The Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute presents a succinct summary of all the prostate cancer clinical updates you need to know from ASCO 2022.
Well again. Welcome everyone and thank you for joining us for the Geo Oncology. Conference highlights from Moscow 2022. We're gonna start with prostate cancer updates. I'll be discussing um the the updates and then we'll have um dr Sweeney provide some commentary and we'll open it up for questions. Here are our disclosures. Nothing I believe relevant for the content we're going to be discussing today. Um So I think you know uh some some interesting updates in the prostate cancer space. Nothing I would say practice changing. Maybe not quite as exciting as the last shogun and asthma which have had positive randomized phase three studies that have changed practice. But there are some interesting updates that I think are worth going over. So um the first trial I'm gonna touch on is a uh positive Phase three randomized study of a drug Shr 36 80 which is a potent air pathway inhibitor versus by colluding in patients with metastatic hormone sensitive prostate cancer, specifically patients with high volume disease. Um This is just sort of an overview of um I included this. This slide just to highlight that S. H. 36 80 is a oral air pathway inhibitor that was that's been developed in china which is where this study was conducted and adds to the compendium of trials and the first line metastatic hormone sensitive prostate cancer space that have demonstrated a overall survival benefit for intensification of therapy. Beyond this is the trial schema essentially. Men with high volume metastatic hormone sensitive prostate cancer. By chartered criteria were randomized to receive a. T. T. With by Kalu demise as the control arm versus this novel compound shr 36 80 in the intervention arm. And and really I'm gonna keep this very high level. But you can see um for the primary endpoint actually I believe they were co primary endpoints radiographic progression free survival. Um first and then overall survival. But a 56% reduction in our PFS that met the statistical um significant boundary and then similarly a 42% reduction in mortality that also achieves significance. And and so you know I think that this adds to our like I mentioned compendium of of randomized Phase three studies that show the intensification of um systemic therapy for patients with metastatic hormone sensitive prostate cancer. Um is the way to go. I don't think this is a drug that we're likely to see in the us but I think given its development and likely regulatory approval in china we may be seeing patients coming in having received this. So I thought it's important to cover moving on to loutish mps M. A. Um new uh standard of care FDA approved systemic therapy um with several sort of interesting sub studies and um follow ups and and even uh phase one studies uh using loutish mps may that I'm going to quickly touch on first. Looking at a sub study of the vision trial by prior and concomitant therapy. So very quick overview of the vision trial. These were patients with metastatic crp c who received at least one air pathway inhibitor and 1 to 2 tax and chemotherapy regimens. They were randomized to receive either standard of care which excluded chemotherapy, immune therapy, radium 2 to 3 and other investigational drugs um versus standard of care plus new T. C. M. P. S. M. A for six cycles with um primary endpoints of our PFS and overall survival. Um These are the high level data that we saw last year showing that a 60% reduction in our improvement in our PFS and a 38% improvement in overall survival. And so this is a this presentation here was a post hoc exploratory analysis based on what can comment comment uh Therapies patients got with loutish. Um And what prior therapies they've gotten. Um Again I'm going to keep it fairly high level. But you can see here um They looked at uh what what patients received in combination with loutish um or standard of care ar pathway inhibitors. Bone health agents, radiation. And really um the effect size, what was largely similar with no um sort of notable outliers by what competent therapy patients received. Pretty much all also groups benefited. And a similar trend was seen with overall survival were really the effect size is kind of very similar across all of the concomitant standard of care treatments the patients received including systemic therapies and radiation. And then um the next analysis was by what prior treatments patients patients had received. Um You see on the left there really most uh standard of care therapies that were given for advanced prostate cancer there and again for our PFS and overall survival. The effect size is very similar in all of these subgroups that were evaluated um sort of um supporting that that loutish mps M. A. Um The our PFS and overall survival benefit seem independent of what prior therapy they got or what therapy they get in combination with loutish um with the caveat that um the