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Feb 20, 2019

Dr. Benjamin Maughan who is the mentee of the GU Daily News Associate Editor, Dr. Neeraj Agarwal, discussed the presentations and research that stood out to him during the recent GU Cancer Symposium. Dr. Maughan is an Assistant Professor in the Division of Medical Oncology at Huntsman Cancer Institute.

Welcome to the ASCO Daily News podcast. I'm Lauren Davis, and joining me today is Dr. Benjamin Maughan, who he was the mentee of the GU Daily News Associate Editor, Dr. Neeraj Agarwal. Dr. Maughan is an assistant professor in the Division of Medical Oncology at Huntsman Cancer Institute. Dr. Maughan, welcome to the podcast.

Well, thank you. It's a pleasure to speak with you, Lauren. So you've just returned from the GU Cancer Symposium. How was this year's event compared with previous years?

It was fantastic. Lauren, I've been going to GU ASCO for a number of years now since I was starting fellowship at Hopkins, and it just keeps getting bigger and bigger. So it's a fabulous meeting. One significant change, I will say, this year compared to the previous year is, as the meeting is getting bigger and there's a lot of research going on in the GU malignancies, we're starting to see more and more practice-changing results and research being presented at GU ASCO.

That's very exciting. What presentations stood out to you?
There, actually, were quite a few, as I was alluding to with your previous question. But definitely the practice-changing data really stands out the most. And we saw that both in the field of prostate cancer and kidney cancer. I guess specifically in the prostate cancer, we saw a number of trials that have been published to date exploring in this M0CRPC space, or patients who have castration-resistant prostate cancer but no identifiable metastases on scans since M0CRPC.
We've seen a couple of these trials with PROSPER and SPARTAN showing that apalutamide and enzalutamide respectively improved metastasis-free survival in this setting. Now, at GU ASCO 2019, we saw the third big trial presented, which was darolutamide with the ARAMIS trial. This, again, was in an M0CRPC patient population, and they were randomized 2-to-1 to darolutamide or a placebo. Of note, the baseline characteristics were pretty similar to what we've seen with the PROSPER and SPARTAN trial, in that the PSA doubling time was pretty short, meaning these were fairly aggressive patients.

That's an important point because some patients have a very prolonged PSA doubling time, and those patients may not benefit from any of these therapy. Those specific trials have not been done. So it's unclear the value of these therapies in those better prognostication patients. But regardless, in the ARAMIS trial, we saw a significant improvement in the primary endpoint, which was metastasis-free survival. It was 40 months with darolutamide versus 18 months with a placebo, and led to a significant improvement as measured by the hazard ratio and it was statistically significant.

Interestingly, all of the other specific subgroups appeared to benefit-- age, prior [INAUDIBLE] therapy, radiation, or surgery. So now we have a lot of data between all three of these trials showing that novel hormonal therapies with either apalutamide, enzalutamide, or now darolutamide significantly benefited these patients. Now, because these patients have no metastases, we always have to ask our question-- and therefore, they're not having any symptoms from their disease-- we have to be very cognizant of any specific side effects that we may cause or a worsening of their quality of life by introducing therapy this early in their treatment process. And that was really encouraging news with the darolutamide.

The discontinuation rate of darolutamide was the same as the placebo group, 8.9% and 8.7% respectively. Fatigue is a big issue with this patient population because of their ADT therapy, which causes a lot of fatigue. We've seen fatigue with apalutamide and enzalutamide. And there was a slight increased rate of fatigue or asthenia in the darolutamide compared to the placebo, but it was small-- it was around 15% or 16% versus something like 11% with placebo. So it appears that it's very well-tolerated. So that was really encouraging news overall.

The other big news with prostate cancer was in a slightly different space, it was in the metastatic hormone-sensitive prostate cancer population. And this was the ARCHES trial, specifically with enzalutamide versus placebo. So in this trial, patients were randomized one-to-one to either ADT with placebo or ADT with enzalutamide. Now, historically for these patients, the treatment-- we've seen a number of clinical trials looking at ADT plus chemotherapy or ADT plus abiraterone, both showing improvement over ADT plus placebo alone. And so this trial, we've been anticipating for a while.

Again, it showed that patients regardless of high volume or low volume disease, if they had de novo metastatic disease, so they were presenting with metastatic disease at presentation of their diagnosis of prostate cancer or if they had previously been treated for localized disease and then progressed to metastatic disease, all of those patients appeared to benefit with the addition of enzalutamide over placebo. Very importantly, though, a number of these patients, just because of the CHAARTED and the STAMPEDE data that came out before, a number of these patients were allowed to receive docetaxel before enrolling in this trial. Somewhere around 20% of the patients had received prior docetaxel, and those patients also appeared to benefit from the enzalutamide.
And that's particularly important because now we're starting to ask the question, since docetaxel and these novel hormonal therapies have non-overlapping toxicities and distinct mechanisms of action, what about trimodality therapy? So again, it's a relatively small subset, only about 20% of the patients, but it's intriguing and interesting to note that they also did benefit. So now in the prostate cancer realm at GU ASCO 2019, we saw further evidence that the M0CRPC population benefits from darolutamide. We saw that in the ARCHES trial, enzalutamide is another therapy that appears to be highly effective in these patients with metastatic hormone-sensitive prostate cancer patients. And so all of that was very encouraging news.

That's very exciting in the research front. What about the education sessions? Were there any that caught your attention?

