hi and welcome to Raton talks a lecture series designed for students and residents of radiation oncology my name is Ria I am currently a pgy5 resident at the University of Pittsburgh and today we will be wrapping up our series on prostate cancer for now with a discussion on metastatic prostate cancer I wanted to have a separate talk specifically on the management of metastatic prostate cancer just because I think there's a lot of unique data in the metastatic setting specifically for um this disease site um so with prostate cancer as we will talk about there is evidence for a benefit to treating the prostate itself so the the primary tumor in certain patients with metastatic disease there's evidence for um a benefit to treating oligo metastatic disease so sprt to oligo metastases which is not necessarily unique to prostate cancer um but there have been multiple studies specifically in the prostate cancer space that have shown a benefit um and then finally um there's also uh radio pharmaceutical therapy um using Isotopes such as radium um 223 and litium 177 um which have shown a benefit in in prostate cancer as well um and so what I'd like to do is kind of start by talking about how we classify metastatic prostate cancer um and and and why we classify it the way that we do and then getting into some of the data for uh some of those treatment parad s that I mentioned if you watched our talk on um systemic therapy for prostate cancer uh we had a discussion about the difference between castrate sensitive and castrate resistant um prostate cancer um now the term castrate is used because we are talking about suppression of uh testosterone essentially um but in in the modern era we're not actually performing castration it's it's kind of a chemical castration because we're giving um androgen deprivation therapy um so what what is the difference between castrate sensitive versus castrate resistant so castrate sensitive prostate cancer is defined as prostate cancer that is responding to Androgen deprivation therapy um so in the metastatic setting um we often will monitor patients PSA and their testosterone levels as well if prostate cancer is castrate sensitive that means that testosterone is adequately suppressed and um the PSA level is adequately either declining or or undetectable um with castrate resistant prostate cancer um we're talking about a state of clinical or biochemical progression in an environment where we have adequately suppressed serum testosterone so a castrate environment is said to be a low testosterone environment so the serum testosterone concentration is less than 50 nanog per deciliter and despite an adequately suppressed testosterone um concentration patients that continue to have clinical or biochemical progression with a rising PSA are then said to have a castrate resistant prostate cancer so we always need to measure the patients um testosterone levels and then we need to monitor their PSA and also look at their U Imaging to see if they are having any signs of progression and that's sort of the difference between castrate sensitive versus castrate resistant all prostate cancers are thought to start out as a castrate sensitive State um but then as they um kind of continue to divide they can sort of become castrate resistant over time um and and sometimes um prostate cancer can even kind of dedifferentiate um and that that can make it castrate resistant um and then finally um sometimes uh we can actually have neuroendocrine histology um which we have to kind of think about as a different disease process um compared to prostate adnoc Carol in this talk we're really going to just focus on um prostate adoc carcinoma keeping in mind that that is divided into castrate sensitive versus castrate resistant and when we think about metastatic castrate sensitive prostate cancer um there's an additional kind of classification that we have to think about and that relates to the volume of disease so with castrate sensitive prostate cancer we can divide it into to low volume versus high volume disease now different trials have used various criteria to differentiate high volume versus low volume disease but I think the the best data that we have and and sort of the most consistently used definition um comes from the charted trial um which was an important um trial for medical oncology and it established the addition of dose taxel to Androgen deprivation therapy um and showed that um addition of dose taxel provides a very significant overall survival benefit for patients that have high volume disease so how did they differentiate low versus high volume disease in the charted trial um the the charted definitions for low volume disease um included um patients that had three or fewer bone metastases in total or bone metastases that only involved the vertebral bodies or pelvis so only um axial bone metastases no appendicular bone metastases and they were allowed to have any number of um pelvic nodal metastases so um I I do want to um kind of classify or kind of specify the pelvic nodal metastases were not included in the charted definition um that this was then later added based on um a revision of of stampede trials that we will talk about um so so the kind of commonly used definition of low volume diseases three or fewer bone metastases in total or bone metastases only involving the axial skeleton and now um based on Stampede we also include patients that had any number of pelvic noal metastases high volume disease on the other hand was any presence of visceral metastases or four or more bone lesions with at least one of those outside of the axial skeleton so at least one involving the appendicular skeleton that was considered high volume disease now like everything in oncology these definitions are a little bit convoluted um so an easy way to remember low volume is three or fewer bone metastases and high volume is four or more bone metastases or presence of visceral metastases um