Darolutamide Approved for Patients with mHSPC - Charles Ryan

August 5, 2022

Drs Charles Ryan and Alicia Morgans discuss the approval of NUBEQA® (darolutamide) tablets, for oral use for metastatic hormone-sensitive prostate cancer (mHSPC). The FDA has approved darolutamide in combination with docetaxel for adult patients with mHSPC. This regulatory decision is based on findings from the phase 3 ARASENS trial. ARASENS is a randomized phase 3 trial of darolutamide versus placebo in combination with docetaxel and androgen-deprivation therapy (ADT) for metastatic hormone-sensitive prostate cancer (mHSPC). Darolutamide is a highly potent androgen receptor (AR) inhibitor with low blood-brain barrier penetration and limited drug-drug interactions.


Charles J. Ryan, MD, President and Chief Executive Officer of The Prostate Cancer Foundation (PCF), GU Medical Oncologist with expertise in the biology and treatment of advanced prostate cancer.

Alicia Morgans, MD, MPH, GU Medical Oncologist, Dana Farber Cancer Institute, Boston Massachusetts

Read the Full Video Transcript

Alicia Morgans: Hi, I'm really excited to talk today with Dr. Charles Ryan of the Prostate Cancer Foundation, because there's been a new approval or an expanded indication in prostate cancer. Thank you for joining me today, Dr. Ryan.

Charles Ryan: Hi. Good to see you, Alicia.

Alicia Morgans: Wonderful. So can you tell me a little bit about this? The FDA's release just came out, release of information. Tell me what we heard.

Charles Ryan: Right. So what we just heard is that the FDA has expanded the indication for darolutamide into metastatic hormone sensitive prostate cancer, based on the ARASENS trial. Now we've talked about the ARASENS trial before it was originally presented back in February. So there's really not new data coming out today, but now the FDA has approved the expanded access. So that's the news for today.

Alicia Morgans: Well, and it's so exciting, this is a population predominantly in the ARASENS trial, that was a de novo metastatic population about 86% or so, where de novo metastatic. Of course, lots of conversation about high volume, low volume in the mHSPC setting, but that's not something that can be assessed within this trial. What we did see is that ADT plus docetaxel, plus darolutamide resulted in an improved overall survival. As compared to ADT and docetaxel, remembering that ADT and docetaxel has been really a standard of care after the CHAARTED study and the STAMPEDE study showed us that would be associated with improved overall survival as compared to ADT alone.

So now we have a triplet, that improves it even more 32% reduction in the risk of mortality for ADT, docetaxel and darolutamide versus ADT and docetaxel alone, so very exciting. As I think about this data and I know that I see these patients in my clinic and they've been, even before this expanded approval, very keen to consider a triplet approach to knock down their prostate cancer. I wonder if my practice that includes a fair number of patients with de novo metastatic disease is really reflective of the practice out in the broader US. So from your perspective, you are the CEO of the PCF, the Prostate Cancer Foundation. What is your opinion there? Do we see these patients [inaudible].

Charles Ryan: Sure. So let me take a step back and talk about sort of a big concepts that come from this approval. So first of all, is this is yet another piece of evidence that what we have been doing in CRPC is progressively helping expand the benefits when we apply it to CSPC or hormone sensitive disease. And what I mean by that is, it's one thing to see a modest reduction in the risk of death in a CRPC population. But when you take that same reduction in the risk, in a hormone sensitive population, it translates into potentially years of added life. And in fact, I believe with this trial, we still have not reached the median survival in the treatment arm with these data. So, we're seeing this transference of therapy to earlier treatment lead to more extended benefits, that's point number one.

Point number two is, I think it sort of highlights this concept in oncology, that combination therapies are beneficial and that the first hit that we get on the cancer should be our best one. And that it's another piece refuting this idea of sequential therapy and it's supporting intensification of therapy at the very beginning. So those are two hugely important points, paradigms in oncology, supported by these data and this approval. To your point, one of the challenges we're seeing in the field and the PCF is monitoring this very closely, is the apparent rise in the number of patients who are presenting at their first time of diagnosis with metastatic disease. And this is disheartening and we're not quite sure why is it the result of decreased screening? Is it result of decreased access?