Yes. So in terms of the educational sessions-- again, that's one of the nice features about some of these disease specific symposia, as opposed to the annual ASCO meeting, is there's a lot of education, as well as just straight research. And so we get lots of debates about controversial topics with a lot of thought leaders in the field, et cetera. So that's another nice part of GU ASCO.

One debate or educational session that I thought was very interesting was this discussion between a radiation oncologist, [? Jason ?] [INAUDIBLE], and a urologic oncologist, Michael Cookson, about what's the ideal first line therapy for patients with muscle-invasive localized bladder cancer. Is it trimodality therapy or is it neoadjuvant chemotherapy followed by cystectomy? This is something that's a growing debate in the field. Now historically, it's always been viewed as the neoadjuvant chemotherapy followed by cystectomy is the ideal treatment for these patients.

First line therapy and the trimodality therapy-- I guess I should specifically mention-- so trimodality therapy is where patients have optimal debulking with the TURBT, followed by concurrent chemotherapy and radiation therapy, followed by surveillance. So they felt that that trimodality therapy is best reserved for those patients that are not cystectomy candidates for a variety of reasons, comorbidities or other such problems.

There's some growing evidence to suggest that perhaps trimodality therapy may be an equally effective way at achieving oncologic outcomes, ie, cures, at the same time, though, preserving the patient's native bladder, and therefore improving their overall quality of life. So this debate was highly instructive and very interesting. I will say, Dr. Cookson was pointing to the National Cancer Database information comparing retrospective data, but comparing the overall survival with radical cystectomy versus trimodality therapy, suggesting that radical cystectomy is more effective in achieving oncologic outcomes with cure.

But Dr. [INAUDIBLE] appropriately pointing out that these are retrospective analysis and there's a lot of patient bias that goes into this, because again, historically, trimodality therapy is reserved for those patients that are not deemed surgical candidates, oftentimes because of comorbidities. So their worst prognosis patients, and you would predict that those patients have inherently a worse overall survival anyway. So it was a very instructive and intriguing debate, and I anticipate perhaps we eventually will see the gold standard of a randomized controlled trial performed, which will answer the debate. But very instructive, very interesting, and a great component of these meetings.

Are there any other takeaways that were important during the symposium?

As I mentioned, prostate cancer isn't the only disease area where there were some interesting and exciting clinical trials that came out that are practice-changing. We also saw a number in kidney cancer. The two highlights in this area were both asking the question, does a tyrosine kinase inhibitor, a molecule targeted therapy in combination with a checkpoint inhibitor improve cure rates over tyrosine kinase inhibitor alone?

Currently, the standard of care for patients with metastatic kidney cancer is either monotherapy with the tyrosine kinase inhibitor or combination checkpoint inhibitor with ipilimumab and nivolumab. So we've seen some data come out recently looking at these molecularly targeted therapies plus checkpoint inhibitors. And so at GU ASCO 2019, we saw updated results on a number of things. One, on the updated results from ipilimumab and nivolumab, demonstrating that the complete response rate is somewhere around 10%, 11%. But then we also saw some updated results of axitinib plus nivolumab versus [INAUDIBLE].

In this trial, about 20% of patients had favorable risk disease, 65% or so had intermediate risk disease, and another 20ish percent or so had poor risk disease, so about what we typically see in clinic. And the response rates were high with the PD-L1-based therapy. The complete response rate was around 4%. The trials that we were really excited to see the results from was the KEYNOTE 426 study, which was axitinib plus pembrolizumab versus monotherapy with sunitinib.
So again, this, similar to the others, w

as a first line therapy. Patients were started on a lower dose of axitinib of 5 milligrams, and it could be dose escalated if it was tolerated. And the enrollment across the trial based on the risk categorization of INDC was similar to what we've seen in a lot of these trials. Again, about 30% of favorable, a little less than 60% had intermediate risk diseases, something around 15% had poor risk disease. So very similar to the other targeted therapy plus checkpoint inhibitor trials that had just recently been reported.
The results were pretty encouraging. The hazard ratio was 0.69 for death or progression, favoring axitinib plus pembrolizumab. Around 90% of patients were alive at 12 months versus just under 80% for sunitinib. The complete response rate was around 6%. So again, very encouraging data. The one potential issue that we need to look to is safety as we're comparing these strategies versus the current gold standard immunotherapy approach, which is ipilimumab plus nivolumab. So the proportion of patients discontinuing treatment on this axitinib/pembrolizumab trial was 30% versus 14% for [INAUDIBLE]. And that's approximately what we see with the ipilimumab and nivolumab data.

Again, this appeared to be well-tolerated and safe, and it seems to have advantages over ipilimumab and nivolumab in that regard in terms of safety. The big question that everyone's asking is, which strategy is more effective and [INAUDIBLE] a larger proportion of patients that have durable responses? These may be cures. Again, that number is around 11% based on the updated data that was presented at GU ASCO for ipilimumab and nivolumab versus in the 5% range that we're seeing so far with the axitinib-based combinations with either pembrolizumab or atezolizumab.
So it's still fairly early with either of these trials. We need to see if with time the complete response rate improves. But overall, really exciting and really encouraging, because these combinations appear to be active, well-tolerated, and are definitely leading to durable responses in patients.

That's great. It sounds very promising. Again, today, my guest has been Dr. Benjamin Maughan. Thank you for being on our podcast today.

Thank you so much. I appreciate the time Lauren.

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