but you do want to keep in mind that they did sort of have that qualifier for high volume that if you're going to have four or more bone lesions and call it high volume at least one of those needs to be outside of the vertebral bodies or pelvis um so these are sort of um wellestablished definitions of low volume versus high volume disease the reason these um kind of classifications are important the castrate sensitive versus castrate resistant and then within castrate sensitive low volume versus high volume um the reason that these uh classifiers are so important is because they help us to group patients into various prognostic groups and it really guides our treatment um for these patients um so not all patients with metastatic prostate cancer are managed the same so on this slide I'd just like to go over kind of a very brief summary and an overview of how we manage these patients and then we'll spend the rest of the talk uh sort of diving into the evidence um Behind These paradigms so metastatic castrate sensitive prostate cancer as we said is divided into low volume versus high volume disease based on those uh charted definitions that we just went over um and with low volume disease um the standard is really to think about doubleit therapy so Androgen deprivation therapy and when we say Androgen deprivation therapy we're thinking about something like a G&R Agonist such as Lolly um certain patients we can also use an um G&R antagonist such as rugal um but but when we say ADT think about something like lolide um and then we're adding an additional um kind of Androgen suppression such as abadone apalutamide or enzalutamide um and and if you want more details about what these drugs are I would recommend checking out the talk on um systemic therapy for prostate cancer um because we do sort of get into the mechanisms of these drugs but doublet therapy so ADT plus some other um Androgen suppressing agent and then as we will talk about there's actually an overall survival benefit based on the data that we have for prostate directed radio therapy for these low volume patients and then there's also a progression-free survival benefit for metastasis directed therapy using either surgery or sprt for patients with up to five metastases for high volume disease um for patients with metastatic castrate sensitive prostate cancer like we said earlier based on the charted trial we add dose of taxel to these patients um so they benefit from triplet therapy which is the ADT plus um the additional suppression using something like Aber or darolutamide and then these patients also benefit from adding that chemotherapy of Dos taxel um and then um we we have some data in an abstract that was presented at ASCO recently um but there's some evidence that prostate directed radiother therapy even in patients with high volume disease um might might provide some benefit it's probably not an overall survival benefit um but it can at least kind of provide um some local control and and prolong their time to adverse um genital urinary events um so so that's sort of um maybe an area of controversy and maybe an area that U that is still developing based on um that the manuscript hasn't been published yet um but that's something to keep in mind so we typically think about an overall survival benefit to prostate directed radiotherapy um and a benefit to um progression-free survival with sprt to up to five metastases and that we think about for patients with low low volume castrate sensitive disease um for patients with high volume disease you know obviously radiation is not out of the question for these patients but we just have to realize that the benefits that we are providing them um may be a little bit different it might have to do more with local control and kind of symptom control as opposed to a progression free survival or an overall survival benefit and we'll talk more about that data very shortly here and and kind of analyze it a little bit further so that's cast sensitive prostate cancer moving on then to um metastatic castrate resistant prostate cancer so we have many options um for treating adnoc carcinoma that's castrate resistant depending on the extent of Prior therapy um and there's you know in the nccn guidelines there's many different systemic therapy options a lot of times these patients can still benefit from ADT and we think about dosea taxel as well um we can look for certain um markers so for example if they are um braa mutant then we can add um olaparib um which is a um PP inhibitor um for patients that are micro satellite unstable um and we we this is true not just for prostate cancer but for you know many other disease sites as well um but if they have Micro satellite instability they can benefit from immune checkpoint Inhibitors um such as pisab um which is a uh pd1 inhibitor and then um if patients um are kind of progressing on dos taxel we can think about other agents like cabazitaxel um or sometimes they can get a rechallenge with DOs taxel so there's many systemic therapy options even for patients with cerate resistant prostate adnoc carcinoma and the radiation oncology team can get involved in a very important way um by treating with radio Pharmaceuticals and so we will talk about about the data for this as well um but there are two main radio Pharmaceuticals um that have emerged that are very very beneficial for patients with prostate adnoc carcinoma at this time um and radium 223 the brand name for this is zigo is typically used for patients that have bone only metastases and then um lutetium 177 um with psma 617 the brand name for this is PLO um this is a drug that is used used for patients that have um bone and soft tissue metastases um so we'll talk about the data for that and then finally um we did briefly mention that if patients have neuroendocrine differentiation um at that point we would think about using um chemotherapy drugs that we use for patients with neuroendocrine