It's probably a combination of a number of factors. But the fact remains is that the number of patients who are presenting with metastatic disease as their first sign of prostate cancer has gone up from below 5%, a decade or so ago, to now, well, between 15 and 20%. And so that's disheartening. And I'll couple that with the observation back in 2021, that the actual number of men in the US who are dying of prostate cancer, went up to about 35,000. So in many ways, we're very concerned about this reversal of the trends and we're monitoring this very closely.

Alicia Morgans: But these are the patients who seemed to have the most aggressive disease, the poorest prognosis. And these were the patients who were enrolled in this study. I think it's really critical that we see, that we are able to make a difference. And I think that the ARASENS trial showed us that we can continue to add, and we can bend that survival curve. And in this case, when it comes to darolutamide at least, it speaks to the fact that we can do this in a way that seems to have relatively limited side effects, in terms of limiting a patient's overall quality of life. And hopefully we can continue to do this for years to come again.

As you said, "The median overall survival of that triplet arm has not been reached". So doing more can help these patients. And even in this population where we see they have the most aggressive and poorest prognosis disease. So as you consider this, is this something that you think is going to impact your clinical care? It looks like you are in clinic today. Is this going to impact your clinical care as you go to clinic in the next few weeks and months to come?

Charles Ryan: Absolutely. Not only is it going to, it actually did today, where I'm seeing patients. And so, this is a very much, a real time piece of news for me in my clinic on this particular day. To your point, I want to raise a couple things. It's one thing to have the actual data that should begin to change our minds. It's another thing to have the FDA approval, which is another thing that changes our ability to deliver it. And it's another thing to disseminate the findings. And that's what we're trying to do today, is to make sure that clinicians and patients around the country, and in fact around the world know that these data exists and that it is available because the outcomes are so substantially improved over previous findings and previous baselines.

Furthermore, your work going back now, several years shows that chemotherapy is associated with improvement in quality of life. And that's a myth that we need to help dispel, which is that chemotherapy reduces quality of life in prostate cancer patients. And I think you should speak to the data that you found around the issue of Taxanes in hormone sensitive disease.

Alicia Morgans: Sure. So we were lucky to perform the quality of life analysis within the CHAARTED trial, which of course is an ECOG led study. So a cooperative group study that compared ADT plus docetaxel and an all-comer population to ADT alone. And we found that ADT plus docetaxel improved overall survival, particularly among patients with high volume metastatic hormone sensitive disease. And we also found that in that population, the combination of ADT and docetaxel was associated with an improved quality of life by the time patients get to a year, which we believe is related to better disease control. But at the end of the day, it was not associated with poor quality of life. And even though there are quality of life effects that we can find in the depths of chemotherapy at about the three month time point, those effects resolve and patients feel better. And when they live longer and feel better, we really do think this is a win.

Charles Ryan: Totally agree. So this is a big day for us. It's a big day for the field, and it's further evidence that we're making progress against this disease on one level, if patients get the right therapy, the outcomes are improved. We just need to ensure that they get the right therapy.

Alicia Morgans: I could not agree more. And as we wrap up, I just wanted to add, this is just another piece of evidence that ADT alone is not enough. We really need to treat these patients with metastatic hormone-sensitive disease with combination therapy. So keep this in mind. And I think in general we, as a field also need to be on the lookout. Lots of studies still ongoing, including the ARANOTE trial, which may lead to the demonstration of benefit to ADT and darolutamide without chemotherapy in this metastatic hormone-sensitive setting. Of course, we wait that data and all the other data from ongoing trials is an exciting time to be in prostate cancer. Thank you so much for your time, Dr. Ryan.

Charles Ryan: Yeah. Great to chat with you, Alicia.