Overall Survival With Stratification by Disease Volume and Metastatic Status – Analyses of the ARCHES Trial - Arun Azad

March 10, 2022

Alicia Morgans and Arun Azad discuss a post hoc analysis of the ARCHES trial data presented at GU ASCO 2022 of overall survival by disease volume and progression to M1 HSPC after initial diagnosis with localized disease or presentation of de novo mHSPC at initial diagnosis.


Arun Azad, MBBS, PhD, FRACP, Medical Oncologist, Associate Professor, Department of Medicine, Peter MacCallum Cancer Centre, Chair of the Translational Research Committee, ANZUP Cancer Trials Group, Melbourne, Australia

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, my name is Alicia Morgans and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston in the US. I'm so excited to have here with me today, Dr. Arun Azad who is an Associate Professor of Medicine at the Peter MacCallum Cancer Centre and the University of Melbourne in Melbourne, Australia. Thank you so much for being here with me today, Arun.

Arun Azad: Alicia, always a pleasure. Thank you so much for the invitation.

Alicia Morgans: Wonderful. Well, always a pleasure to talk to you too. And I really want to dig into a presentation that you and the team had at GU ASCO 2022, really looking into a post hoc analysis of some of the aspects of the ARCHES data. Love to hear you sort of set up that trial for us so we can dig right in.

Arun Azad: Yeah. Thanks, Alicia. So ARCHES is a phase three double-blind, randomized study in metastatic hormone-sensitive prostate cancer of ADT plus enzalutamide versus ADT plus placebo. So this is a 1,150 patient study, a global study, a large study. The primary endpoint was presented a couple of years back showing a significant improvement in radiographic progression-free survival. And then last year at the ESMO meeting, the study, co-study chair, Dr. Andy Armstrong presented the overall survival data, which also showed a significant improvement in overall survival, which was the key secondary endpoint. So this particular abstract that we presented at GU ASCO was then drilling down a little more on that overall survival data. And it was a post hoc analysis looking at the overall survival stratified by disease volume, and also by whether patients presented with their stage of presentation with the disease. So either being M0 as their initial diagnosis and then relapsing later versus presenting with de novo or M1 disease.

Alicia Morgans: Fantastic. And, can you tell me, I think those distinctions have become so important as we think about patients with metastatic hormone-sensitive disease. Can you put that into context for us? Why is that something we are thinking about now?

Arun Azad: Yeah, thanks, Alicia. That's a great question. I think we started thinking about particularly disease volume when the CHAARTED data came out with upfront docetaxel and really when there was a difference between CHAARTED and the STAMPEDE data for upfront docetaxel, which we won't go into today, but certainly, I think it's clear that the benefit of chemotherapy may be most apparent in men with high volume disease, particularly de novo high volume disease. And Chris Sweeney showed that very nicely in a post hoc analysis of CHAARTED, but it is also very clear that in the clinic, we are always faced with a very diverse group of men with metastatic hormone-sensitive prostate cancer and a man who has de novo, high-volume metastatic hormone-sensitive prostate cancer, who is unfortunate enough to have a very high tumor burden in the bones or in viscera, clearly has a worse survival than a man who has relapsed 10 years after radical prostatectomy with two bone metastases.

And yet they are all lumped under the metastatic hormone-sensitive prostate cancer care group. And so really the importance of actually looking at these in clinical trials and looking at these various subgroups and how these drugs work across these subgroups, I think is very important in terms of informing our discussions in the clinic, because clearly, you want to intensify treatment in men with worse prognosis and on the other hand, some men with better prognosis disease, perhaps we do not have to escalate the treatment as much, or we don't have to convince them as much to have an intensification of treatment, which is something that we want to do with high volume disease, for example.

Alicia Morgans: Absolutely. So what did you find in this analysis?

Arun Azad: Yeah, so we actually found that across the subgroup, so there were four subgroups we looked at, so there was M1 high-volume, and M0 high-volume, remember the M0 is when they were first diagnosed, so it's effectively relapsed high-volume. And then we looked at M1 low-volume and M0 low-volume.  We saw that there was a consistent effect of adding enzalutamide with benefit to that agent when added to ADT versus the placebo group. And the point estimates were all in favor of enzalutamide. Obviously, some of the subgroups were smaller than others, so that impacted the confidence intervals for the hazard ratio, but it was a very consistent effect and benefit of enzalutamide over placebo in these men on ADT. One of the important points to remember is that this study was actually unblinded.

