TITAN: update on the data and where next for patients with hormone sensitive PC
Prof Axel Merseburger - University Hospital Schleswig-Holstein, Lübeck, Germany
Prof Kim Chi - Vancouver Prostate Centre, Vancouver, Canada
AM: Dear colleagues, good morning, good day, good afternoon, good evening. Welcome from the virtual ASCO GU 2021 edition. It has been different times and I’m very happy to welcome you for this expert interview ecancer and it’s my privilege to introduce Professor Kim Chi from Vancouver, Canada. My name is Axel Merseburger, I’m a uro-oncologist from Germany – Lübeck, Northern Germany. We’ve been working on this TITAN trial since it came out, say, five years. This story started, I think five years ago on the development of novel substances in metastatic hormone sensitive prostate cancer. When we started, at this time, ADT was still the standard treatment for metastatic prostate cancer. Within the five years we really had some kind of avalanche of data, really a lot to discuss. You excellently presented the final overall survival data out of the prospective randomised phase III TITAN trial looking at apalutamide in combination with ADT compared to ADT alone in men with advanced metastatic hormone sensitive prostate cancer. Can you share your results from the TITAN update at ASCO GU 2021?
KC: Happy to, Axel. So what we found… well, I’ll start back with the initial analysis because you know that TITAN was a randomised double-blind placebo-controlled trial. It enrolled a broad spectrum of patients with metastatic castration sensitive or hormone sensitive prostate cancer. When we first analysed the results back in 2019 and reported them we found an improved rPFS, radiographic progression free survival, as well as in the first interim analysis of overall survival we also saw a survival benefit. So this result that we presented at the 2021 GU cancer symposium was the final event-driven overall survival analysis. This was conducted at a median follow-up of around 44 months compared to the 22 months that we analysed the data initially. This has occurred after 405 death events had occurred.
In this final analysis the risk of death with apalutamide was reduced by 35%, so this is a hazard ratio of 0.65 and the p-value was less than 0.0001. This hazard ratio was very similar to the hazard ratio of 0.67 at the primary analysis of TITAN but this is despite that at that primary analysis almost 40% of patients on the placebo arm crossed over to receive apalutamide. So because of this, to adjust for this crossover we did a pre-planned sensitivity analysis using the inverse probability of censoring weighting method. With this analysis we saw that the effect of apalutamide on overall survival increased with a hazard ratio of 0.52, indicating a reduction in the risk of death by 48% compared with placebo. These are some of the best hazard ratios we’ve seen with ADT intensified therapy trials.
AM: Thanks for the insight those very impressive dual primary endpoints. There were a handful of secondary endpoints which I found, as a clinician, very interesting and important for our patient. One new endpoint, one new secondary endpoint, reported now at this conference, could you do a little bit more on these secondary endpoints and how you see them for everyday clinical practice?
KC: Yes, there are a number of secondary and exploratory endpoints, including PFS2. This looks at the second progression after next subsequent therapy and this was, again, substantially in favour of the apalutamide arm. We also looked at time to castration resistance and this was a combination of PSA, radiographic progression free survival, overall survival and progression and whatever was the first to come. Now, what’s important to note is that the time to castration resistance in the ADT only arm was about 11 months but it was substantially higher in the apalutamide arm and the median had not been reached yet. So it just goes to show you that with earlier treatment, and not that much earlier, we’re talking about within a year on average or by median, the benefit on overall survival is substantial.
AM: I think this is also what surprised me most and also what changed my view on metastatic prostate cancer. When I learned urology years ago there was always this politics or this treatment paradigm to just give ADT and this was awarded the Nobel Prize eighty years ago from now. But since then a lot changed and a lot of developments and, as you said, it’s about a year until the patient develops deadly castration resistant disease when you just give ADT. So I think it’s vintage when you just give ADT and you need to combine nowadays with a novel hormone substance or maybe chemotherapy as an option. So we have a handful of options. Can you explain a little bit the development of castration resistance? Will this be the same mCRPC as we know from just progressing from ADT and previous treatment? There was some discussion here in the community and around the virtual congress if this is the same or if we have to judge this differently.
