DEAR: Comparative Real-World Evidence on Darolutamide, Enzalutamide, and Apalutamide for Patients with nmCRPC in the United States - Neal D. Shore

June 23, 2023

Alicia Morgans engages with Neal Shore about the DEAR study, an analysis of real-world outcomes for non-metastatic castration-resistant prostate cancer (nmCRPC) patients treated with darolutamide, apalutamide, and enzalutamide. The study is made possible by an organization called PPS, which has access to electronic data. It includes information about when patients started their treatments, associated side effects, PSA progression, and the duration of treatment. Importantly, the study finds patients on darolutamide appear to experience fewer adverse events and remain on their treatment longer, possibly leading to a greater impact on disease progression. Although it is not a direct comparison, it provides valuable insight into the real-world application of these therapies. The discussion highlights the importance of early and intensified treatment for non-metastatic CRPC patients, selecting drugs that are well-tolerated, and considering patient quality of life.


Neal Shore, MD, FACS, Director, CPI (Certified Principal Investigator by the Association of Clinical Research Professionals), Medical Director for the Carolina Urologic Research Center and practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Neal Shore where we have the opportunity to speak about the DEAR study. It's a really exciting real world analysis of patients with non-metastatic CRPC who were treated with darolutamide, apalutamide, and enzalutamide to understand how the patients actually fared on these treatments and how things seem to happen in the real world. Thank you so much for being here with me today, Dr. Shore.

Neal Shore: Oh, my pleasure.

Alicia Morgans: Wonderful. So Neal, you did a great job with this work. I think really a hypothesis generating and hopefully reflective of what we do in the real world and in our practices. Can you tell me a little bit about the DEAR study? How was this composed? How were you able to do a real world study in a population that's actually a little bit difficult to pin down the non-metastatic CRPC setting?

Neal Shore: Yeah, well this was through the efforts of US community urologists and with an electronic data capture through an organization known as a PPS. And they have over 3000 urologists in the US and they have their EMR accessibility and so they really have a pretty powerful way to interrogate for the data. And they really looked at an index date of over 800 patients and we have this great advance of three wonderful trials in nmCRPC, PROSPER, SPARTAN and ARAMIS. And they took real world data with not only looking at when patients were started on these approved nmCRPC agents, enzalutamide, apalutamide, and darolutamide, little over 800, but were able to also do chart polls with the sites and look at what the start dates were and what the associated adverse events were, what the associated issues were in terms of PSA progression.

Of course their baseline demographics, age, PSA at start of therapy, doubling times. And I think it's a really cool study because it's real world. It's basically looking at that analysis, it's retrospective, it's not necessarily a direct comparative analysis, but it is descriptive and important because you're seeing how long are patients staying on these medications, when would they be switching over to other medications? What's the time to CRPC and what are the associated adverse events?

Alicia Morgans: Great. So this was a pretty large population I think, which is one of the reasons I think it was so interesting to have a real world population of around 800 or so patients, to me is pretty compelling because it is hard to identify non-metastatic CRPC patient population. You do need to do that chart review, you do need to have those extra steps. There are not claims that can pull these patients out. And so I wonder, can you tell me what was the breakdown between the three treatments that were monitored and what were you, in terms of patient numbers, and what were you looking for in terms of outcomes? You've kind of alluded to this, but just to sort of state that concretely.

Neal Shore: Yeah, I think so it's about almost of the 800, it's about almost even between the patients who received darolutamide, enzalutamide, a little bit less on the apalutamide side, but healthy numbers, 200 plus in the, or close to 300 in the Enza-Daro, little less than I think about 150 in the Apa arm. So a significant exposure and really trying to understand how long did patients stay on therapy and what were the associated adverse events that were reported? What were some of the reasons why they may have switched to another therapy? Those kinds of real world decision making metrics that happen in the clinic, but then also the time to CRPC, the time to progression.

Alicia Morgans: Great. So when you looked at the data and certainly presented it, and I think you presented this data at AUA and a different take was presented at ASCO just this year as well, what did you see in terms of time to discontinuation? Were there differences between these three drugs?

Neal Shore: So yeah, I think I said CRPC, I meant to really say mCRPC. So there obviously radiographic and really bond conventional imaging. I mean the patients were there when we looked at just simply the AE profiles there seemed to be a less AEs in the categories that have been noted before in comparison to apa and enza somewhat favoring daro. I think that's important to recognize because if drugs are tolerated better, then patients tend to stay on drug longer. If they're not having issues with cardiovascular variables, such as hypertension, or if they're not having any cognitive issues or they're not having rash, then they're going to stay on drug longer. And that seems to be born out in this population of nmCRPC patients and as we said, a little over 800.

