans at different times so that’s why you can’t just rely on time to progression. So time on apalutamide is better because this is corresponding to real life for patients and clinicians.

HP: Thank you, I completely agree. This is what happens in everyday practice. The named patient programme started in March 2018, it involved 536 men in 34 countries and these included Germany, Italy, Ireland and the UK. The data was based on comparison of initial follow-up at ten months in both cohorts. When we compare, because you often hear that argument that these patients don’t exist in real life but they do, they were put into this programme, they were put into SPARTAN, and in the named patient programme it was actually very similar to the patients in SPARTAN. The median age was 74, both studies included men in their 90s. There were slightly more men over 80 in the NPP and slightly less men with a PSA doubling time of less than six months. Stéphane, I know this is difficult because you know the answer to the study but would you have anticipated that we would see similar results in the NPP that we did in SPARTAN?

SO: Yes, I think so. I think maybe the endpoint of looking at ten months, the outcome of the study, is maybe too short if you want to criticize this study. But this is due to the fact that the study was performed in March 2019 and we need maybe more follow-up because, as you know, for apalutamide the MFS is very long and maybe we will have better results in case of mature data in real life. But, nevertheless, as you can see that patient characteristics were maybe the same, maybe a little older, because in real life you may allow to prescribe this drug for any kind of patient without or with comorbidity and so on. So that’s why maybe we have a more elderly patient population but we will see at the end that, in fact, the efficacy is the same.

HP: I think that this study does show that the data confirms that the results from SPARTAN translate very well into everyday practice. The results of the study showed that more men remained on apalutamide at this ten month period. The reasons for discontinuation in both studies were investigator assessed progress, progression, adverse events or withdrawal by patient. There was a difference in adverse events – there were more in SPARTAN than in the NPP. Does that surprise you?

SO: I would say yes and no. I think that yes because these drugs, ADT and hormonal therapy, have some side effects. But no because now investigators and clinicians know how to handle this drug and how to prevent side effects – fatigue, hypertension, cutaneous problems and so on – so they know how to modify, to decrease the dose, to use supportive care for the patient. We know that when you use a drug at the end you have the experience of side effects and how to manage them in daily practice.

HP: I think that’s absolutely true and certainly from personal experience I’ve found this to be a really well tolerated drug and my patients have done extremely well. There were no new safety signals identified in the NPP which is obviously very good news. The patients who were older, certainly more over 75 as opposed to under 65, had more risk of earlier discontinuation. Again, does that surprise you in any way?

SO: I would say no because in the SPARTAN study was found that the younger patients may benefit the most from apalutamide plus ADT as compared to the elderly patient population. So this is just a confirmation of the SPARTAN study. Maybe this is due to, I don’t know, maybe comorbidity or other problems that the patient may face. But it’s very few patients so it’s not a huge category of patients.

HP: And we want to give this opportunity to all our men don’t we, really? I got very excited at ASCO this year when we saw the overall survival benefits in these studies. Do you think that’s going to change practice? Do you think the data from the real world is going to change practice, make us look for these patients and treat them early?

SO: I think so for two reasons. The first one is that we have outstanding data regarding MFS and now OS. As you know, they also looked at those patients who do not receive apalutamide later on in terms of no crossover, I would say. They found out that the difference in terms of OS is huge regarding this no crossover. So it means that you can use this drug, hormonal therapy, much earlier on. You don’t have any cross-resistance regarding the second hormonal therapy that you give to the patient later on, I’m speaking about PFS2. So based on these two factors, OS and PFS2, I think that we are going to use this drug much earlier on.

HP: Again I completely agree, a 14 month difference in overall survival is really compelling. We’ve now seen that this is the same in everyday practice in the real world and the study demonstrating a trend towards improved rates of apalutamide continuation after the first ten months, no new safety signals and it’s been well tolerated and shown similar efficacy in real-world practice.

Now to the second abstract which is looking at quality of life, health-related quality of life. This is longer term follow-up of quality of life from the SPARTAN study. I think that obviously we’re giving men a longer life expectancy but we want that to be a good life. Can I ask you, how did you measure on quality of life in the SPARTAN study?

SO: In the SPARTAN study quality of life was evaluated using the FACT-P and EQ-5D questionnaire. At the beginning of the study every month and then every two months and every four months post-progression up to one year, as you know, each treatment cycle was 28 days and based on that it was possible to find out that there is no difference of quality of life until I would say cycle 11. At cycle 21 and 25 you begin to have a pronounced and statistically significant difference between apalutamide and placebo plus ADT.

HP: You might anticipate that with longer exposure to a drug that quality of life would change. What was the difference between apalutamide and placebo in the longer term?

SO: In the longer term you don’t have any chronic side effects or side effects which impact on quality of life and the quality of life is maintained. In this study we asked the patients whether, first of all, I am bothered by side effects of treatment, yes or no, and it was no mainly for the patients on apalutamide. The second question was men having a lack of energy, yes or no, based on the fatigue due to this treatment. It was not more reported in the apalutamide plus ADT compared to placebo plus ADT so it means that apalutamide does not add any new side effects impacting on quality of life in daily practice.

HP: This is really important, isn’t it, especially for men who have no side effects at the beginning and the fact that for the men on placebo their quality of life started to decline after one year. This again is going to have a big impact on the way that we use these drugs in the future because they are well tolerated.

I think it’s important to also mention that there have been two other studies that have shown very similar results, we said at the beginning, darolutamide in the ARAMIS study, enzalutamide in the PROSPER study, but today we’ve given you some updates on apalutamide. We could talk all day but I guess we all have other things that we need to do. So thank you very much for joining us today and for your attention, we’ve really enjoyed the discussion which I’m sure will carry on afterwards. Please stay well and safe in these difficult times and we look forward to seeing you again in the very near future. Thank you.