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Daniel Spratt: Thank you so much. My name is Dr. Dan Spratt. I'm a Professor and Chair of Radiation Oncology at the University Hospital Seidman Cancer Center, and I am very pleased today, on behalf of UroToday, to have Dr. Amar Kishan here, who is an Associate Professor at UCLA's Department of Radiation Oncology. A seminal paper that Dr. Kishan led on behalf of the MARCAP Consortium was recently just published in Lancet Oncology, and I'd love to hear, Dr. Kishan, what was the reason you undertook this study?

Amar Kishan: Sure. Well, thanks very much for the invitation and the kind introduction, and I want to give a shout-out too, that you are the co-PI for this MARCAP Consortium. So, let's talk a little bit about that. There have been many trials over the years, looking at different treatment intensification strategies in prostate cancer, specifically with respect to definitive radiotherapy and localized disease. These have been adding hormone therapy or androgen deprivation therapy, prolonging the duration of hormone therapy that comes before radiation, called neoadjuvant ADT extension, and then extending or prolonging the duration of ADT that comes after radiation, adjuvant ADT prolongation.

One thing that we haven't had in localized prostate cancer is a concerted global effort to pool together data from these various randomized trials to try to quantify treatment benefits and harmonize data from these incredible efforts that have been taking place across the globe. We have seen meta-analyses like these in other disease sites, in breast cancer and head and neck cancer, and they have been invaluable in defining and quantifying the benefits of different intensification strategies. So the idea here was to try to establish this Consortium where different trial groups and different institutions would pool data, individual patient data, for these different randomized trials and allow us to analyze them. And so this is the MARCAP Consortium. The data are housed at UCLA and at your institution, University Hospital Seidman Cancer Center, and we worked together to form this Consortium. And basically, this first report was looking at those three strategies that I mentioned, doing a traditional meta-analysis. We had 12 randomized trials in total that we looked at.

Daniel Spratt: Great. So it seems like a tremendous amount of work. But I guess taking it a step back, why hasn't this been done before? There are so many trials of prostate cancer, and it sounds like other cancer types, other groups, have been successful,  What do you think the secret sauce was here to be able to get all of these groups to come together or really have, what I think, is going to be practice-changing results.

Amar Kishan: Yeah, and that's a great question. I think, to some extent, it's just someone needs to basically form a link between the different groups. You have the NRG/RTOG, which is doing a lot of practice-changing trials. You have the EORTC, you have TROG, all of these institutions and cooperative groups are carrying out important work, but they are not necessarily working together, through no fault of their own. And I think where I and you came in, is trying to link people together. And I'm not going to lie, it took a lot of emails and certain instances and some persistence, but I think people were very receptive to doing this. It's just a matter of having the bandwidth and trying to link the groups together.

Daniel Spratt: Great. And so diving into some of the results of the paper. If you were to say, what is something that you feel this study showed that wasn't necessarily known before, or maybe there were some discordant or inconsistent results that you feel when people read this, they are going to say, "Huh, I didn't know that?"

Amar Kishan: Yeah. Many of the original trials did hint to kind of a benefit to adding hormone therapy to radiation, and specifically to prolonging the duration of hormone therapy that came after radiation. But I think what we weren't able to do before was quantify that result in terms of, for example, a number needed to treat. How many men do you need to add hormone therapy to in order to avert a distant metastasis at 10 years? We weren't able to quantify that before. Moreover, there is a lot of controversy in the field. Do you really need these intensifications if, for example, you are delivering high-dose radiation? Or based on our NCCN risk groups, do you need it for intermediate-risk disease versus for high-risk disease? And I would add, also, what about older patients, patients who are over 70, maybe they have comorbid conditions, is the long-term hormone therapy going to cause more harm than good?

These are some open questions and controversies, and I think we were able to address these because these were pre-specified subgroup analyses that we performed. We found that adding ADT and prolonging adjuvant ADT actually benefited everybody, regardless of the dose of radiation delivered, regardless of the risk group, and regardless of patient age. So everyone really benefited and we were able to quantify the number needed to treat, which is pretty good. It ranged from 10 to 18, in many cases, for intermediate and high-risk prostate cancer. Those are pretty robust numbers needed to treat.

