Robert Bristow: Thank you. So there will be a talk of surgery in the setting of hormone sensitive prostate cancer and I will stick to radiotherapy. Just when we think of oligometastic disease and the clinical concept, we talked a lot about this yesterday about the definitions of oligometastases, different systemic treatments, et cetera, and really I'll focus then on what is shown here in the red diagram, hormone sensitive disease. And as we look to the right table by Charles Ryan and colleagues, we can see that in fact, CHAARTED, STAMPEDE, and GETUG all used the same definition of high versus low volume in terms of the metastatic concepts. So a clinical concept is quite clear. What we're really talking about is running after the number of metastasis, but there's a biologic concept and that's what I want to focus on this talk, that is implicit in the oligometastic concept from Hellman and Weichselbaum was that it was a less aggressive disease course.

It was a unique subset of patients that might benefit. It was having unique biologic characteristics and that would allow a therapeutic window of treatment and limited in numbers. And of course, metastasectomy and ablative MDT approaches were known to occur for lung, liver, and brain. So the first hypothesis, of course, is that the primary tumor has polyclonal disease and this can give rise to a limited number of metastases, oligometastases. And the second component could be polymetastatic in terms of some clones and we don't know which or which within a given tumor.

A second hypothesis, but not mutually exclusive, as in fact those oligometastases can metastasize as a data from Steve Bova and others. So, in fact, ablating those oligometastases might prevent a progression. But of course the biology could change with treatments. So the rationale for treating the primary, clinically, is that retrospective now, level one with radiotherapy suggests improvements in survival. There has been a discussion about local symptomatic progression, lethal cancer clones left in situ.

This is either rare or unknown and also that it's safe and it's probably true. The biologic entity, however, of this disease is unknown. We don't know whether or not that polymetastatic, oligometastatic, arch actually exists in patients. We don't know about the immuno landscape. And of course, metastases themselves may be heterogeneous with respect to genomics, immune surveillance, AR signaling and the tumor micro requirement.

So we saw this plot yesterday quite a bit to pre-specified analysis, looking at low and high burden within the STAMPEDE trial, Parker et al, showing again the standard of care plus local radiotherapy and men with hormone sensitive metastatic cancer showed improved overall survival and failure free survival. And this is data from Noel Clarke, and I thank Adnan Ali and Noel Clarke for giving me this data.

Again showing the sensitivity analysis in terms of a hazard ratio with respect to increasing number of metastases in the patient. And here what was really exciting was that for the first time we had a predictive assay for outcome. That is the bone scan itself, and it didn't appear to differ whether these were lymph node or bony mets in terms of the effective rate of therapy and overall survival.

So the question is, does the imaging really matter? In an era where we were talking about yesterday about PSMA, sodium fluoride, whole body MRI, I don't know whether or not these tests would actually give a different result. The bone scan, remember, was predictive. The hazard ratio in that low burden with a pre-specified analysis was important and it may be that more specific or sensitive, rather [inaudible 00:03:36] than using different imaging modalities may just call out the population that will benefit from radiotherapy.

Hence the ROTC imagery group really asking for different imaging modalities we looked at within the clinical care pathway for these men. Recently a meta analysis, rather, has been completed by the stopgap M1 looking at the HORRAD trial as well as the STAMPEDE trial was discussed yesterday and showing a 7% improvement in three year survival in men with fewer than five bone metastases when radiotherapy was used was standard of care.

So does the radiotherapy dose and volume matter? Well in terms of dose? Apparently not weekly radiotherapy to 36 gray or daily radiotherapy over four weeks over to 55 grays did not show a difference within the STAMPEDE trial. However, the pelvis was not irradiated and we don't know whether that would've changed the result because the lymph nodes [inaudible 00:04:32] an immunomodulatory effect.

In terms of bowel and bladder toxicity, it was well tolerated and what we don't know at the present time is whether or not there'll be some late side effects associated with this result. We heard yesterday about metastasis directed therapy in the presence of oligometastic prostate cancer. Again, a number of different definitions just showing this STOMP trial again by Piet Ost, but there are a number of other randomized studies in lung and in prostate cancer now showing an overall survival benefit with MDT and there are ongoing clinical phase three trials in this space.

What about surgery versus radiotherapy? We can talk about that. So clearly retrospective reviews have suggested that there could be a benefit, and now that has been tested in the g-RAMMP trial. The SWOG trial in TROMBONE is a feasibility and if positive, these trials would start to inform a trial between surgery and radiotherapy, but if it's negative then it suggests that radiotherapy may have a specific effect beyond surgery. And of course, the STAMPEDE M arm to Noel Clarke in the STAMPEDE group here will be randomizing now patients to MDT plus local radiotherapy versus local radiotherapy alone in hormone sensitive disease.

The target hazard ratio is 0.75, 1800 patients for recruitment. There'll be a sub stratification in terms of number of metastases as well as lymph node involvement. And there also will be a surgery sub trial based on the slide before.

So do we know in the last minutes the biologic state of M1 hormone sensitive prostate cancer that we are treating? Well this as data from Howard Scher's group, really showing that the alteration frequency on the left of a number of mutations that we care about is probably intermediate in the metastatic non-class rate setting between that local, regional and metastatic castrate resistant. But we have to admit and looking to the right that that plot of non castrate metastatic disease versus local regional disease is actually, there's a paucity of mutations there and whole genome sequencing [inaudible 00:06:30] done in this setting. So there's a paucity of data on genomic and immune cell heterogeneity with an untreated primary and the metastases in N1 and M1 disease and then MOVEMBER Gap6 project and Combi-Mets studies are addressing this.

We are looking now to start a biomarker trial soon. HYPROGEN in which we will be giving patients Pimonidazole, an oral agent that will actually label all of the hypoxic cells in the body including metastases and the primary tumor and with multi parametric MRI as well as PSMA tracking the outcome of these patients. But actually trying to define the genomics in untreated M1 disease and then to track those metastases over time.

I think it's important also that in terms of a hypothesis and thinking about biomarkers going forward, we do know that radiotherapy can elicit an immune response and abscopal response so that DNA breaks and micro nuclei associated with that therapy can change the environmental milieu within the primary tumor and this can give rise to cytokines and growth factors and different immune responses that may have an effect on systemic disease.

So some conclusions then for level 1 evidence. Radiotherapy should be added to standard of care systemic therapy in newly diagnosed M1 low burden prostate cancer and consider similar treatment as we discussed yesterday with node positive disease and we're awaiting the PEACE-1 trial to look at docetaxel versus abiraterone as additions to ADT in the setting of radiotherapy.

But importantly, it's a treatment that is effective for overall survival. It's relatively inexpensive if you give the prostate radiotherapy alone and it's well tolerated even for weekly radiation. This is important as our population ages. The surgical trials are ongoing to determine if removal of the prostate gives a similar result. Appears to be well tolerated, important to continue these trials I think to [inaudible 00:08:17] mechanism between surgery or radiotherapy.

So it's not yet about choice, but hopefully soon it will be about biology. So some speculations for me. Future trials should answer questions regarding rules for different surgical volumes or radiotherapy volumes, modern imaging. What about germline changing the systemic therapies and then also MDT. And we need more biologic information around the micro environment, immuno landscaping, and the missing information on genetics. Thank you.