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Alicia Morgans: Hi, I'm so excited to be here with Dr. Soumyajit Roy, who is a radiation oncology resident at Rush University, speaking with me today about some work that he has done in the COU-AA-302 data set. Thank you so much for being here with me today, Dr. Roy.

Soumyajit Roy: Thank you so much, Dr. Morgans, for inviting me today. It's all my pleasure to discuss our work on the UroToday platform here. Thank you.

Alicia Morgans: Wonderful. Wonderful. And your work is really fascinating. Recently published in European Urology, so really a very high-impact journal. And this work was analyzing whether treatments that patients with mCRPC may have had in their earlier setting. Definitive treatments to the prostate may affect outcomes when they're treated with abiraterone in this COU-AA-302 study and in that matter. So I wonder, what was the impetus for this study? Why would you think of asking this question?

Soumyajit Roy: Yeah. So as a radiation oncology resident, I always think about local therapy induced changes in the cancer cells, particularly prostate cancer cells. There have been some seminal prior translational works, that have shown that prior ionizing radiation therapy to the prostate can portend neuroendocrine differentiation. Similarly, radical prostatectomy can actually lead to treatment resistant clones. So whether such phenotypic changes have any impact on the response to subsequent blind systemic treatment, when the cancer progresses to a metastatic stage, or when the cancer relapses, that largely remains unknown. And this was the major motivation that prompted me to do this secondary analysis of the COU-AA-302 study, to determine whether receipt of prior prostate-directed local therapy had any impact on response to first-line abiraterone in these patients.

Alicia Morgans: Well, and such an important question it is, and certainly, a clinically relevant one. And this COU-AA-302 population is an mCRPC population, as you mentioned. And this is before chemotherapy, right?

Soumyajit Roy: Yes. So COU-AA-302 actually tested the utility of abiraterone as a life-prolonging therapy, in chemotherapy naive metastatic castrate-resistant prostate cancer patients, who never were on anti-androgen, but never received any androgen receptor signaling pathway inhibitors, and also, didn't have any visceral metastasis.

Alicia Morgans: Wonderful. So really, a population that we see regularly in clinical practice. Now I wonder, what dataset did you end up using, and how did you get access to this COU-AA-302 data?

Soumyajit Roy: The access to the dataset was obtained through a peer-reviewed application at the YODA, which is the Yale Open Data Access project, which has a collaboration with Janssen. So I got access to the publicly available data set of the COU-AA-302 trial by this, submitting this application. And then, once it got granted, then I got access to the individual patient dataset of this study.

Now, definitely, given the study was done quite a long time back, and there was some missing data in about 33 out of 1086 patients. So a total of 1053 patients were included in my analysis. And then, we primarily looked at two objectives. Number one, whether receipt of prior prostate directed local therapy, whether it is radical prostatectomy or radiation therapy, or a combination of both, had any impact on response to first-line abiraterone, in terms of radiographic progression-free survival or overall survival.

And number two, whether as such, receipt of prostate directed local therapy had any independent association with overall survival and radiographic progression-free survival in this chemotherapy naive metastatic CRPC patients.

Alicia Morgans: Great. So what did you find?

Soumyajit Roy: Interestingly, we noted that the hazard ratio for abiraterone, for both radiographic progression-free survival and overall survival, actually varied with time. So we had to calculate the time varying hazard ratio for abiraterone for both these times to event endpoints. And we didn't see any significant heterogeneity of treatment effect from abiraterone on radiographic progression-free survival, or overall survival, among the subgroups stratified by receipt of prior prostate directed local therapy. Or even subgroups stratified by type of prior local therapy, such as radical prostatectomy or radiation therapy, or a combination of both.

We also looked at the heterogeneity of treatment effect on patient reported quality of life outcome. And interestingly again, when we analyzed various subdomains of the FACT-P instrument, there was no difference in treatment effect on these subdomains, based on receipt of prior local therapy.

