Leslie Ballas: Hi, I'm Leslie Ballas. I am a professor of radiation oncology at Cedars-Sinai Medical Center in Los Angeles. And I am honored to be joined today by both Dr. Alexander Sherry, an assistant professor of radiation oncology at the Mayo Clinic in Minnesota, as well as Dr. Bilal Siddiqui, an assistant professor of medical oncology at MD Anderson Cancer Center. They are going to review with us today their recent publication in European Urology, Continuous Androgen Deprivation Therapy with or without Metastasis-Directed Therapy for Oligometastatic Prostate Cancer, which is part of the Multicenter Phase 2 Randomized EXTEND trial.

Welcome, you guys. Thank you so much for joining me today.

Bilal Siddiqui: Thank you for having us.

Alexander Sherry: Thank you so much, Dr. Ballas. It's an honor to be here and discuss the results of our study with you. First, by means of background, the management of patients with oligometastatic prostate cancer is evolving. Recent data suggest the potential to improve outcomes with metastasis-directed therapy, which is most commonly given as radiotherapy. The EXTEND study at large sought to ask the question of whether adding MDT to standard of care systemic therapy might improve outcomes. And to study this specifically in patients with oligometastatic prostate cancer, which we defined as one to five radiographic lesions, we did two different baskets, each with a separate randomization. In one basket, we used an intermittent hormone therapy backbone. And in the second basket, we used a continuous hormone therapy backbone, as these both represent possible standard of care options for patients with metastatic prostate cancer.

We previously reported the primary results of the intermittent hormone therapy basket. And in the present work, we present the primary analysis of the continuous hormone therapy basket. We also report a pre-specified analysis combining these two baskets together and also present additional exploratory work evaluating immune profiles and immune responses to radiation-based treatment. As previous data have suggested, this may play a role in improving disease control in patients with oligometastatic prostate cancer.

We did find that the combination of MDT and continuous hormone therapy improved progression-free survival, which met the study's primary endpoint. In the control arm, as you can see in the Graph A, the median progression-free survival was 24 months, which was extended to 47 months in the combination therapy arm. We also provide updated follow-up for the intermittent hormone therapy basket, and those results are shown in Panel B. The PFS signal that we initially observed was maintained on this longer-term follow-up. And lastly, in the pre-specified combined analysis of both baskets shown in Panel C, we also saw a PFS benefit regardless of the hormone therapy backbone used with the combination therapy.

Interestingly, we also observed some improvements in longer-term secondary endpoints in terms of radiographic progression-free survival. We observed in the aggregate population an improvement with combination therapy compared to hormone therapy alone. And interestingly, in the patient subset that had hormone-sensitive disease at the time of enrollment, we also observed longer castration resistance-free survival, and this is notable because the transition from hormone-sensitive to hormone-resistant disease is a sentinel clinical event, and the natural history of these patients represents a transition to a more lethal disease state. This also hearkens back to some of the original hypotheses regarding oligometastatic disease and the potential of local therapies to intervene and interrupt the natural history of disease. And to our knowledge, this represents some of the first randomized data validating those initial hypotheses on the natural history of metastatic progression.

In terms of our immune profiling, we first evaluated patients with profound responses and also poor responses to MDT, and we observed that immune activation events were largely clustered among the patients with profound responses. This was true in terms of both T-cell proliferation and T-cell activation as well as secretion of cytokines that are known to promote T-cell activation. We then profile these across our full data set and observed immune activation events associated with MDT plus ADT as compared to the control arm.

We also did T-cell receptor sequencing, which is essentially studying the barcode that represents the unique functionality of each individual T-cell, and we did this before and after treatment in both arms. We then estimated T-cell clonal expansion and contraction, which is thought to represent the end product of a highly effective immunostimulation cascade. We observed, as you can see in Panel D, significantly greater T-cell expansion and contraction in the combination arm as compared to the hormone therapy arm.

We were curious to see if this was a phenomenon primarily associated with the combination treatment or with MDT. In a separate trial called the ORIOLE trial, which randomized patients to MDT versus observation, we were able to collaborate and obtain peripheral blood samples for TCR sequencing by the same assay and found that MDT consistently produced T-cell expansion and contraction as compared to the control.

Lastly, in our data set, we found that patients with this immune response had longer progression-free survival than patients that did not. This led us to hypothesize that one of the mechanisms we might be observing among these patients, at least in a subset that leads to improvements in systemic disease control from local therapy, is immune activation events that allow for better immune profiling of distant micrometastatic sites that are not necessarily included in the radiation field.

In summary, EXTEND did meet its primary endpoint, suggesting that MDT might be beneficial when added to continuous hormone therapy. Our secondary outcomes were also improved in terms of radiographic progression-free survival and castration resistance-free survival. And our early translational work suggests a potential biomarker of effect that may also be therapeutically exploitable.

And of course, there are limitations to this study. This is a phase two signal-finding trial. We certainly encourage enrollment on the multiple activated phase three trials that are seeking to more definitively answer this question. Of course, our correlative observations are early in nature. They do need validation and in vivo models as well as subsequent clinical trials. But we do feel overall these results are positive and support a promising role for MDT even when combined with a standard of care hormone therapy option. Thank you again for the invitation, and looking forward to discussing further.

Leslie Ballas: Congratulations on this very well-put-together, well-thought-out trial and manuscript. And thank you for sharing your perspective and the results. One of the things that I noticed was that one of your surrogate long-term endpoints was radiologic progression-free survival.