differentiation right so something like a platinum based um treatment um with a topocide like CIS platin topocide or carboplatin topocide something like that um and so um this is kind of just a big overview of how we think about managing metastatic prostate cancer when it comes to systemic therapy and then I did try to kind of pepper in and and and talk about where radiation oncologists might be useful um so now let's kind of take a step back and get into some of the data uh for these paradigms let's start by talking about evidence for uh radiating the prostate um with patients with cast St sensitive prostate cancer that have a low metastatic burden um remember we said that for patients with low volume disease um and castrate sensitive prostate cancer um radiation to the prostate itself can actually improve overall survival um in these patients and this is something I think that's very unique to prostate cancer you know obviously when patients have metastatic disease we think about treating anything that's causing symptoms such as pain or bleeding or or any kind of local problems we can always do paliative radiation um but I think it's pretty unique to have uh to have evidence for improving overall survival um with radiation to the primary tumor even in the metastatic setting um so so let's talk about where that comes from so the Stampede data uh was the first um data that we had to support radiating the primary tumor for patients with metastas IC disease um that had um prostate cancer so this um trial was run in the UK and I always got confused when I heard Stampede because people would use Stampede to justify doing a lot of different things for a lot of different uh types of prostate cancer not just metastatic prostate cancer um and and I really didn't understand you know why Stampede did so many different things but this was actually a multi-arm multi-stage study um that compared the effects of various agents um and one of the questions that they also looked at was radiating the primary tumor so Stampede had multiple Publications not just this one um and and I don't know of a good way of kind of like numbering it or anything you just have to kind of know what you know which specific study when it comes to the Stampede data you're talking about so there was one um study within kind of all of the studies that were conducted as part of the Stampede umbrella that investigated the question of radiating the primary tumor for patients with M1 disease so they took um about 2,000 men in a phase three randomized controlled trial who had denovo metastatic prostate cancer and when someone is being diagnosed with a denovo metastatic prostate cancer it's said to be castrate sensitive um from the get-go um because they haven't yet been exposed to Androgen suppression so they stratified patients with denovo metastatic prostate cancer um based on the definitions that were used in the charted trial that we talked about so um High metastatic burden versus low metastatic burden and um these patients were staged using CT or MRI based Imaging so importantly you know in the modern era we now use psma pet CTS a lot pretty much everyone with um either unfavorable intermediate risk or higher disease and metastatic disease is going to get a psma pet scan um but we do have to take that with a little grain of salt um and keep in mind that Stampede did not stage these patients with a psma pet skin so they divided patients into um into strata so they stratified them based on high or low metastatic burden as per the charted definitions um and then they were randomized to either the standard of care which was lifelong Androgen deprivation therapy and then once um dosea toxel received FDA approval um about 18% of patients on this study received dose of taxel once that became approved and then um the experimental arm involved the kind of standard systemic therapy plus external beam radiation to the prostate and the radiation regimens that they used were either 55 gray in 20 fractions delivered daily over four weeks or 36 gray in six fractions delivered once a week over 6 weeks total um and it was about a 5050 split in terms of who got which regimen um and then you know obviously they received that systemic therapy um that was standard so the the patients with denovo metastatic prostate cancer were stratified based on high or low metastatic burden and then randomized to either just systemic therapy or systemic therapy plus um radiation to the prostate the results showed that at 5 years there was a significantly improved overall survival only for patients with low metastic burden so for patients with low metastatic burden the 5-year-old overall survival was 53% without radiation improved up to 65% with radiation so a 12% 5year overall survival benefit for patients with high metastatic disease um the 5-year overall survival was not significantly different it was 35% without radiation 30% with radiation the failure free survival did improve across all patients um but importantly that overall survival benefit was really just seen in patients with low volume uh disease there was no significant difference in the quality of life between the groups so it was just around a 73% versus 72% average global quality of life score at 2 years um no significant difference in um grade three or Worse overall toxicity between the arms um and the toxicity really was um sort of um kind of even between the two different arms these are the Kaplan Meyer curves for overall survival from these Stampede patients just to sort of drive home the point um so when they looked at all patients there did not seem to be a benefit to radiating the primary tumor but when they um separated them out based on those stratifications so low versus high metastatic burden in the low metastatic burden group um the overall survival did significantly improve so it went from 61 months um median overall survival up to 85 months with radiation to the primary tumor um