Daniel Spratt: Yeah. That seems, for a lot of things, the number needed to treat, which I guess, especially for patients listening, what does that statistic mean?

Amar Kishan: Yeah. So, essentially, adding or intensifying a treatment is not going to help everybody. You do this because of the probability of helping somebody. So when we say a number needed to treat 10, that means you have to treat 10 men with hormone therapy added to radiation to benefit one person. So when we say, the number needed to treat ranges from 10 to 18, that means adding hormone therapy to 10 to 18 patients will avoid a distant metastasis happening in 1 patient. And so that's actually a pretty good ratio. That's pretty favorable.

Daniel Spratt: Yeah.

Amar Kishan: And that's not factoring in earlier endpoints too, for example, like a recurrence, which would probably have a larger effect or a smaller number needed to treat.

Daniel Spratt: Sure. And so, talk about, you mentioned distant metastases and earlier metastasis-free survival, what's the significance, really, of choosing those endpoints to study and not, let's say, survival or biochemical recurrence in this study? Why did you focus on metastasis outcomes?

Amar Kishan: Yes. A great question. Obviously, the holy grail, in many ways, is overall survival. You want to make sure that men are living longer because of the interventions that we are delivering. Now, thankfully many men with prostate cancer live for a long time, and so to see an overall survival benefit may take a long time to manifest. Additionally, there may be other causes that are leading to mortality events. Patients might be passing away of something else. So there's been a really robust effort to look at, what we call, surrogate endpoints or earlier endpoints, where, if we see that something is impacting the surrogate endpoint, it will impact overall survival later. So metastasis-free survival is one of those. What is metastasis-free survival? It is developing metastasis or passing away of any cause. And so it has been shown that if you can improve metastasis-free survival, to a certain extent, you will improve downstream overall survival. It gives you an earlier readout.

When we designed this analysis, we didn't know if we would have enough follow-up to really look at overall survival, so we chose to look at metastasis-free survival. Now, we actually did find an improvement in overall survival as well for these interventions of adding ADT and prolonging ADT in the adjuvant setting. So they actually did have a direct endpoint benefit, but we looked at MFS for that reason. On the contrary, biochemical recurrence-free survival, which is kind of a PSA rise or passing away from any cause, or maybe initiating a salvage treatment because of some other reason, has not been shown to be linked to overall survival. Meaning, if we improve biochemical recurrence-free survival, we might not actually improve overall survival. So it's not a traditional surrogate endpoint, a separate discussion and there is a lot of controversies. It doesn't matter to patients? And that's a separate issue. But we didn't choose to look at that because of that reason. Now, we did look at BCR or biochemical recurrence and distant metastasis themselves, and those were improved. So, likely, BCRFS would have been significantly improved, even more than MFS, by these interventions.

Daniel Spratt: And so than going to, you talked about adding hormone therapy, which clearly it sounds like has a major benefit to patients, and then prolonging the long-term hormone therapy after radiation. Can you discuss, because using prolonged or extended neoadjuvant or hormone therapy before radiation is something that is variably used around the world? Sometimes it's just how they practice, sometimes it's logistical in nature. So what did you find there with the benefit of adding a couple of months of hormone therapy before radiation?

Amar Kishan: Sure. We looked at neoadjuvant ADT extension, so this idea of prolonging the hormone therapy before radiation, which has only been studied in three randomized trials. And we found that intervention, on average, extended the hormone therapy from 3 to 4 months, total duration, to 6 to 9 months, total duration, but the front-loading of that hormone therapy did not improve anything. So it didn't improve even the earliest endpoint of biochemical recurrence.

Now, you've done a prior meta-analysis that looked at the two trials to look at traditional sequencing, which hinted, as well, that maybe there is a bigger bang for your buck when there is a back-loading of the hormone therapy. And I would say our results are consistent with that, with the caveat that the adjuvant ADT prolongation that we studied was a longer duration than the neoadjuvant ADT extension. But certainly, there was no benefit to neoadjuvant ADT extension for a moderate amount.