KC: I want to touch on the first part of your question first when you were commenting about we really have to do more than ADT alone. What I found interesting at the GU ASCO symposium was there were several abstracts presenting on real-world experience of what patients are receiving in the community since 2015 when the CHAARTED study was reported out. In several of these the use of ADT intensified therapy is very low, in one series it was 10% of patients since 2015 had received ADT plus some sort of additional therapy. So I really hope that’s changing now; it may be because of the challenges of docetaxel and the challenges of administering abiraterone and the monitoring required and so on. So hopefully with these new options like apalutamide which has an ease of use and that’s well tolerated that we’ll see that change and we’ll see more patients being offered really this very life-prolonging therapy.
Going on to the other part of your question which was what is the disease that’s now progressing on ADT plus some additional therapy. I think it’s really different whether the patients receive docetaxel versus a next generation AR pathway inhibitor like apalutamide, enzalutamide and abiraterone. For the latter we have to really consider the cancer at this point castration resistant but also previously exposed to abiraterone, apalutamide and enzalutamide. So giving another AR pathway inhibitor after these treatments I don’t think will be very useful based on all the studies that have been done. Because if you think about it biologically, it is the same disease that’s progressing afterwards.
AM: On the other hand, I really found your data very interesting. I think you presented at ESMO with the AR alterations – that you have less AR alterations in the apalutamide treated patients than in the ADT subgroup, somehow giving the hypothesis that it might be an option to treat with, for example, abiraterone post-apalutamide progression. Does it make sense or is it hypothesis generating?
KC: Yes. I think we have to be careful with that kind of observation. So, yes, I did present it but we have to remember that it was a subgroup of the patients and it was a ctDNA based analysis. So ctDNA is very dependent on the level of ctDNA that you sample at the time. So we’re doing further studies to try to look at that more in a larger number of patients to really quantify that, to look at what the molecular mechanisms or genomic mechanisms of resistance could be afterwards. Personally I think it’s about the same. I think the other element to that is that we also have other treatments that we know are also very active after abiraterone, apalutamide and enzalutamide and that would be docetaxel and cabazitaxel. So we shouldn’t forget about chemotherapy and we should reach for those, certainly in patients that are progressing.
AM: Yes, thanks. Maybe a final word, being a principal investigator of some trials myself, I know we get a lot of reports of adverse events and we have to sign and so on. So within this four year follow-up from TITAN how was it safety-wise, how was it quality of life-wise? I think you also presented some data with regards to these aspects.
KC: Yes, so the health correlated quality of life data was reassuring with the extended follow-up. Really, there is no difference between the two arms. In terms of the adverse events, if we look at just the raw numbers we have to remember that the patients on apalutamide were on treatment for much, much longer than the patients that were receiving just ADT and placebo. So if you just look at the raw numbers of course they are going to be higher for the apalutamide arm. So what we’ve done in addition with this analysis is looked at the cumulative incidence of adverse events over time. Looking at that there was actually no difference in many of the adverse events, including fatigue, fractures, grade 3 or 4 adverse events etc. Really there was no difference between the arms. The only difference was in rash and we know that that’s a side-effect of apalutamide. But after six months there is a plateau on the cumulative incidence of rash, meaning that if it doesn’t occur within that first six months it’s unlikely to occur after that.
AM: Well, Kim, it has been a pleasure speaking with you and it is great, thanks for sharing your really deep expert insights, this deep dive on TITAN. Maybe share some final thoughts on the future? We all have to deal with the pandemic right now, usually we would have sat together now with the coffee and planned further projects, unfortunately. Hopefully we can see each other soon again. I think there is some discussion also within the pandemic view on what to give – chemo or not, prednisone or not – and here this all-comer education with the tablet without prednisone, with apalutamide, is pretty convincing, at least from this point of view. Would you agree? And then I hand over for your final words and thanks a lot for participating in this ecancer interview. Thank you.
KC: Yes, I really would agree apalutamide has that advantage as well, not a lot of monitoring either. We want to keep our patients out of the health system until this COVID pandemic settles down. It’s easy to assess a rash on Zoom or by video camera and so on so I think it does have that ease of use.
I guess I’ll leave on what’s next and I think here we’re seeing the new molecular targeting and we’re seeing a number of trials that have been launched or just started up looking at the new targets and that includes the lutetium PSMA studies that are looking at it in castration sensitive disease. Also AKT inhibitors and, of course, PARP inhibitors in patients with underlying DNA repair alterations. So the story continues and I think it’s going to be an exciting next few years as these trials accrue and read-out.
AM: Thanks a lot. Thanks on behalf of ecancer for giving us an opportunity to share your thoughts and especially share the most recent data on apalutamide from the TITAN trial. Thanks a lot, stay safe and all the best.
KC: Thank you Axel.