Did every patient get the same type of imaging? And what radiologic imaging shows progression-free survival?

Alexander Sherry: It's a fantastic question and also speaks a bit to the design of EXTEND as a pragmatic trial. EXTEND initially started enrollment in 2018, and at that time, conventional CT scan and bone scan were the most common forms of imaging.

As the enrollment progressed, we transitioned to doing a lot of fluciclovine PET CTs, and then near the end of the study, we began incorporating PSMA PET scans. Patients were staged in a heterogeneous manner, and also determinations of radiographic progression-free survival were made in a heterogeneous manner, although we did use a RECIST 1.1 criteria to determine all of those. That is a limitation of the study in that patients were not universally staged and followed with PSMA PET scans.

There are, of course, barriers to doing this serially in terms of insurance costs and also given the nature of the trial whose primary endpoint was based on progression-free survival, which was a composite that also included PSA measures. I think those data do need to be interpreted in that regard in future trials. Especially those that use PSMA PET-dedicated radiographic progression-free survivals may give us more conclusive answers as to that endpoint.

Leslie Ballas: Thank you. Another question that I have is recently we saw the publication of the RADIOSA trial, which it was a phase two randomized trial looking at ADT plus METS-directed therapy versus METS-directed therapy alone. They allowed one to three oligometastatic lesions, and their ADT was for six months. Certainly a different patient population, but in many ways, perhaps even a less aggressive patient population than what was seen in your EXTEND trial.

They had a median progression-free survival of 32.2 months with 31 months follow-up. Shorter follow-up, certainly, than your median follow up. But regardless, I'm wondering, do you think that that difference in median progression-free survival is due to just the six months of ADT?
Do we need continuous ADT in all of these patients with oligometastatic disease?

Do you think that your patient population benefited from ARPIs? I'm just trying to sort out sort of the difference there in timing.

Alexander Sherry: It's another terrific question, and certainly cross-trial comparisons are quite challenging. Although there were overlapping inclusion criteria with RADIOSA, our study did allow for synchronous disease. Also allowed for castration-resistant disease. Accordingly, the schedules of ADT and options were different between the two studies.

We did study the role of intermittent hormone therapy in our prior reported basket with updated outcomes in the current manuscript, which involved at least two months of induction hormone therapy followed by six months of hormone therapy after enrollment.

But again, it's, I think, difficult to compare outcomes directly between trials. As to inferring what the optimal duration of ADT is, I think it certainly depends on the underlying patient characteristics. For some patients in particular with more indolent disease features, an intermittent ADT, of course, is appealing, especially from a quality of life perspective. But on the other hand, some patients really do benefit from continuous hormone therapy. Our study is not designed to directly compare that question with RADIOSA.

And also, ARPI usage was at the discretion of the treating medical oncologist. Although most of our patients did receive ARPIs, again, that wasn't something that we formally pre-specified or studied. Although our post-hoc subgroup analyses did not suggest an interaction with that term, it's very difficult to definitively answer that. We do have an individual patient meta-analysis in collaboration with RADIOSA that's under preparation, termed the WOLVERINE meta-analysis, to hopefully shed some more light on this particular question, including other trials as well that did not or did use hormone therapy. But I think, at least at this juncture, we don't have a direct randomized trial that's really comparing those that have been published today.

Leslie Ballas: I was interested in the translational work and the T-cell receptor expansion contraction that you guys reported. I'm wondering if you're seeing that same connection between immune stimulation that you report here with the other baskets and other disease sites that have been studied on the EXTEND platform. I know you guys have looked at breast, pancreas, obviously the two different prostate cancer patient populations.
What are you sort of seeing?

Bilal Siddiqui: We have seen actually different relationships between the immunological changes and outcomes, which actually potentially do seem to support the role for systemic immune activation linked to clinical outcomes. For example, whereas in the breast cohort, we actually did not see these changes and did not see as much of a clinical benefit. By contrast, in the pancreatic basket, Dr. Sherry and Dr. Tang's work did which certainly would point toward a contribution of systemic T-cell activation to these outcomes. Of course, these are hypothesis-generating studies that require mechanistic validation.

Leslie Ballas: And I guess my final question for you guys is obviously your study shows the benefit of MDT to up to five sites of disease. Do you think it would show benefit if it were that there were seven sites of disease? What is the upper limit of the MDT possibilities?

Alexander Sherry: I think that the clinical benefit has to be weighed not only against the feasibility of doing SBRT to those disease sites but also what we think the burden of micrometastatic disease is in certain patient populations. And I think as you see more evidence of gross allegiance on imaging, and this may be influenced, as we mentioned earlier, by more sensitive imaging assessments like PSMA PET scan, there may be a greater likelihood of micrometastatic disease for which even MDT to comprehensively treat all gross disease may not render as much of a benefit.

I think we need better markers than strictly lesion counting as well to define the oligometastatic disease state, and there are lots of different groups working on this, whether that's in terms of certain mutational genetic risk signatures or looking at other measures of potential micrometastatic disease burden in conjunction with PSA such as circulating tumor DNA. But I think our understanding and, really, definition of oligometastatic disease, as we progressed in our understanding of the biology, will better inform which patients would be most likely to benefit from a local therapy-based strategy as compared to systemic intensification or systemic de-intensification.

Leslie Ballas: Great. Well, that's all I really wanted to cover. I can't thank you enough for joining me today to talk about this important and exciting study. Thank you.

Alexander Sherry: Happy to be here, and thank you again for your time.

Bilal Siddiqui: Really appreciate the invitation.