Alicia Morgans: Hi. My name is Alicia Morgans and I'm a GU medical oncologist at Dana-Farber Cancer Institute. I am so excited to have here with me today, a good friend and colleague Dr. Tom Beer, who's a professor of medicine and a GU medical oncologist, as well as being the deputy director of the OHSU Knight Cancer Institute. Thank you so much for being here with me today, Dr. Beer.

Tomasz Beer: It's really great to be here, Alicia.

Alicia Morgans: Wonderful. Tom, can you tell us a little bit about the ARASENS trial, which of course was recently presented at GU ASCO 2022 and also was recently published in the New England Journal?

Tomasz Beer: The ARASENS study addressed patients starting therapy for metastatic prostate cancer. And this is an area where the field has been very busy and productive and we've seen a wholesale change in how we take care of patients. It wasn't very long ago when conventional hormonal therapy alone was the standard of care. We now have level one evidence that combinations with docetaxel as well as with three different next generation hormonal agents all do better than hormonal therapy alone. And ARASENS asked the triplet question. In ARASENS, patients who had previously untreated metastatic prostate cancer were treated with hormonal therapy, with docetaxel and were randomized to the androgen signaling inhibitor darolutamide or placebo and patients were followed for the primary endpoint of overall survival, as well as a comprehensive set of secondary endpoints.

Alicia Morgans: Great. Well, thank you for walking us through that. And I think importantly and something that's very exciting for the field is that it seemed that there was actually quite a positive outcome from this trial. What were the primary findings?

Tomasz Beer: Yeah, so the most important finding was that ADT plus docetaxel plus darolutamide produced a better overall survival than ADT plus docetaxel and placebo. And that effect was characterized by a hazard ratio of 0.68, indicating a 32% relative improvement in the risk of death. And at 48 months, that translated to 62.7% of participants receiving the triplet alive as compared to 50.4% of those receiving ADT and docetaxel with placebo. Pretty significant improvement in overall survival and at least the early reports out on secondary endpoints were consistent with that. We saw a delay in time to development of castration resistant disease, delay in time to pain progression, delay in time to first skeletal related event or time to next antineoplastic therapy. Clearly a favorable treatment effect for the addition of darolutamide to ADT and docetaxel.

Alicia Morgans: Well, and I think that's of course important but in clinic, you and I both know that some of the things that are the most important are actually how well the patient tolerates the treatments. How was the safety profile?

Tomasz Beer: Yeah, well there, the news were really quite good as well. When the two arms were compared to one another, it was pretty difficult to see a significant difference in toxicity. Numerically, there were a couple of places where you could see a little bit more frequent side effects. For example, if one looks at serious side effects, it was 44.8% for the experimental arm and 42.3% for the placebo arm, tiny little difference that's surely not statistically significant. And then, looking at the specific side effects that one would expect, they're really quite similar, especially when corrected for duration of exposure, which was of course longer with the darolutamide arm. Things like fatigue, fractures, falls, cognitive toxicity, depressed mood, really were quite similar in both arms. Now that's not to say that darolutamide has no side effects but in the context of hormonal therapy and docetaxel, both of which produce significant side effects, the addition of darolutamide did not seem to add much in terms of significant adverse events and I suspect whatever it added might have been counterbalanced by the anti-tumor effects.

Alicia Morgans: Thank you for walking through that and I think that generally gives quite a positive light I would imagine to this from your perspective, although I'd like to hear your actual perspective. What do you think about this data? And what do you think about it in the context of the patients you see each day in your clinic? Does this study make a difference for you and your patients?

Tomasz Beer: Yeah, I think this study makes a difference but I do think it's worth discussing this area in a little more granular detail. One of the things that I think is important to note is that for patients who are starting therapy for metastatic disease, there are really four prognostic groups. It's important to recognize that people who have de novo metastatic disease, who present with metastatic disease from day one, are a distinct group compared to those who have recurrence of disease after an initial therapy with curative intent. And then volume of disease also matters. High volume versus low volume makes a significant difference in prognosis. And so one can think of this as a two by two box, de novo high volume is the worst prognosis, recurrent low volume is a relatively favorable disease state.

