Prostate cancer updates: TITAN and ENZAMET

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Published: 3 Jun 2019
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Prof Ian Davis and Prof Axel Merseburger

Professor Axel Merseburger and Professor Ian Davis discuss the latest data from the TITAN trial and ENZAMET trial presented at ASCO 2019 in Chicago, commenting on key efficacy and safety data and the distinguishing features of each trial. The experts also reflect on the ARCHES study presented at ASCO GU 2019 and the anticipated impact these trials will have on the clinical landscape.

Latest data from the TITAN trial
Key findings from the ENZAMET trial
Potential treatment combinations for patients with prostate cancer
Overview of the ARCHES trial

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

 

ID: Hi, my name is Ian Davis, I’m a medical oncologist from Monash University and Eastern Health in Australia; I’m also Chair of the ANZUP Cancer Trials Group. I’m here at the ASCO 2019 meeting where we’ve heard a lot of interesting information about developments in the treatment of prostate cancer. I’m pleased to be talking with you, Axel Merseburger, a urologist from Germany. Axel, you’ve been involved in the TITAN clinical trial which generated a lot of interest a few days ago. Can you give us some information about that?
AM: Yes. Ian, thanks a lot. Thanks for the introduction, it’s an honour to be here and I’m flattered to be involved in this trial. It was presented a couple of days ago by Kim Chi from Vancouver. We all know him, he’s publishing a lot of game changers and a couple of days ago this was another game changer. It was apalutamide in a randomised phase III trial recruiting more than 1,000 patients one to one. ADT plus apalutamide versus ADT and placebo in primary metastatic, de novo metastatic as we could say, prostate cancer. In this situation this resulted in a 33% reduction of death and also a 66% reduction of progression. So the hazard ratio was 0.67 for death, for overall survival, and 0.48, so this is really clinically relevant, for the combination of apalutamide and ADT versus standard ADT treatment in this situation.
ID: And how was the treatment tolerated?
AM: When looking at the adverse events and especially the adverse events of interest, it was in the ones we want to know as clinicians, grade 3 and 4, it was equally balanced – 42% versus 43% in both arms, so no real relevant differences in apalutamide. We had a little bit more rash which has to be known but it can be managed by topical corticosteroids or I had some patients where we just stopped the treatment for a week and then restarted and the rash disappeared. Don’t ask me about the mechanism but I will consult my dermatologist. So the safety profile was there and this is something that was new. But on the other hand I’ve learned a lot from ENZAMET yesterday, the presentation by Chris Sweeney, where you were the first author in ENZAMET, now published also in The New England Journal of Medicine, congratulations.
ID: And on yours.
AM: So what is your perception or how do you see the differences among those two trials?
ID: So ENZAMET was a very similar concept. So men starting androgen deprivation therapy for metastatic hormone sensitive prostate cancer were randomised to receive enzalutamide or a standard antiandrogen – bicalutamide, flutamide or nilutamide, which is one of the distinguishing factors of ENZAMET from TITAN and ARCHES. We found a very similar outcome, so the hazard ratio for overall survival for the whole population again was 0.67 in favour of enzalutamide and about a 60% reduction in the risk of PSA or clinical progression. We saw pretty much the expected enzalutamide side effects. One other distinguishing factor of the study was about 45% of patients also received concurrent docetaxel.
AM: 45?
ID: 45-50%, depending on the arm, received concurrent docetaxel. There’s been a lot of interest about that triplet therapy. What we found with that was that there was no additional benefit for a man who is on testosterone suppression and docetaxel, physician choice, to add enzalutamide on top of that appeared to give no additional overall survival benefit at this first interim analysis. We did see a signal in favour of progression free survival but so far no survival benefit. And in addition to that we did see more toxicity with the combination. So it’s yet to be determined whether there might be a long-term advantage. A survival benefit may yet declare itself, this was just our first interim analysis after 50% of the expected deaths. But right now we cannot recommend that men should have the triplet combination of androgen deprivation therapy, docetaxel and enzalutamide.
AM: So you would agree that like starting with apalutamide, once it’s approved since we have the TITAN data now makes sense and you’d rather use a sequence like in TITAN 11% of the patients had up front docetaxel and then later on had treatment with apalutamide and ADT, learned from the ENZAMET data that the combination, the triple therapy, probably doesn’t make sense as of yet, as you just alluded to, in the first interim analysis. Would you agree or what would be your sequence 2019?
ID: So I should say that ENZAMET was not designed to answer the docetaxel question, that came in after the CHAARTED data were published in 2014. Uptake was quite good but not everybody on the study received it and it was not a randomised treatment. We did stratify for it. But what we have now is very clear evidence that there is value in adding additional treatment to androgen deprivation therapy. Docetaxel still works and is a very good option for patients where other treatments are not available. Abiraterone also works if that’s available, apalutamide works, enzalutamide works. But combinations of treatments beyond that so far we’ve got no evidence that that’s helpful and some evidence that it might actually cause additional harm. So I think that men going to talk to their doctors now should feel confident that they have several options, potentially, to choose from if these agents are available in their jurisdiction and also that they should not feel that they’re missing out on any treatment if they’re offered one and not the other. There will be reasons why one treatment might be suitable for one man and not for the other.
AM: I totally agree. Maybe we have to consider also the approval status for apalutamide. We have it right now in some countries in M0 CRPC, we might have it in de novo metastatic prostate cancer when we await the TITAN data or we use the TITAN data now but we will not have it as last line where we can still use docetaxel or abiraterone. So it’s a wise decision which one to start with first and here not to have all options available for our patients.
ID: Yes. I think if we did have all options available, and certainly in Australia we don’t and may not for some time, then it would be a matter of sitting down with the patient and ascertaining their own personal preferences.
AM: Toxicity, yes.
ID: If there’s the toxicity profile, there may be financial issues to be dealt with as well. Patients may have comorbidities that might mean one treatment is more suitable than another. So, for example, if a patient has a cardiac failure or diabetes abiraterone and prednisone might not be the best option, you might want to go for one of the lutamides. If a patient has cognitive impairment or a seizure disorder enzalutamide is probably not the best option. If a patient has financial issues or a preference to have all of their treatment out of the way very quickly six cycles of docetaxel, which is very cheap, is a perfectly reasonable alternative.
AM: At the beginning of this year in San Francisco we saw the ARCHES data. To my knowledge it’s not fully published yet but we saw the abstract showing a benefit in PFS in enzalutamide use in primary metastatic prostate cancer. Could you elude on the ARCHES trial and what’s the difference to your trial presented yesterday, the ENZAMET trial?
ID: So there are a lot of similarities between ARCHES and ENZAMET, so the overall idea was similar – the use of enzalutamide. Some differences, though, so the primary endpoint for ARCHES was a co-primary endpoint of overall survival and radiographic progression free survival and the control arm was placebo not standard antiandrogen. ARCHES started about two years after ENZAMET, began to recruit so it’s follow up was shorter, a median of about 14 months compared to 34 months for ENZAMET. Of course ENZAMET was an academic study led by the ANZUP Cancer Trials Group, ARCHES was industry sponsored. But the outcomes for progression free survival are remarkably consistent with what was seen for ENZAMET and also for TITAN. So I think we are seeing confirmatory information there. When the data were presented in February at ASCO GU we’re not yet seeing a survival benefit but I think that’s really just a function of the shorter follow-up and the low number of events that have occurred.
AM: Okay, perfect. Thank you.
ID: So that’s all we have from ASCO 2019, it looks like we have several new options potentially available for men with prostate cancer. Thank you very much for your attention.