Daniel Spratt: So I guess a question that is very relevant, especially during COVID, is, some patients are being recommended maybe a little longer hormone therapy. Did you show, at least regarding the tumor control, did it hurt their outcomes? Did the men do worse?

Amar Kishan: They did not do worse. So, from a logistical standpoint, it certainly makes sense if you need to hold something at bay while the treatments are delayed, it's certainly fine to use neoadjuvant ADT extension. It just doesn't improve outcomes.

Daniel Spratt: Got it. And so what would you say, because you just said earlier that treating 10, 15, 18 men are reducing the chance of developing metastatic disease, it's improving survival, and not a lot of things in localized prostate cancer improved survival, so what would you tell people regarding what is the standard of care in terms of using hormone therapy or prolonging hormone therapy? Is this relevant to the practice still today?

Amar Kishan: Yeah, I would say it is highly relevant to practice. I think what we have shown is that, unfortunately, the tools that we have at our disposal right now, the risk groups, the [inaudible], and dose escalation, do not tell us who we can avoid the hormone therapy in. Certainly, for intermediate and high-risk prostate cancer, these results, we need to counsel patients, you should be adding hormone therapy. And even for intermediate-risk prostate cancer, we sort of benefit from prolonging adjuvant hormone therapy, and certainly in high-risk prostate cancer.

So I think another question, though, is, what is the difference between a relative benefit versus an absolute benefit. And so a patient with very favorable intermediate-risk cancer may have an absolute risk of distant metastasis of 3%. And let's say you cut that significantly by adding hormone therapy, you are only reducing that by a little bit. And that's where shared decision making and talking to the patient and seeing what their values come into play to decide whether that is worth it or not. But I think we should be clear about whether there is a benefit to adding the hormone therapy or not, and there appears to be a benefit in almost everybody.

And then a lot of the future work that is ongoing in current trials is looking at whether we have genomic biomarkers that can, say, predict who is actually going to benefit or not from adding hormone therapy. So there is an ongoing trial, GU009, looking at that for high-risk prostate cancer, maybe intensifying or shortening therapy. And in intermediate-risk prostate cancer, GU0010, looks at potentially avoiding hormone therapy in people with favorable genomic biomarkers.

Daniel Spratt: Got it. And so would you say, around the time that this was presented and published, at the same time there was the latest randomized trial just presented, still not published, kind of hot-off-the-press, NRG or RTOG 0815, which is, for those listening, is a randomized trial of purely dose-escalated radiation, with or without hormone therapy, for intermediate-risk prostate cancer. Would you say the results of this meta-analysis were consistent or discordant from the results of the trial?

Amar Kishan: Yeah, I would say they are very consistent. That trial, which was presented in an abstract form, did show a benefit in terms of adding the hormone therapy, even in the presence of dose-escalated radiotherapy, in a largely favorable intermediate-risk cohort. Now, we do not have the exact breakdown of who is unfavorable, who wasn't, but based on the enrollment criteria, many of them were favorable. They showed a distant metastasis, and even a prostate cancer-specific mortality benefit, adding to 6 months of hormone therapy, which I would say is very consistent with our results.

Daniel Spratt: Got it. Any last thoughts, comments about this great work?

Amar Kishan: Well, I would say that there are many questions that have been asked in individually randomized trials that we get a good answer from, but perhaps we can get a better answer by working to get others as a global community and trying to pool data and doing these kinds of work. There are going to be other analyses coming from the MARCAP Consortium, and I would like to invite anybody that is watching and is conducting these types of trials that wants to participate, to contact me or you to discuss joining the MARCAP Consortium.

Daniel Spratt: I think that's great. And it's been a pleasure from a personal note working with you, developing this Consortium. I think it's just amazing to see, bringing people from around the world together, all who want to improve outcomes for men with prostate cancer. And I think there has been a change in tone and pace, in terms of data sharing, and really I think the cooperative groups, it's been fantastic working with them and seeing even the response to this paper and this Consortium, people wanting to join. So I would just echo, I think this is transformative, and just congrats. It's awesome. It's awesome work and I look forward to our next journey together.

Amar Kishan: You too.

Daniel Spratt: And thanks again to UroToday and everybody for listening.

Amar Kishan: Thank you so much.