there was no such benefit seen for patients with high um metastatic burden so um Stampede in conclusion improved overall survival with prostate radiotherapy in patients with metastatic Den noo prostate cancer who had lowb burden metastatic disease the dose regimens that they used varied um based on institution um so they used both 55 gray and 20 fractions daily or 36 gray in six fractions weekly um I have heard of you know people doing many different things in actual practice and I think this just varies based on institution um in in my practice what I have seen is 55 gray and 20 fractions most commonly I think some people might extrapolate the 36 gray and six fractions weekly and and think about offering sbrt um and this is actually going to be allowed in the next iteration of stampede um but I I think institutional practices just vary but they didn't use kind of like that full definitive dose of 60 Grand 20 fractions they used 55 gray in 20 fractions um and I think that's important because with that lower dose they showed no significant worsening of toxicity um and keep in mind we're treating patients with metastatic disease so we really don't want to do anything to cause worse toxicity for these folks there's a few other trials that are important to be aware of that ask similar questions um so the horad trial looked at patients that were treated with Androgen deprivation therapy with or without radio therapy and they used different doses so they used either 70 gray and 35 conventionally fractionated or 57. 76 in 19 fractions um and the horad trial actually showed no significant overall survival or um failure-free survival benefit um but they did kind of include patients with PSA greater than 20 and Bone only metastases and the definition of low metastatic burden in the horad trial was a little bit different so they included patients with less than five bone lesions a PSA less than or equal to 142 so they might have had kind of higher um risk or more advanced patients within their low metastic burden group and they did not end up showing any overall survival benefit the Stampede and horad trials were then kind of prospectively um com looked at in a meta analysis so a prospective meta analysis of these two separate studies Stampede and horad um in what is known as the stop cap metaanalysis and in this stop cap meta analysis when all of these patients were looked at together prostate directed radiother theapy did actually show a 7% Improvement in overall survival at three years in patients with less than five bone lesions um so the three-year overall survival was 70% um without radiation and and improved to 77% with the addition of radiation and that was significant so once again stop cap kind of supports the conclusion from Stampede that in unselected patients with denovo metastatic disease there does not really seem to be an overall survival benefit um but there still is kind of a 10% failure free survival and biochemical progression free survival benefit um but then once we do select based on metastatic burden for patients with low volume disease it turns out that there is um some degree of overall survival benefit for patients with low volume disease and keep in mind that the definitions of low volume disease were different between Stampede and horad and that stop cap meta analysis used the definition of less than five bone metastases um also in all of these studies once again I want to reiterate these patients were staged by kind of conventional Imaging so using CT or MRI they did not get a psma pet scan in the era of psma pet scans we are likely to upstage some of these patients um because you know psma psma pet scan might show certain things that we don't see just on CT or MRI Alone um so again we have to take the psma scans with a grain of salt um when we're thinking about how to manage patients in the modern era I just briefly want to mention um the piece one trial which was presented in abstract form at ASCO um recently and um the only reason I want to mention this is because it sort of adds another consideration for treating the prostate itself for patients with metastatic disease um so we we talked about Stam peed and stop cap which showed that for patients with low volume denovo um metastatic prostate cancer we actually have an overall survival benefit with primary radiotherapy to the prostate um piece one was interesting because it took patients with denovo metastatic castrate sensitive prostate cancer and it had a 2X two factorial design so there were four different arms ultimately the systemic therapy question was do we do standard of care which is anden deprivation therapy with or without dose of taxel or do we do that standard of Care Plus abadone and prednizone and then the radiation question was do we do systemic therapy alone or do we do systemic therapy plus radiation to the prostate 74 gray and 37 fractions and so that 2x two factorial design led to four different arms and they found that the addition of abadone to the standard of care did improve radiographic progression free survival as well as overall survival and they found that in the low volume population the addition of prostate radiotherapy improved radiographic progression-free survival um from 4. 4 years without prostate radiation up to 7.
