Mike Morris: Good afternoon everybody and thank you very much to Silke and Aurelius for allowing me to discuss de novo oligometastatic disease and to distill some of the issues around which we need to make decisions in terms of what is consensus versus controversy on the aims, options and rationale of treating these patients. These are my conflicts of interest and none of them bear on today's discussion. So we do, as Rob just pointed out, have a unique opportunity with de novo oligometastatic disease. First of all, we have an untreated primary cancer. We have an untreated metastatic disease and we have a limited distribution of disease and I think that we would have consensus and agreement that our best chance at prolonging overall survival or achieving a cure is probably most feasible when we attempt to do so early. That is before lethal treatment-related biology emerges.

I think in terms of consensus, we can agree that oligometastatic disease is subset of M1 disease and that in M1 disease, at least for AR directed therapy, we have really the best level of evidence that medicine has to offer in terms of treating these patients with AR directed systemic therapy. We have mutually reinforcing phase three randomized prospective studies, all of which suggest except for LATITUDE which examined a different population, all of which suggest that low volume disease does indeed benefit in terms of prolonging survival. I won't recapitulate the subtleties that Nick pointed out earlier today in terms of STAMPEDE with docetaxel in low and high volume disease, recognizing that we're probably not going to solve this discussion today as to whether lowest volume disease should be getting chemotherapy or not. We'll probably see more data in regards to this at ESMO coming up in regards to STAMPEDE, there are healthcare systems issues, financial issues, quality of life issues as Nick pointed out. But probably we would not all agree that docetaxel would be an appropriate therapy for this minimally metastatic patient population.

Now in terms of addressing the primary or addressing metastatic disease, I think first of all, we should go back to biology for a moment to at least assure ourselves that there's a biologic basis for doing this. And at least in breast, colon and melanoma, there are experimental models that do define the biology that could justify the rationale for irradiating either metastatic disease and/or the primary. This is the experimental animal model, the xenograft from the breast cancer experience, and you can see that if you implant both primary breast cancer and lung, brain, or bone metastatic tissue in a xenograft, you will find that the metastases have migrated from the metastasis site into the primary breast cancer. You can see the same not just in terms of implants, but a mouse outright lung metastases. You will find that metastatic disease has honed back into the primary tissue and in fact that the correlation of the degree of homing that you get is correlated with the number of circulating tumor cells.

So you have a distant site, you have the point in transit, and you have the primary site suggesting that there is some benefit biologically to reseeding the primary, which can then rebreed new metastatic disease with even more lethal clones. This has been described in cartoon form from MSK, from Larry Norton, showing the mathematical basis of this trafficking between metastasis and primary and metastasis to metastasis. And fortunately in prostate cancer we actually don't have to rely on preclinical models. We actually have human data showing from the Cancer Genome Project, the relationships between metastatic disease in terms of their genomics and this has been mapped out. So you can see from in these 10 patients, the common truncal mutations that the metastases share and then by virtue of interclonal cooperativity, the relationships that spring from those truncal mutations into different branches and therefore the transmission of evermore lethal clones from metastasis to metastasis justifying why you might want to arrest this process early on with radiation as opposed to waiting until the very end of the patient's life.

So we actually do have, as Nick and others have shown, clinical data justifying radiation therapy to the primary in low volume patients and recognizing that oligometastatic patients are not the totality of low volume patients, but low volume is agnostic to the number of lymph nodes that a patient could have. You could have lymph nodes really from stem to stern and still be low volume. That's not quite the patient population of oligometastatic disease, but nonetheless they're a subset of low volume patients and as Nick and others have shown, they do have a survival benefit when examined in Arm H of STAMPEDE. It would be nice to have more than just one phase three trial before we say that there is a standard of care and both the PEACE-1 study and SWOG-1802 are looking at this, although it's not specifically looking at the oligometastatic population and they are not specifically looking at irradiating the metastases. These trials do look at irradiating or surgically resecting the primary. So while these don't have as a primary endpoint quite the answer to this question, it's part of those studies and it's part of the pre-specified design of those studies and we should have those data within a few years.

Now in terms of irradiating the metastases, we have much less data on the clinical benefits of doing so. In fact, I would say we have no data on the clinical benefits of doing so. On the left hand side of this slide, you can see a report by Matt O'Shaughnessy and Howard Scher from our center looking at a small number of patients retrospectively who had either localized disease plus nodal disease in the pelvis or localized disease plus nodal disease plus distant disease. These are color-coded in blue and in orange respectively, who either received ADT alone, ADT and surgery or ADT and surgery and radiation.

What you're looking at is the histogram of achieving a CR at least by biochemical means that is achieving a PSA of no measurable amount and not surprisingly, the more therapy you get, the lower your PSA is. Now we don't know of course whether that translates into later times of relapse or into a disease-free survival or overall survival. But it is a suggestion that you are doing something that is biologically active and perhaps clinically relevant by treating more.

On the right hand pilot panel is a Japanese series. We've about 45 patients who received either metastasis directed therapy or not in conjunction with ADT in those patients who had metastasis directed therapy, developed CRPC at a later time point than those who didn't. But as Rob just discussed, we don't really know what that endpoint means. We don't have any idea if that's clinically beneficial or not. And so it's sort of like ADT free survival. It's been published, but there's no validation as to whether that's really clinically relevant or not. 

Fortunately, there are several phase two and phase three studies (VA, ARTO, PLATON, Metacure Cohort B1, STAMPEDE) that are exploring the oligometastatic population, combining either systemic therapy with locally addressing the primary, either with radiation or surgery as well as SBRT to the oligometastatic sites, but the big gorilla that's about to enter this stage and this slide is courtesy of Nick, is the proposed 2000 patient Arm M of STAMPEDE, which is coming up in which patients with oligometastatic disease, which will be defined as five or fewer metastases, will be getting a standard of care systemic therapy plus radiation therapy or surgery. There's a surgery sub-study plus SABR to the oligometastatic sites with overall survival as a primary endpoint. So I think this should definitively answer whether there is clinical benefit to this approach.

So in conclusion, this is a subset of M1 patients with a primary in place. There is no justification as far as I can see for denying these patients systemic therapy. Its level data confirmed many times over but the only thing that's open to question is the duration of therapy. If you're looking for cure in these patients and you're going to treat the other sites of disease with definitive focal therapy, there's a rationale biologically and data to support radiation therapy to the primary but we do need confirmatory studies. But those are underway.

And then finally, in terms of radiation therapy to the metastatic disease, all we can say is that it's anecdotal at this point. I certainly wouldn't call it the standard of care. There's no definitive prospective data. The data that we have doesn't have outcome measures that relate to feel, function, or survival or any other validated interim endpoint. And so I think that we look to the Arm M of STAMPEDE to really address that issue. And I'm very proud to say that I didn't hit a single cowbell there. So I think I'm the first one today. Right? And with that, I will conclude. Thank you very much.