standard of care arms um or standard of care therapies that were allowed in the trial were not all encompassing of our advanced cRP C. Therapies. The next uh presentation I'm going to discuss is a sub study of the vision trial um where they looked at outcomes by um some PSm a pet metrics. This is presented by Andy Armstrong and so here here's a list of the outcomes or the variables they were looking at um the mean suv which was um a sort of aggregate. Um They looked at all of the PSm a positive lesions and looked at the average suv intensity S. U. V. Max which is the highest suv in any of the positive lesions. And then I'm not going to go into the the tumor volume or tumor load because they don't go into those in much detail on the rest of the study. And then the other thing they looked at is the distribution of PSM A positive lesions, bone liver lymph node other so the feature that had the most strong correlation with outcome was whole body. Mean Suv you can see here they've broken down the mean suv in the vision study by quartile and really um with each increasing quartile you see an improved radiographic progression free survival and overall survival um Really seemingly with the patients in the highest quartile of mean Suv uh having the most a favorable are PFS and overall survival when treated with Leticia. The other feature they looked at was the sort of distribution of disease by metastatic site. And and this is showing um by the absence of bone or liver lesion. So you can see favorable hazard ratios for our PFS and overall survival for the absence of bone and the absence of liver suggesting that patients with lymph node positive disease or lymph node only disease have the most favorable radiographic PFS and overall survival. Not surprising. Um But I think notable that you know, we've seen before that patients with liver lesions might not do as well with the T. C. M. P. S. M. A. And this suggests that patients with bone um lesions as well. And really the lymph node patients are the favorable cohort Move on to the three year follow up from the therapy trial presented by Michael Hoffman. These were patients who um had progressed on on prior chemotherapy and were randomized underwent PSm a pet and F. D. G. Pet. And if met if they met inclusion criteria were randomized to receive capacity Taxol chemotherapy or M. P. S. M. A. Um This is an overview of the primary outcomes but um you can see sort of the primary endpoint of reduction and several secondary endpoints of PFS um response rates favored loutish mps M. A. And here they report for the first time, I believe the post trial treatment and you can see about um 20% of patients on the campus attacks, alarm received subsequently. T. C. M. P. S. M. A. I think important when looking at the overall survival data here consistent with the earlier reports from this trial, improved progression free survival uh positive P. S. A. And radiographic PFS with loutish in PSM. A. Compared to today's attack cell. But notable that overall survival um has a ratio of .97 and a p. value of essentially one um suggesting no improvement in overall survival with Loutish vs Kabbah's attack cell in this setting. Come back to that in a moment. But one other finding that they showed in this presentation that I think is really important as we think about um unmet needs in advanced prostate cancers. These are the patients from the therapy trial who um screen failed. So so they did not meet the inclusion criteria of PSM A pet positivity and no F. D. G. Positive lesions that were not PSm A positive and the screen failed patients shown in red clearly do much worse than the PSM A positive patients treated with luke more capacity axle. Really identifying I think a poor risk subgroup that that we're going to need to pay attention to to figure out how to improve outcomes there. And then finally the Prince trial, this is a phase one um that I believe we were seeing the data for for the first time of loutish sema in combination with embolism. OB an M. C. R. P. C. These are patients who have progressed on prior HR pathway inhibitor who had or had not received prior dist axle. And they it was a single arm study where they received um loutish in PSM a standard dose NG plus Pemberley is MEB every three weeks with a co primary endpoint of P. S. A. 50 response and safety. Just going to show this to say that there was no new safety signals. Kind of the the adverse events were in line with what would be expected with these two drugs. And really an impressive response rate. A 76% P. S. A. 50 response rate and a 78% radiographic response rate by recess criteria. Um And then when you look at the secondary endpoints of our PFS and OS the media and radiographic PFS was 11.2 months which is 3.5 months longer than the median are PFS from the Leticia marm of the vision trial. Obviously single arm phase one small numbers but I think um indicative of a potentially active combination that certainly merits further investigation. So quick conclusions from the loutish um um