And 31% of men in the placebo arm actually crossed over and received enzalutamide after the initial analysis was done for the primary endpoint, which is radiographic progression-free survival. And so there was a further sensitivity analysis done to adjust the crossover, but I think that is particularly impressive, that the overall survival data in the overall population, which was presented at ESMO last year, as well as in these subgroups that were still maintained, even though there was 31% crossover. And so I think that is an important point to make.  But I think the fact that we are seeing it, the benefit of enzalutamide across all these clinically relevant subgroups is also really important because it informs our discussions in the clinic. When you can say to the patient and his family in front of you that look, this drug has to benefit, irrespective of your disease volume, whether you are presented with metastatic cancer or you relapsed after prior local therapy, that is really important and useful information to have in the clinic. And it informs our discussions with patients and families.

Alicia Morgans: Absolutely. And I thank you also for emphasizing the point about the crossover, because that really, from my perspective means that earlier intensification is so important, that we just can not make up the lost time, but that we lose essentially by not doing that upfront. And I think that was one of the conversations at GU ASCO 2022, also, that really we, as a field need to think about ADT and an AR targeted agent, that intensified strategy, as is the new backbone of therapy for the metastatic hormone-sensitive setting. It seems like the data from ARCHES supports that kind of an approach.

Arun Azad: Yeah, look, we are completely on the same page there, Alicia. There is no doubt, that I think for the majority of men, really ADT alone is not enough. And ARCHES adds to that growing data set, that is showing that, and there has obviously been a series of pivotal practice-changing studies in the metastatic hormone-sensitive space. And we've seen all the UroToday interviews with the various PIs and study chairs for those trials over the past few years. I think that there is no doubt that going hard early with systemic therapy is important in metastatic prostate cancer. And you summed it up perfectly, just waiting till progression is not the answer and yet, and you are very well aware of this, and lots of people are aware of this. And yet when you look at real-world data across the globe, the majority of men with metastatic hormone-sensitive prostate cancer are still getting ADT.

And in a country like Australia, where we do not have, unfortunately, reimbursement for novel hormonal therapies upfront, which is very frustrating, I can understand that because obviously, there are men who are not suitable for chemotherapy, who do not want chemotherapy, but the data coming out of the US, and we've seen many of the investigators presenting data now, the data coming out of the US, where there is more access to NHT upfront, it is just baffling that we have these life-prolonging therapies that also, the question of NHT also, maintain quality of life very well and prolong life, and we are not using it. And it's really frustrating and sad to see. I think.

Alicia Morgans: I really agree. And I think I'm hopeful that the continued data that you and your team, as well as you, said, the PIs from other trials, and the data that we continue to see roll in that really helps to change things. But I appreciate that you and the team are working to get us the information that we need to continue to just hammer that message home. So as you think about this updated post hoc analysis for ARCHES on the survival data, what would your message be to clinicians who are trying to sort out how to put it into practice in the clinic?

Arun Azad: You know, what I would say to clinicians is that the ARCHES data, this latest ARCHES data adds to a very growing body of evidence that supports the use of novel hormonal therapies with ADT across all men with metastatic hormone-sensitive prostate cancer, irrespective of disease volume, irrespective of whether they presented with metastatic disease as their first presentation, or whether they have relapsed after prior local therapy. So this really adds to that evidence. And we know as a field, and this is multidisciplinary across medical oncology, urology, radiation oncology, even, we need to get these drugs into the clinic in men so that they can actually realize the benefit because it's fantastic to see per presentations at GU ASCO and ASCO and ESMO and New England journal of medicine and JCO papers. These are fantastic to see, but unless we actually get these into the clinic in our patients, they are not going to realize the benefit. And we all want our patients to do better. And incorporating more potent systemic therapy upfront is actually a critical factor in our patients doing better.

Alicia Morgans: I agree. It's really that difference between efficacy and a clinical trial and effectiveness in our clinic that makes a difference for the population of patients that we treat. So I sincerely appreciate you talking us through that as well as doing the work that you and your group are doing to make sure that we have the data to support the recommendations that we make in our clinical practices each day. Thank you so much for your time and your expertise.

Arun Azad: Thanks, Alicia. Always a pleasure. Thank you for having me.