5 years with radiation but they did not see a significant overall survival benefit and then in the overall population they actually found that there was an improved time to Serious um genito urinary events as well as castration resistance free survival um so again this study has not yet been published in manuscript form and so we really need to wait for that to kind of draw more conclusions um I think it was a little bit murky because they defined time to Serious gu events um one of the definitions was receiving radiation to the prostate um so I think that makes it a little bit hard to kind of interpret but um some folks um I I just wanted to mention this are using um the piece one data to kind of provide a rationale for treating metastatic prostate cancer um with prostate directed radio therapy um because it does um you know it can improve that time to gu event and ceration resistance free survival um so you know in this setting when we're treating the prostate for patients with um kind of higher volume metastatic burden we have to keep in mind that we're not necessarily providing an overall survival benefit as we saw in those previous trials um but we might be providing some sort of local benefit at least um so it's just important to be honest about what the um the end point is what the goal is with the radiation if we do treat the prostate so that wraps up the studies that I wanted to talk about regarding radiation to the primary tumor in the setting of metastatic prostate cancer so what we saw is that it does provide a benefit and we have different options for dosing for this situation so um 55 gray in 20 fractions daily over four weeks was done in Stampede they also did 36 gray in six fractions weekly um and some might extrapolate this and and consider doing s sprt um 55 and 20 is what I have most commonly seen used in this setting now we have to be honest with ourselves and with our patients obviously about the benefit of this therapy so what is that benefit as we saw in the Stampede and then the stop cap meta analysis for patients have low metastic burden um and and per the charted trial low metastatic burden is defined as three or fewer bone metastases or bone metastases that are only involving the axial skeleton so really the vertebrae and the pelvis um and so the overall survival benefit for these patients um was around 12% in Stampede at 5 Years Around um 7% in stop cap at 3 years um and and that's really the benefit that we're providing to these patients with low volume metastatic disease there's also a progression free survival benefit for low metastatic burden that's supported by piece one and um you know obviously piece one we're still waiting for the the manuscript but some people will use this to justify treating even patients with higher volume metastatic disease with the idea that we're not necessarily providing an overall survival benefit or a progression fre survival benefit but at least a a local control benefit in terms of time to serious urinary events and castration resistance-free survival um so again many different indications to treat the prostate itself I think the strongest indications are for patients with low volume disease because we do have that overall survival benefit and the last thing I want to just reemphasize is that in the era of psma pet scans we do really need to exercise caution and and be very careful when we're interpreting those psma pet scans moving on then let's get into some evidence for sbrt to sites of metastasis in patients with oligo metastatic prostate cancer I think this area is no longer unique to prostate cancer um because we are providing sprt to metastatic disease and many different um kind of um diseases and finding that it does improve progression free survival um there's a lot of phase 2 data for this and phase three trials are ongoing um and and it looks very promising especially for prostate cancer so a very famous trial that looked at um sbrt for oligometastatic cancer um across many different disease sites was the saber Comet study and it was a phase 2 study and it actually showed an overall survival benefit for patients that were treated with s sprt um for their oligometastatic sites um in this study however only 16% of patients had prostate cancer in saber Comet there were a lot of patients with lung cancer and other primaries as well um so what I want to share here is sort of disease or sorry studies that were specific to just prostate cancer patients um so the first of these studies is the stomp trial um this was a phase 2 randomized control trial um I believe this is a Belgian study and they took 60 patients with recurrent prostate cancer with three or fewer oligometastatic lesions on a choline PET scan um and they had to have a testosterone greater than 50 when they were diagnosed with that recurrence and they were randomized to either surveillance or metastatic directed therapy with either surgery or sprt to all sites of metastasis and the Androgen deprivation therapy free survival improved when they received metastasis directed therapy so the adtf free survival was 13 months with surveillance compared to 21 months when they added metastasis directed therapy um and the median time to progression um or PSA progression was six months with surveillance versus 10 months with metastasis directed therapy and they found no significant differences in their health rated um quality of life so stomp provides some Phase 2 evidence for um oligo metastatis metastatic directed therapy um so either sprt or surgery and found that it improves adtf free survival and time to PSA progression orol was a very similar study Phase 2 randomized controlled trial um similar sample size 54 men with um recurrent metastatic castrate sensitive prostate cancer and one to three oligo metastatic lesions seen on either CT MRI or um bone skin and these patients had to have um prior treatment to the primary tumor um and no Androgen deprivation therapy in the last 6 months and these patients were then randomized uh very similarly stomp to either observation or sprt to the metastatic lesions um and what they found is that there were lower rates of progression with metastasis directed sbrt so the six months rates of progression were 19% with sbrt versus 61% with observation and that was statistically significant um sprt did improve the median progression free survival um and the you know the other kind of caveat is that they did have higher rates of glein score 9 and 10 disase in the arm that was observed um they did not see any grade three or Worse toxicities um so Stomp and oral now or orial adds another