Another interesting finding that I would like to emphasize here, although, given the fact this is a post hoc exploratory analysis, this finding is merely hypothesis generating, but it is interesting that we found that patients who actually received prior prostate directed local therapy had a 28% reduction in the risk of mortality, compared to those who never received any prior local therapy.
Now, again, I reemphasize that this is a hypothesis generating finding, but I can think of possibly two reasons why we found this. Number one could be that, patients who actually received prior local therapy could have had lower disease burden at their metastatic presentation. And number two, the receipt of prior local therapy could be a surrogate marker for overall superior functional status, or maybe a better adherence to systemic treatment, or even local treatment. So they might be in a better situation, or better position, to have superior overall survival. So these were the two possible reasons that could explain our findings.

Alicia Morgans: Well, and certainly, prior local therapy was not something that was randomized. It was all directed by patients, by doctors. And so, I'm sure that many things can influence, and that was a wonderful discussion of those two things. And really importantly, I think, also sets the stage for us, as we continue to try to treat low volume metastatic patients, even now with radiation, that if we can reduce the burden of disease, and perhaps reduce heterogeneity by eradicating as many clones as possible, maybe we are shifting the disease trajectory, at least in that setting. But perhaps, that's a bit broader even than that particular utilization of radiation to the prostate. Either way, really interesting data, that seems consistent in so many ways with what we see in practice. And also, suggests that we're not necessarily inducing some super clones that are going to maybe react less effectively when treated with abiraterone. Is that your take home?

Soumyajit Roy: Correct. So localized and locally advanced prostate cancer patients always undergo definitive treatment. But with the recent STAMPEDE RMH data, and the HORRAD study, and the stop gap meta-analysis, there are expanding domains of utilizing local therapy in metastatic hormone sensitive setting as well. Particularly, in patients who have limited metastatic burden at hormone sensitive setting.

So our findings are reassuring that, hey, this does not affect response to subsequent systemic treatments, when the patients unfortunately progress to a castrate resistant setting. And this would probably reassure our medical oncologist colleagues that, okay, you should not worry about what kind of local therapy the patients receive. You can actually still use the standard treatment, regardless of what kind of treatment they have received. That's the major part here.

Alicia Morgans: And such a reassuring message, not only to those radiation oncologists, but also to all the clinicians, and certainly, to the patients who are trying to make these really complex treatment choices each day. So I'd love to hear that, and just wonder, what are your next steps? What are you investigating after this paper?

Soumyajit Roy: Yeah. So the thing is that, now that we have seen this in the metastatic castrate resistant setting, I'm also wondering whether we could see something similar in the non-metastatic castrate resistant setting. So SPARTAN, PROSPER, and ARAMIS, these are some of the trials that have already explored and established the role of apalutamide, or enzalutamide, or darolutamide, as first-line therapy in patients with non-metastatic castrate resistant prostate cancer. So I'm thinking of performing, and actually, I have already got access to the SPARTAN dataset. So my next venture is going to determine whether there is any heterogeneity of treatment effect from first-line apalutamide in the SPARTAN patient population, depending on the receipt of their prior local therapy.

Alicia Morgans: Wonderful. Well, we look forward to seeing that investment.

Soumyajit Roy: Thank you.

Alicia Morgans: And seeing it in publication form, so that we can have another conversation with you about this exciting work. And really, I think, helping us to reconsider how we continue to use the data, and the efforts that patients and clinicians provided, even a decade ago, to learn new things about the biology of prostate cancer, and how we can best take care of people in the real world, even today.

So thank you so much for your time, your expertise, and your continually questioning mind. We love to see the work that you do. I appreciate it.

Soumyajit Roy: Thank you so much, Dr. Morgans. It's a real pleasure meeting you. And I would like to thank all my co-contributors who are stalwarts in the field. I just work under the shadow of them, and try to do this work as much as I can. Thank you.

Alicia Morgans: Thank you.