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Alicia Morgans: Hi. I'm so excited to talk today with Dr. Michael Morris, who is a Professor of Medicine at Memorial Sloan Kettering Cancer Center and a GU Medical Oncologist, and Dr. Chris Sweeney, who is a Professor of Medicine at Harvard Medical School and a GU Medical Oncologist at Dana-Farber Cancer Institute. Thank you both so much for talking with me today.

Michael Morris: Thank you, Alicia.

Chris Sweeney: You bet. Yeah.

Alicia Morgans: Wonderful. So I wanted to really pick your brains about the treatment of metastatic hormone-sensitive prostate cancer or some people say mCSPC, castration -sensitive prostate cancer, because I think that there has been a lot of data in this space. There's a lot of confusion. The first thing being that it's not always clear to everyone that the backbone of all treatment is really testosterone suppression with GnRH agonist or antagonist, or if you want to do bilateral orchiectomy, but these treatments to lower testosterone are actually critical.

But then we're really, I think, in the United States moving to a place where we need to combine, for all appropriate patients, which is most patients, use combination therapy. Whether that is ADT plus docetaxel or ADT plus an AR targeted agent, is actually something that we all need to work out. And I just want to talk to you both, about how you make those decisions and what your thoughts are. So maybe we can start with Chris. What are your thoughts when you see a new patient with metastatic hormone-sensitive prostate cancer, of course in addition to traditional ADT, what are you doing to help make that decision about that other treatment that you're adding on?

Chris Sweeney: I ask myself three questions. I think it's three, let's see how we go. One, what is their prognosis? And that's driven by, did they present with metastatic disease as their first presentation and the amount of cancer on a CAT scan or a bone scan. So when we're talking about metastatic disease, we're talking about the amount of cancer that we can see on conventional scans.

Alicia Morgans: Okay.

Chris Sweeney: So that's the first thing and second thing. And chemo fit, volume of disease, and the... How they relapsed or did they present de novo?

Alicia Morgans: Okay.

Chris Sweeney: Because they have very different prognosis and outcome and I think that's what's causing some variations in the trials that we're going to talk about in the outcomes and why one trial may be giving one signal and another trial may be giving another because of patient mix. We looked at the Dana-Farber data set of about 450 patients and it's published, about a third of patients are this high volume de novo metastatic and with just the ADT testosterone suppression, half of those patients would die by about the three-year mark.vWe've made major progress in that group of patients, with the drugs you've mentioned.

And the other spectrum, the other third, is the late relapsing person who years later, has a two bony metastases. You put them on testosterone suppression and their median survival is actually eight years, from the start of the hormones and then this is middle ground. De novo low volume, which is... has a median survival of about five years and some of them have a rapid progression and some of them would be slow. And then there's this very rare bird if somebody has surgery and then a year later they have a high burden of disease because they rapidly progressed after the radiation or their surgery. So I think the more we can annotate the patient in front of us, we can personalize the options for them and then look at all the treatment data sets that have come out. And I suspect Mike and I probably would actually offer the same treatments for the different groups of patients based on their chemo fitness, volume and the timing of the presentation with metastatic disease.

Alicia Morgans: Yeah. And how do you think about things Micheal because... And maybe comment too on the STAMPEDE trial, the CHAARTED trial, which we just got an update from for the STAMPEDE trial, in terms of thinking about volume of disease and sensitivity to docetaxel in addition to ADT, which was a little bit disruptive in a really interesting way to the paradigm that had been laid out by the prior STAMPEDE data and the CHAARTED data. So what, what are your thoughts there?

Michael Morris: Yeah, I'm not sure I see the update of the STAMPEDE data, which had suggested that perhaps the low volume patients actually did have a benefit. I'm not sure that that changes all that much in our landscape. In this case, we know a lot of what we don't know and we know we have one outright negative study. We know that we have CHAARTED, which was a positive study, but there was a readout that led us to believe that perhaps some patients benefit more from others and now we have a look back at a study that didn't initially separate patients by volume, which suggests that there's still more questions to be asked on this front. So it's an ambiguous situation. I think it's an ambiguity that has new information to inform what we're ambiguous about. I also think though, that there are unknown unknowns here that we have to consider.