studies the the I think um efficacy and the vision study um or subgroup analysis by the vision and the vision study by prior and concomitant therapy suggests benefit regardless of what prior treatments or concomitant therapy has given. Um There this exploratory analysis found that mean hi I mean pet suv um on PSN a pet scan and absence of liver lesions and bone lesions were associated with favorable response to petition PSM. A. And I think that the therapy um results with the overall survival I think are disappointing that we don't see um more of a uh incremental improvement in overall survival with the acknowledgement that a significant proportion of patients treated with cuba's attack cell did get subsequently. T. C. M. P. S. M. A. And you know most secondary endpoints were improved with the with the M. P. S. M. A. So I think you know um uh further support sort of this is a standard of care therapy and M. C. R. P. C. Um That analysis also identified the PSM A pet refugee discordant disease or patients with low absent PSM expression as as a particularly poor prognostic group. And then as I mentioned sort of highlights in pembroke as a promising combination therapy. I'm gonna move on to a few updates in the apartment bitter space. Nothing um terribly exciting or practice changing but I think um a few notable findings. So the first is a small uh randomized I believe phase two study the BRAC away trial that is similar to the magnitude study and design. So if you remember magnitude we saw at ask ogu randomized or performed HR biomarker analysis and and and so then stratified patients into HR positive or HR deficient and HR proficient subsets and then um randomize the HR um proficient or deficient patients to receive abiraterone, placebo or abiraterone plus rapper rib. Um This this study is similar in that it patients undergo um genomic profiling, germline somatic testing and if they have a H. R. Um deleterious HR alteration, they are eligible for this arm that was reported here back to one back to a. T. M. And were randomized to receive abiraterone alone, elaborate alone or the combination of L. A. Probe and abiraterone. Um I included this year just to see that you see it's a it's a small study and we shouldn't make too much of this but I think with sort of the ambiguity from the magnitude and the um propelled study that having more data in the space is important. So there could be certainly value from this study. The data is fairly early. Um You can see here. The only real outcomes data they they report is the PFS data. Um And you see that arm three which is the combination of the lap rib and abiraterone clearly has a favorable progression free survival relative to either therapy alone. And so I think you know preliminary data early we shouldn't make too much of this but I think um will will be another trial in the space that could be uh informative as we figure out what to do with or which patients will benefit from part and whether it's a combination with Abby or used as monotherapy later on. two sub studies from magnitude the first was looking at a gene by gene analysis. I just went through the schema but here it is quickly just overview of the magnitude study design and busy slide. But here they showed in one table the breakdown of really all the outcomes of interest the RPF s was the primary outcome. Um time to set a taxi chemotherapy, time to symptomatic progression, overall survival and secondary outcomes. Um and you know some really interesting findings I think you know uh starting with Bracha one bracket to a nice um improvement in our PFS with the combination of of part and Abby versus Abby alone. But interestingly the overall survival actually was was close to one which which you know was maybe surprising. I mean I think um you know we we feel common wisdom at this point is that the Bracha to patients especially which make up the bulk of this cohort benefit the most. I'm wondering if the reason that we don't see the improvement in overall survival is because those patients are probably most likely to get um part inhibitor as standard of care subsequently. And so I wonder if if this, you know, we can't make too much of this. But I do. I thought it was interesting and made me wonder whether it's because these patients are then subsequently getting part and suggest that the combination may not be necessary and giving them sequentially could be okay. Again, that's that's a hypothesis but I found that really interesting um really uh you know, their conclusions in this presentation, we're that, you know, basically every gene or every subgroup had some improvement in one of the other primary secondary or other outcomes um with the combination of a lap rib and um or sorry, no crib and abiraterone. But I think this analysis, while important in my mind, doesn't really clarify much and I think we need ultimately overall survival data and um larger numbers and and further follow up so, but but I I sort of applaud them for doing this and it will be great to see this as