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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston in the U.S. I'm so excited to have here with me today Dr. Richard Cathomas, who is a Medical Oncologist in Chur, Switzerland, where he's also the Deputy Head Physician at Kantonsspital there. Thank you so much for being here with us today, Dr. Cathomas.

Richard Cathomas: You're welcome, Alicia. Thank you for having me.

Alicia Morgans: Wonderful. So I wanted to talk with you about an abstract presentation that you and your team had at ESMO 2021. Really an interesting strategy of using maintenance darolutamide in patients with metastatic castration-resistant prostate cancer after they'd had an AR targeted agent, as well as a taxane chemotherapy. Can you tell us a little bit about your study?

Richard Cathomas: Yes, certainly. So this was a phase two trial. It was an international multicenter study and it was placebo controlled and double blind. And patients, as you already said, had to have prior treatment with a novel hormonal agent. This was usually abiraterone or enzalutamide or both, and then followed by a taxane, either docetaxel or cabazitaxel with a certain dose level that they had to reach from the docetaxel or cabazitaxel. And when they had stable disease on the taxane, they were allowed to enter the trial and were randomized to receive either darolutamide twice daily 600 milligrams, or placebo twice daily, and the treatment started two to eight weeks after the last taxane dose.

Alicia Morgans: So I think that's a really interesting strategy. And we talked before we started recording that you and the team in Switzerland, you've been thinking about this maintenance strategy. Can you tell us why you're inspired to think about that approach?

Richard Cathomas: Well, we thought that actually, if you had a stabilization of your disease on chemotherapy, it's somehow a waste of time to wait until your disease is progressing again, and actually, then the patient is often clinically symptomatic. It's difficult to get another response. And so we thought since we have very good and very well tolerated novel hormonal agents, such as darolutamide, which actually is indeed very well tolerated as we could demonstrate in our trial, that give patients the chance of having a maintenance treatment right after the end of chemotherapy to prolong their good quality of life, and the response they had on chemotherapy, would be a good idea.

Alicia Morgans: I think that's a great idea. And I think that we just saw in a different disease setting, of course, the metastatic hormone sensitive disease setting with piece one, that the strategy actually has quite a bit of effectiveness potentially. So thank you for going through that. Now, what did you find in this study?

Richard Cathomas: Well, we included 90 patients in the full analysis set. Two patients had to be excluded due to major protocol violation. So each arm had 45 patients and the median age was 71 years. And actually the majority had the abiraterone as a prior novel hormonal agent, 60%, 30% that had enzalutamide, and 9% had both. And the vast majority was then treated with docetaxel, around 90%. And so our primary endpoint was the radiographic progression-free survival at 12 weeks. And our aim was to show an improvement of 20%, from 50% to 70% for the rPFS 12.

And so the final result was that 65% had radiographic progression progression-free survival at 12 weeks, compared to 52% in a placebo arm. So that led to a difference of 12%, which was actually statistically significant. Looking at the median rPFS, the difference was one month, 5.5 versus 4.5 months. So again, it was statistically significant, but it was a modest improvement.
So we went on to look at some other secondary endpoints, which were event-free survival. And we defined the event as being either death or progression with two out of three factors, so PSA progression, radiographic progression, clinical progression. If you had two out of these three factors, you had an event. And that event free survival was prolonged from 2.9 months on placebo to 5.4 months on darolutamides, which was a major improvement, I think.

And interestingly, we also looked at overall survival, and we demonstrated a three months improvement in overall survival. It was 24 months on darolutamide and 21.3 on placebo. The hazard ratio for that was 0.62, but it was not statistically significant. The trial was also not powered to show overall survival benefit.

So I think, in essence, it's a positive proof of concept study and that we also looked at some subgroup analysis. And the interesting subgroup analysis we found was looking at rPFS and OS, depending on the response to the latest novel hormonal agent. And this is an interesting concept that we have seen before, which is somehow also intuitive that if you had the response to your latest novel hormonal agent, that you're more likely to respond again if this type of agent is reintroduced, and this is actually what we could see with a very clear rPFS and OS benefit in patients who had a PR or CR to prior abi or enza.

And so this, I think, should make us aware that these are very good candidates to go on very early to start a next NHA treatment after chemotherapy.

Alicia Morgans: I think that this is particularly exciting and really raises interest because these patients had already had progression on a prior novel hormonal agent, and still they could have this subsequent response, particularly among men who had had an initial response that was very good. So I wonder, and this is completely speculation, but I wonder if the responses were stronger because we were at least switching from the SIP 17 inhibition with abiraterone for most patients to a direct androgen receptor inhibitor in this second novel hormonal agent space. What do you think?

Richard Cathomas: We actually looked at this subgroup as well. So we checked for patients who had abiraterone as compared to enzalutamide as a prior novel hormonal agent and actually we could not see a difference. On the other hand, we know from crossover trials like [inaudible 00:07:06] and published in Lancet Oncology 2019, that if you switch from abi to enza, the response is better than the other way around. We could not demonstrate the same here with giving chemotherapy in between, but I'm pretty sure that changing from a testosterone synthesis inhibitor, such as abiraterone, to a very potent androgen receptor inhibitor, such as darolutamide, is the better sequence than if you had an androgen receptor inhibitor like enzalutamide, and then you switch to daro.

But then also having said that, daro is a different androgen receptor inhibitor. It has a bit of a different structure and it might well be that you can still respond, even though you have had enzalutamide before. So our subgroup analysis did not show any difference whether you had enza or abi. So all we could see is that the patients responding prior were doing better.

Alicia Morgans: That's still really, really interesting and important information. And it's also important to know that we didn't see a difference, even if we're underpowered, I think, for that particular analysis, that the fact that there is no signal is important information too. So very, very interesting.

So where does the study team go from here? Because I know that you and the team do many clinical trials and would love to hear next steps.

Richard Cathomas: Well, it's interesting you're asking. I just had a longer discussion this week with Silke Gillessen whom we designed the study together with, and we have designed several other studies over the past 10 years. So, which is the next step now to go for? And well, we think since everything is changing much earlier, so we've just heard the results from piece one, we will treat essentially, I hope, all the patients would receive ADT plus a novel hormonal agent, maybe even in some cases with docetaxel right from the start being hormone sensitive. Our idea is to really go into this space, what do we do next if they are then progressing? And so we're kind of thinking about the next trial will be in this kind of space, like first-line mCRPC with patients who have progressed on a double or a triplet treatment, and what do we do best in these patients? And so I cannot tell you many more details, but this is what we're thinking about.

Alicia Morgans: I think that's the perfect place to investigate. I know our patients and of course the docs need the information, so I encourage you to continue along those lines, and I really do look forward to seeing where you and the team end up and what novel data you add to the field when the study concludes. So if you had to summarize the findings from this work, what would they be?

Richard Cathomas: Well, I think we could really show that you can prolong radiographic progression-free survival with such a maintenance approach, a switch maintenance approach. There is improvement. There is especially encouraging improvement in overall survival. And for myself, I think we should, in patients who are on this third line or even fourth line setting, not wait too long until we install the next treatment after they have had those ataxel or cabazitaxel chemotherapy. So I would personally not wait until they become radiographic progressive or clinical progressive, but would rather start treatment earlier on, even if they only have PSA progression in this very late field of disease.

Alicia Morgans: Well, the field continues to change from these switch maintenance approaches to combination therapies and imaging that's really got us all turned on our heads. It just is a moving target. And I really appreciate you and your team. And of course the patients for adding to the data and helping us find our way. I appreciate your expertise today as well. Thank you.

Richard Cathomas: Thank you very much, Alicia, it's been a pleasure.