So, for example, you know, for patients who are really high-risk patients, I do try to profile those patients, at least with germline sequencing, if not somatic as well. And germline for those patients who have high-grade disease at presentation for an initial diagnosis with a localized disease with a family history or anyone with metastatic disease is standard of care.

Alicia Morgans: Yes.

Michael Morris: So I know that volume isn't the great teller of who may respond and who may not. P53 and RB status, would probably make me think about even a low volume patient who I know is probably not going to respond particularly long to any of the AR directed therapies that may trump the volume of disease. So there are other factors here that we know that we don't have enough information about beyond disease distribution, which may be very informative, which are coming into their own as the... As we appreciate as well, that the DNA repair population has yet another set of options to be explored.

Alicia Morgans: Yes.

Michael Morris: That... I think that that's going to factor into our consideration as well. I think that there's some really basic fundamentals... Factors to consider. Even beyond data sets. Not everybody has access to the same drugs. Insurers won't necessarily reimburse for the same drugs. Chemotherapy has great advantages in terms of brevity, a limited course, and financial economy.

Alicia Morgans: Yes.

Michael Morris: So those factors are really important to patients because that really impacts their lives. Beyond distribution, beyond genomics, there's some real practical considerations even in choosing the AR inhibitor that you might be selecting. Different side effect profiles. Some of those drugs get along better with other drugs.

Alicia Morgans: Yes.

Michael Morris: So there are many factors to consider beyond an update on STAMPEDE or beyond a new analysis of the data of head to head, for example.

Alicia Morgans: Absolutely. Go ahead.

Chris Sweeney: So let me pick up on a couple of things there and I agree 100% it is not an easy conversation. This is one where you've got to sit the whole time and sit down and have the patient tell you what their interests are. Sometimes it may be, get the chemotherapy out of the way. Others may be saying, "I've got a lot going on. I just need the simple hormones approach." But two things I want to just pick up on. One is there's a fantastic collaboration that's developing between the ENZAMET team, the CHAARTED team and the STAMPEDE team where we're gene expression profiling, exome sequencing, all the patients, and we'll actually have some data at GU ASCO where we are starting to see some prognostic and predictive markers.

Alicia Morgans: Wonderful.

Chris Sweeney: So hopefully that'll get... We'll have everything ready and have some air time on that to make some progress on that. We've got the gene expression profiling, but we're now doing the whole exome sequencing. We're just pulling the DNA now to send that off from CHAARTED and we're going to train in CHAARTED and validate with the STAMPEDE and the ENZAMET, so we're on the case.

The second thing is just breaking down, thinking through this new information where, well, the high volume de novo we... You're absolutely right, your options are chemotherapy, or the new hormones. It's very unlikely that you wouldn't do something adding that. That's, there's no controversy there. This low-volume de novo metastatic, is one entity, and I just want to say the... If you look at the pattern of the studies, so if you pull out the low volume de novo metastatic from GETUG-12 they actually have a survival curve and European urology paper and they're overlapping, in their study for that patient population. When we look at it and CHAARTED, it's a hazard ratio of about 0.86 for docetaxel and it was 0.72 or something for the low volume. So the STAMPEDE data is a little bit of an outlier when you look at all the other data sets, granted this power issue and they're missing 25% of the scans because they've did it retrospectively.

But let's just take a step back and just look at the pattern across the data because this trials... We can see there's probably a subgroup in there and it's going to be our job to find what that biology is, who's got the rapid proliferating that may benefit from chemotherapy and who can we take a slower approach?

Alicia Morgans: Absolutely.

Chris Sweeney: But let's also recognize that low-volume de novo metastatic group has another really good option in addition to the hormones and that's radiation to the prostate that can be considered, which looks like it has as much as a treatment effect as the docetaxel. So if a patients and physicians sit down and think through those different options and what can you access and what's right for them. Let's also take another extreme. Is there a patient that you'd never had on these other agents?