kind of um layer to the evidence that there seems to be reduced rates of progression with metastasis directed s sprt um and these are both Phase 2 trials there was also a pulled analysis of the oral and stamp studies um and this showed a significant Improvement in the med progression free survival with metastasis directed therapy so I think these are good numbers to remember the median progression free survival was 6 months with observation versus 12 months with metastasis directed therapy in the Stomp and orial pulled analyses um so remember both Stomp and orial um compared observation versus metastasis directed therapy for patients with three or fewer bone metastases so that kind of meets that low volume um definition as well um that we talked out um and and there was a significant Improvement to progression-free survival and then finally um the last Phase 2 trial I'll mention here is the extend trial that actually looked at patients with five or fewer metastases so slightly higher number of metastases in oligo metastatic um cerate sensitive prostate cancer and these patients received Androgen deprivation therapy for at least 2 months so they were randomized to either continued Androgen deprivation therapy alone or Androgen deprivation therapy plus sprt to the metastatic lesions and extend showed a significantly improved progression free survival with the addition of sbrt the median progression free survival was 16 months in the group that received 8T alone and it was not reached in patients that received ADT plus sbrt there was also significant Improvement in the time from testosterone recovery to progression so what we call the eugonadal um progression free survival um and what they found is that they did a flow cytometry and sort of t- cell receptor uh sequencing analysis and they found that there were increased markers of t- Cell Activation proliferation and clonal expansion in the arm that received s sprt suggesting that s sprt might actually result in immune stimulation and help contribute to systemic Disease Control so once again extend is another trial looking at ADT versus ADT Plus sprt for patients with up to five metastases and it demonstrates that sprt may even allow for sort of intermittent Androgen deprivation for patients with aligo metastatic disease and androgen deprivation therapy is not fun for patients to go through it has a lot of toxicities and adds morbidity for patients um and so anything we can do to kind of reduce the duration that they need to be on Androgen deprivation I think is really important these Phase 2 trials that we talked about stomp oral and extend they do provide um I think robust evidence for us to to be treating patients with oligo metastatic disease with um metastasis directed therapy using sprt um and there are kind of more ongoing trials as well so um there is a cctg um pr20 trial which is a phase three trial that's ongoing comparing local ablative therapy versus standard of care for patients with olom static um castrate sensitive prostate cancer that have less than or equal to five metastases so similar to extend but it's a phase three trial um there's a trial called the Promethean study or NRG gu11 which is a phase 2 trial for early recurrent oligometastatic prostate cancer that's detected by pet treated with sbrt Plus relugolix versus a placebo and then there's also pcs9 which is the phase 2/3 adaptive trial um for patients with metastatic castrate resistant prostate cancer with alligo metastases so so far we've really been talking about castrate sensitive um the pcs9 is looking at Cate resistant um so these are just some of the ongoing trials um but there's a lot of work being done in this space um and and it'll be exciting to see the results of these trials I think the biggest takeaways from what we've talked about so far is that we have a lot of phase 2 Data supporting uh benefit to metastasis directed therapy for up to five oligo metastatic lesions um and we saw based on the Stomp and oral meta analysis that there was a progression-free survival benefit that doubled right 6 months with observation versus 12 months versus with metastasis directed therapy um and then based on extend we saw that there was a significant ADT free survival as well so time that these patients did not have to be on Androgen deprivation therapy so we've talked about the evidence for prostate directed radiotherapy in patients with metastatic disease we've talked about the evidence for sbrt to oligo metastatic disease in prostate cancer and we're going to end our talk with a discussion of a couple of Trials um showing the role of radio pharmaceutical therapy for patients with metastatic castrate resistant prostate cancer and it turns out that these radio Pharmaceuticals that we mentioned so zofo which is radium 223 and PLO which is luteum 177 attached to psma 617 um these actually improve overall survival for our patients with metastatic castrate resistant prostate cancer so radium 223 or zofo um was first um used as a radiopharmaceutical to treat prostate cancer based on the Alima trial um which was published more than 10 years ago now so this was a trial of around 900 patients with metastatic castrate resistant prostate cancer um who had two or more bone only metastases and they were randomized in a two to one fashion to either six injections of zofo administered every four weeks or uh standard of care um therapy and the zofo injections given monthly for uh for 6 months um Turned out that actually zofo improved overall survival time to First skeletal event as well as time to increase in Al fos um in in these patients so the median overall survival improved by around 3 months so it went from 11 months with standard of care up to 15 months with the addition of zofo um the median time to skeletal event improved by around 6 months so from around 10 months up to 16 months and the medium time to rise in Al fos increased um by about double from 3. 8 to 7.