In that context, most of the studies that have looked at intensifying chemotherapy and ARASENS is no exception, have primarily focused on patients with de Novo disease. And the majority of patients, large majority of patients in this study had de novo metastatic disease. That's a higher risk population. So far, we don't have a report from this study on the volume distribution of this disease. I would expect that many patients will be high volume but we don't know how the study recruited in terms of volume of disease. I think it's pretty clear that the study is positive for those de novo patients that are likely at higher risk. For the recurrent population, that's a relatively small subset of the study and we don't know how many of those were low volume. I think the results are particularly relevant to the higher risk patients and we're awaiting more detail about the composition of the participants.

Alicia Morgans: I think that's a good analysis. And just for the viewers to know, I think this was explained at GU ASCO but the breakdown of the population by volume was not performed because at the time of study design, it was not necessarily the thing that we all were so eager to think about. That of course, the study was designed right after CHAARTED and STAMPEDE came out and there of course, was this controversy around volume that seemed to be important for CHAARTED but not necessarily for STAMPEDE and so the folks who were designing the trial did not necessarily include that. Although what we understand is that the investigators are going to go back and do that analysis so that they will be able to help us answer that question.

Tom, I think it's interesting and I appreciate the way that you broke out the population into that two by two table. I'd love to hear your thoughts on how ARASENS given that two by two table sort of assessment that you've done, relates to the PEACE-1 data that we heard back in September or so, 2021. That population was a little different than ARASENS and it's all based around that two by two table.

Tomasz Beer: Yeah, I think there were small differences. Although PEACE-1 also was a study that predominantly enrolled higher risk patients. But I think what the two studies have in common is that they demonstrated that a next generation hormonal agent in the case of PEACE-1 abiraterone, in the case of ARASENS darolutamide, do add to ADT and docetaxel. Neither study asked the other question that a lot of our colleagues are asking, which is what is the contribution of docetaxel in the context of intensified hormonal therapy that includes a next generation agent? And I think that's where a lot of us are thinking about this. What I took away from both PEACE-1 and ARASENS is that in those patients in whom I'm recommending docetaxel as their initial therapy, I really ought to strongly consider adding a third drug. We've got two randomized studies that are showing the benefit of that. But for those lower risk, lower volume patients where I might favor a hormonal therapy combination, do we need the triplet? I think that's a matter of discussion and debate in our field now.

Alicia Morgans: I would certainly agree with that and I'm hopeful that we'll be able to answer the question. Though at this point, I don't know that any ongoing trials are specifically really going to address that question. Do we need the chemotherapy? But I agree, for those patients where I'm planning to use ADT and docetaxel or where that would be considered a reasonable and beneficial option, I think that it doesn't take much to extend that to adding the AR directed therapy and providing a triplet for those patients. I'd love to hear your thoughts on any other aspects of this, any other, I guess, things that are really compelling or questions you have as you think about the ARASENS data in your clinical practice or where we should go next as a field.

Tomasz Beer: Well, in my clinical practice, I'm talking to my partners and colleagues and we're thinking about how widely to adopt this approach. I think clearly today for healthy, fit patients who have high risk disease, I'm comfortable recommending a triplet either with abiraterone or with darolutamide. It's really those lower risk patients where the added toxicity of chemotherapy has to be weighed against the potential benefit in that context. And I'm not sure that we have a perfect answer for that.

In terms of where the field should go next, I think first of all, it's wonderful to see that we're energetically pursuing more effective therapy upfront. I think the difference in patients that we're making with regard to survival is greater than when these agents are added later in the course of a disease. I think we need to build on these findings and certainly for the highest risk patients, we have extended their survival but they're still succumbing to the disease typically within five years. And I would like to see us apply the principles of precision oncology to better characterize these tumors and conduct clinical trials that add rationally selected precision allocated agents. Be it immunotherapy, be it PARP inhibitors, PI3 kinase inhibitors or other agents that would be deployed based on individual tumor biology. That's what I'd be the most enthusiastic about.

Alicia Morgans: I am enthusiastic about that too. I really look forward to the day where we could do some molecular characterization and use that to help us understand how to best intensify or deintensify therapy, rather than just the volume on the scan when the patient walked through the door. Because I feel like there can be such heterogeneity in some of the things that we use to currently categorize patients, even though as generalized buckets or things on a two by two table, they for a population make a lot of sense. I think there can still be nuances on the individual level and I really look forward to you and your team helping all of us understand these things better. Thank you so much for your expertise and your time today.

Tomasz Beer: Thank you, Alicia. It's been a real pleasure to discuss ARASENS with you today.