it matures. And then finally just one slide um on the patient reported outcomes, health related quality of life from magnitude really essentially at a very high level overlapping curves for all of these patient reported outcomes suggesting that at least there wasn't a detriment in quality of life with um the combination and and so I think you know um as as the outcomes data matures you know we at least know that that it seems to be okay from a quality health related quality of life. So if the outcome data continues to look good it looks better than I think um could certainly justify the combination. Um I think I went over all these conclusions so for the sake of time I'm gonna lose move on to my last stretch of some some predictive and prognostic biomarkers first. Uh Starting with the benefit of dose of Paxil by volume and timing of metastatic disease. I'm certainly hoping dr Sweeney provide more commentary on this but a few updates in this space, the first being uh the updated overall survival data from Enzo Met presented by Ian Davis. Um we now have 68 months of median follow up and you know I think just two notable things to call out is the first the impressive performance of the control arm, a median overall survival of um is that six years chris on the control arm just over six years and not reached for the thalidomide arm. And but but obviously still a um um significant improvement, 30% reduction in mortality um with the addition of thalidomide and then you know a few findings were reported but the one that I'm going to focus on here is a breakdown of out of overall survival by um by whether patients had synchronous versus Mata Cronus. So de novo or or prior local therapy and high volume or low volume by chartered criteria. Again I'm gonna I'm gonna call it chris to comment more when I wrap up in a moment but but sort of my takeaway here is that if you look at all the curves um there's a very consistent uh effect that the addition of saluda meid over um nonsteroidal anti androgen um has an improvement in overall survival. But the one place where the addition of dose of Paxil may suggest that there's a benefit is sort of in this high synchronous high volume cohort where there's a it seems like there's sort of the addition of just axl, there's an early prevention of death in these highest risk patients, you know with synchronous um And and high volume disease being sort of the two highest risk factor risk factors for um death in this setting. So um and and then there's two abstracts that that substantiate sort of a very similar finding. The first is a eight year follow up from the charted study that led to the approval of the tax cell in the setting and they looked at the overall survival by subgroup um with with the hazard ratio reported as well as the sort of absolute overall survival. And you can see that in the attack Cronus, low volume. So the lowest risk group. There's actually a uh trend towards the detriment in in overall survival with the addition of dose of Paxil uh compared to 80 t alone whereas in the high volume and sort of progressively as you go to um attack bonus high volume and an oval low volume. And then with both risk factors. Clearly a bigger effect towards the benefit of early dose attack cell. And then finally in this space there was a meta analysis of individual patient data from the three randomized studies in this space charted stampede in J. F. U. 15 very similar treatment and um looking here at the absolute Improvement in overall survival with the addition of dose of Taxol. Very similar results sort of going from no benefit in the low volume attack bonus up to a 12% benefit in the high volume synchronous and about 8-10% in the patients with one risk factor. So really sort of solidifying um what what dr Sweeney has been saying for years that the high volume synchronous patients are the highest risk and derive the most benefit from this tax very quickly. There was an interesting study that that I think is exploratory and early but shed some light on where where we may be heading as a field using C. T. D. N. A. To sort of risk stratify and monitor patients. Um These were patients with treatment naive metastatic crp c from two cohorts starting an A. R. Pathway inhibitor. Um The study looked at baseline cell free DNA or plasma samples prior to treatment and then four weeks on treatment. And um results essentially showed what we've seen in several solid tumors in several settings. The patients with undetectable C. T. D. N. A. At both time points had the most favorable outcome. Radiographic PFS and overall survival patients who had C. T. D. N. A. At both time points had the worst survival and radio R. P. F. S. And then patients who went from detectable to undetectable had sort of an intermediate um outcomes so early But I think sort of promising early data that we can use C. T. DNA to monitor and re stratify patients. And then finally um this was a retrospective analysis of of a prospective cohort looking at the prognostic value of P. S. M. A. Pet