And so with that one can then make the assumption that if they're going to stay on drug longer, because these are all three very effective drugs, they clearly are inhibiting very competitively the antigen receptor and they're slowing down prostate cancer, cellular proliferation, if you stay on drug longer, if you don't have discontinuation, drug holidays, dose reductions, then arguably you can make the assumption that patients will have a greater effect on impeding the development of mCRPC or ultimately worsening progression and resistance.

And I think that's sort of the takeaway that I have from it, that patients seemingly or stayed on drug longer in real world setting for folks with daro versus enza and apa. And so you would naturally see these clinical benefits as well. I don't think it's fair to say that one drug necessarily has a better mechanism of action or has greater potency or efficacy, but we know that in all forms of cancer and prostate, neuro-oncology, medical oncology is no different. If you can stay on drug for a longer period of time and you'll get the benefits of the MOA. I think all things considered, we didn't see much difference in terms of any economic issues or commercial insurance issues that would've impacted the use of the therapies.

Alicia Morgans: Yeah, I think so, so interesting and so important. So as you said, longer time to discontinuation for darolutamide, interesting that this was born out in adjusted analysis, adjusting for things like age and time of the analysis and PSA doubling time, some factors that are really considered pretty important in prostate cancer, multi-variable analyses. So in those adjusted analyses, longer time to discontinuation on darolutamide versus enzalutamide and apalutamide, at least in this real world cohort and then numerically fewer adverse events. It was also interesting, and I think you also mentioned this, that there seemed to be a longer time to metastatic CRPC for patients treated with darolutamide than for patients with treated with enzalutamide and apalutamide. Again, born out in those adjusted analyses. But to your point, I think it's really important, especially in a real world study where we are not randomizing patients, we are not following them prospectively.

These kinds of findings are hypothesis generating, may influence our clinical decision making, but it's not a randomized comparison, but it is interesting information and this real world cohort perhaps we see that. But to your point, intensifying therapy in the non-metastatic CRPC setting is so important. Choose a drug, get the drug that your patient has access for, and get your patient on that drug. But interesting that there did seem to be a longer time to mCRPC with darolutamide versus the other two. And I don't know if you have any messages beyond that. It's tough in a non-randomized retrospective real world study.

Neal Shore: Yeah, you make all really great points. Looking at the baseline demographics, it's nice to see that real world, a little over 20% of patients were non-white. We don't see that typically in the larger trials, and so I think this was again really good when we look at some of the underrepresented patient populations from the larger phase three trial. So that I thought was an important finding as well. Most of the patients had doubling times of less than 10 months based upon the inclusion criteria. In the US It's not in the label. You can order these or prescribed these therapies. Some countries it's different. They have it in the label of less doubling time, less than 10 months. I think it's important that that gets calculated. And it was nice to see that in doing this analysis that the overwhelming majority of patients were prescribed who met the PROSPER, SPARTAN, ARAMIS inclusion criteria of doubling time less than 10 months.

Alicia Morgans: Great. So if you had to make a conclusion or a summary just to have a take home message for those viewers who are trying to sort through all of the data that's come out in the last number of months across prostate cancer for this particular trial, what would that be?

Neal Shore: Well, I think you made a really good point that nmCRPC, these patients, if we treat earlier based upon conventional imaging, we can have a subsequent discussion about using molecular targeted imaging or the PSMA pets, but I don't think it's going to really change much. I think intensifying therapy with these oral medications, making sure you pick the one that is well tolerated, it's not going to impact their quality of life or certainly have a full throated discussion about what the adverse events could be, but we clearly now have great level one evidence in the guidelines. These patients need to be treated and not wait for them to develop metastatic CRPC. Certainly by conventional imaging these patients, it delays that progression. And all of those trials have certainly demonstrated an improvement in their overall survival. So intensifying for these patients is a very important thing. These are three very active and high quality and efficacious drugs. So this is just another window into thinking about what patients may tolerate which drug at what point in time.

Alicia Morgans: And really I think the message is so consistent, intensify in metastatic hormone sensitive, intensify in non-metastatic CRPC, intensify, intensify, intensify as our patients can tolerate. And I think that we as a field can continue to move in this direction and we've had so many advances that we really have the opportunity to do it and we can do it in a way that is pretty minimally toxic to our patients. And in fact, multiple studies have shown that patients seem to feel like these are tolerable treatments and that they're very minimally different than ADT alone. So wonderful and great to see that we have some real world data to add to our knowledge base. Thank you so much for your time and for contributing this really interesting study. Thank you for your expertise.

Neal Shore: Oh, thank you.