Michael Morris: Yeah, I would say that that's the one, you know, in a problem created by an embarrassment of riches in this space, the main mistake that can be made, is not to do any of these options and just do some testosterone lowering agent alone. There aren't that many patients that I can think about except for those with significant comorbid disease.

Chris Sweeney: Exactly.

Michael Morris: So at the end of life.

Alicia Morgans: Or advanced dementia.

Michael Morris: Advanced dementia or for whom you'd think that just the prostate cancer is not their primary medical issue, but pretty much everybody else should be on ADT plus something.

Chris Sweeney:We'll annotate that patient, that rare patient. It's the 85... Depends on which practice you are. It's the 85-year-old patient with severe congestive heart failure. Maybe some memory disturbance, frail who's relapsed 20 years after their bony... With two bony metastases. And you could just maybe get away with some radiation and some hormones because you know they're going to live a long time and you can maybe just radiate the two spots as per the STOMP. Maybe give some hormones and just de-escalate in that rare scenario.

Alicia Morgans: Maybe, but I do think it's still going to be, you know, if there are things like repeated admissions for CHS and dementia, I think though what you've both said is it's a conversation and that each of these decisions is probably going to be a real negotiation and education process for both the patient and for the physician on what's going to be the right thing. And, and my 85-year-old be may be different than your 85-year-old. And I think that it's important for us as we see new patients to at least consider that the standard of care is combination therapy and potentially radiation to the prostate if it's low-volume disease, and we need to at least think what is the reason why I would not use this combination.

Chris Sweeney: Exactly.

Alicia Morgans: Before we just default to using single agent.

Michael Morris: Yes. And I just to pick up something that Chris said that we're going to explore much more deeply in a session that we're planning for a GU ASCO is this issue that for the patient for whom this standard of care is not appropriate, that creating a new standard of care that has no evidence of clinical benefit is appropriate. That is the SBRT. Is...

Chris Sweeney: Work in progress.

Michael Morris: Is cause presuming that the patient has no symptoms, there is no organ threatening, that there's not an impending fracture. There actually is no need to make that lesion disappear without some evidence that you're doing some benefit. And we don't really have that evidence. So I just put a little caveat into what Chris just said.

Chris Sweeney: Absolutely.

Michael Morris: That we don't know that ADT free survival is a beneficial thing, but we do know that ADT plus is a beneficial thing. So...

Chris Sweeney: I've got... I have to admit, I'm not a fan of the radiation alone, approach to the MDT. I always have some testosterone suppression with everything I do, including the radiation. Now the bigger question is what about the patient who is three, two years in, their PSA is less than 0.2, if you image them and there's nothing growing at all, and they've got significant quality of life impairment from this profound androgen deprivation and four pills a day.

Michael Morris: Yeah.

Chris Sweeney: We need to think about, can we actually revisit intermittent dosing or dose de-escalation?

Alicia Morgans: Yes. Well, lots of questions to be answered and just so that everyone understands these are questions that we should answer in a clinical trial. And so referral to clinical trials or consideration of clinical trials in your own center is always the way that we should go about trying these approaches and so many patients can benefit. So much work for us to do. But I so appreciate both of your perspectives and I hope that our conversation brings... Sheds some light on what has become a very murky, set of questions that it's really those physician, patient, caregiver, family conversations about practical and even molecular, potentially at some point and disease volume. All of these considerations are going to be important.

Chris Sweeney: And patient preference.

Alicia Morgans: Patient preference, of course.

Chris Sweeney:What... I don't think we've talked about it enough, but we need to start saying that every conclusion of every hormone-sensitive conversation.

Michael Morris: Especially when this murkiness or ambiguity is because you have so many good choices.

Alicia Morgans: Yes.

Michael Morris: That the patient's voice needs to be heard so that you can make the right choice for that patient.

Alicia Morgans: Absolutely. Well, we will definitely end on that high note, and I appreciate the time that you've both given to this. Thank you.

Michael Morris: Thank you, Alicia.

Chris Sweeney: Thank you.

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Standard of Care in the Treatment of Metastatic Hormone-Sensitive Prostate Cancer - Michael Morris & Christopher Sweeney - UroToday

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