scan and patients undergoing radical prostatectomy. Um Two cohorts from UCSF where patients underwent pet and then radical prostatectomy. What they found was was a really strong um negative prognostic association with PSM a pet positivity outside of the prostate. And when they stratified by P. S. M. A. And pathologic node status essentially you know further stratify these patients, patients who were um pathologic node negative and psm a negative did the best whereas patients with both did the worst and then there was sort of an intermediate outcomes for patients with one or the other. I think I covered all those and for the sake of time. Um Please put any questions in the chat and I will open it up to chris for some commentary on the prostate updates. Um chris you're still on mute and there. I'm thanks. Um jake. That was a tour de force. I'll try and keep it as simple as possible. I think when a patient presents with metastatic hormone sensitive prostate cancer, seed on cat scans or bone scan for all categories attacking us synchronous high and low. The backbone of therapy is testosterone suppression plus any of the potent hormonal therapies that you can get access to. So that's the first thing we should be doing for all patients who have had life expectancy more than a year across the board. Even the attack with a slogan There five years lava goes from 65% to 85%. So even in the best prognosis, there's no role for holding off on the most important therapy. The next question is who do we add those attacks or to? And who do we add radiation to the primary and I uh well de novo low volume. I will give radiation to primary and a potent hormonal therapy combination. And we await the results of the piece. One data where that will be looked at for patients who have poor prognosis where we see those attacks or works as a single agent attack. Synchronous high volume. I feel confident that their data suggests in intimate though they're not direct comparisons that there may be an incremental benefit. The patient you've got to tax and intimate joakim a fit and had um we're poor prognosis and we can tell that by looking at the data sets. So even then it still looks like the triplet did better than the potent hormonal therapy combination. Another way of looking at this though is that there really is no role for a dose of tax as a single agent. Um it's pretty normal therapy and then work out if you're going to add dose attacks on for all the other precision medicine therapies it to biomarkers matter. So it comes down to the patients who have a greater evidence of a psm. Positivity should get loutish in PSM. A um at some stage the ends up studies with therapy really says loutish in peace. May does not replace Kapus attack cell. It is in addition to these attacks. So although we didn't see a startling survival benefit, it's another therapy that we have to offer patients this heart that Leticia was going to be the best best thing since sliced bread hasn't panned out. It led to problems with the study contact that we saw. So managing the height with patients. It is a very good therapy when we can get to it if you're having trouble getting getting to it have them as a tax and then get salutation. So it's not either all it's one or the other at some stage and I'm still for patients who are park inhibitors candidates, I'm very strong in getting a single agent Breaker one bracket to maybe ATM and everything else in my mind is still a maybe. And chemotherapy if the chemo fit is a better option, petition pieces made peace made, that positive is a better option for all of those other maybe DDR defects. I think there's still work to be done there. Thanks chris really appreciate you sort of synthesizing all that data. And I agree. I mean I think that the probably the most important thing that we've seen over the last four or five meetings is really solidifying er pathway inhibitors. The standard of care um with um for for patients in the setting and thanks for sort of going through how you think about adding radiation in this tax with with that I think for the for the sake of time I was going to switch to No one More question in the forest plot that Ian Davis short when we look at those attacks all yes and high volume unlike the low volume and no does attacks all the hazard ratio despite their own less than one, they're less impressive than the low volume. I mean that that's because partly because a few things um there's a confounding that the characters attacks, it was much more present in those who had heart disease. So once you pass out those who got and deluded made for high volume without taxing the hazard ratio is closer to the low volume. But the bottom line is it would appear that the patients with low volume are much more dependent than seem to have a better treatment effect. So there's much nuance that will pass out in the paper. But even for high and low building, the normal therapy is the backbone and add chemotherapy into a select few. Perfect, Great, Thank you dr Sweeney.
