This video features Fern Anari, MD presenting on Data Behind the Approvals of Key Hormonal, Chemotherapeutic, and Targeted System Treatments for Advanced Disease. This presentation was given at our November 9th Optimizing Treatment Strategies for Localized and Advanced Prostate Cancer CME in 2022.
Hi everyone. My name is Fernando sorry. Um One of the geo oncologists at Fox Chase. Um And tonight we're gonna talk about updates in advanced prostate cancer mostly over the last year because so much has gone on. Unfortunately we're not highlighting part inhibitors tonight. Um But there is a lot to talk about. I have no disclosures so we're gonna talk about some updates in the castrate sensitive setting as well as the castrate resistant setting. So in august of 2022 the FDA approved Daryl Hmeid um for metastatic hormone sensitive prostate cancer a medication that was previously approved in the non metastatic hormone resistance setting. Um And this was approved in castrate sensitive disease in combination with A. D. T. And does attack cell based on the data from the air a sense trial. So the Garrison's trial was a phase three randomized trial that looked at men with newly diagnosed metastatic castrate sensitive prostate cancer and randomized them to what they considered standard of care at the time which was 82 dose attack cell. They either received Marilou Hmeid or placebo. Their primary endpoint was overall survival. Baseline characteristics were very similar between the two groups. Average age in both arms was 67. Um Most men had metastatic disease at the time of diagnosis. So de novo metastatic disease was about 86%. And then about 13 14% of men had recurrent disease after initially being diagnosed in the M. Zero space. So the primary endpoint was overall survival and this trial met that overall survival endpoint. So in the Dare Allude. Um I'd group The median Os was not yet met at the time of analysis and the placebo group was 48.9 months with the hazard ratio of 68. So there was a the addition of Daryl Hmeid to the dose of Paxil A. D. T. Combination, decreased the risk of death by about 30 to 33%. And this OS benefit was seen across both sub most subgroups but including men with the nova metastatic disease as well as recurrent metastatic disease. Some secondary endpoints that they looked at were time to castrate resistant disease as well as time to paint progression. And this trial also met both secondary endpoints here with improvement in time to see our pc and time to pain progression. They also looked at other secondary endpoints. The this SSC free survival that was met um was symptomatic skeletal event survival and then time to initiation of their subsequent anti neo plastic treatment was also improved with the addition of Daryl Hamid in terms of safety. Um It was very comparable between the two groups, including uh neutropenia, febrile neutropenia were comparable with the addition of Darryl hmeid um versus the placebo group. The biggest difference scene was hypertension, which was not unexpected. That was 6.4% versus 3.2% in those who received Daryl Hmeid versus placebo. The serious a ease or grade 34 adverse events were also similar between the two groups. Um And there were treatment related deaths in both groups whether or not they received the dare allude. Um I'd So in conclusion from the Saracens trial, the addition of Daryl Hmeid to A. D. T. Endo said axel significantly prolonged the overall survival compared with placebo. Um And this benefit was seen in both de novo and recurrent metastatic disease. And in general this was well tolerated combination. Um And the investigators concluded that this should be a new standard of care in the same vein. Another triplet study that was reported within the last year is the piece one trial again, another phase three trial looking at standard of care which was defined as a T. T. Plus does attacks all at the time. This has been ongoing since 2013. Um And they looked at several arms, they had standard of care plus abiraterone and or radiation therapy. We're not going to discuss the radiation arms today, we're going to focus more on standard of care plus abiraterone. There were two primary endpoints for this trial uh radiographic progression free survival and overall survival. And this trial met both of those endpoints. There was a little over two. There's about 2.3 year improvement in radiographic progression free survival and men who received abiraterone and then a one year improvement in overall survival again, and men who received abiraterone in addition to a d tiene dos attack cell in general, this was a well tolerated regimen as well. Again, the neutropenia neutropenia fever were all very similar in the two groups. The biggest difference, which again was not unexpected due to toxicity from abiraterone was uh liver toxicity was higher as well as hypertension was higher in peace One they also looked at the benefits in radiographic radiographic progression free survival as well as overall survival based on volume of disease. So the volume of disease was defined by the charted study um which looked at um Men will go into a little bit of detail afterwards, but in the charted trial volume was defined as four more bone mats. One had to be outside of the axial skeleton as well as visceral mats. So we can see here that in terms of radiographic progression free survival, there was a benefit in both high volume and low volume disease. When you look at overall survival by metastatic burden. What you see is that the high volume population is the one that really benefited most from this triplet therapy. So the standard of care plus abiraterone group had an overall survival of 5.1 years versus 3.5 years in the standard of care arm. And the low volume. They had neither group um whether they received abiraterone or not had reached uh their median os yet. So conclusions from peace one. Um The addition of 80 the addition of abiraterone to 80 tiene dos attack cell was was associated with a significant improvement in overall survival mainly in the high volume group. I think the data for the low volume group um Is not yet mature. The survival benefit was seen on the order of 1.5 years. Um toxicity was as expected. So again just like in the Harrison's trial, the addition of this novel hormonal agent or abiraterone was felt to be practice changing in this setting. So I think it's important to put these two trials into context. This is just a snapshot of some of the trials in the metastatic castrate sensitive space. Um Like we talked about charted here, the charted trial looked at dos attacks plus A. D. T. Versus A. D. T. Alone because A. D. T. Alone was the former standard of care in this setting. And the most recent update in this data was there after 9.7 years of follow up. Men who received dose of Taxol had a 60.4 months overall survival as opposed to 47.2 months. Uh And men who got A. D. T. Alone. It's important to note that in these trials the populations are not all the same. So you can't directly compare. Um And charted men were included if they had de novo or recurrent disease latitude is another trial in this setting that looked at the addition of abiraterone to um A. D. T. And latitude used a little bit of a different definition instead of high volume, low volume, they looked at high risk, low risk. Um So they're definition was basically your high risk if you had two or more risk factors if you had Gleason eight disease or higher if you had three or more bone mets or if you had visceral Metz and what they found and all these men who were de novo disease so not recurrent disease. And what they found is that the overall survival was 53.3 months with the addition of abiraterone compared to 36 months. Um In the A. D. T. Alone group stampede. Similar in that it looked at the addition of abiraterone to A. D. T. The difference here is that this arm g. Of the stampede trial included a more diverse patient population. Men were locally advanced. They had um recurrent or de novo metastatic disease. What they found was that adding abiraterone to A. D. T. That had of all of these trials thus far. And again not all the data is in the same level of maturity right now but a 6.6 year overall survival with the addition of A. D. T. Um And abiraterone as opposed to you know almost four years in the A. D. T. Alone. And then the piece one of Harrison's data is listed under that. So I think the most important thing to highlight here is that what we don't know in my mind is do we actually need dose of Taxol? Because the piece one in the area since trials were designed to say how does novel hormonal therapy? Daryl hmeid abiraterone compared to dos attacks on A. D. T. Um But there's no trials that are head to head looking at triplet therapy versus doublet therapy when the doublet therapy is A. D. T. Plus a hormonal agent. Um So I think that question is not really answered. So my take away points from these trials are if it's someone you're going to use chemotherapy and you should be adding a hormonal agent if this is someone sitting in front of you that you think doesn't necessarily need chemotherapy um Then likely A. D. T. Plus you know abiraterone and saluda might apple automate all of these medications um are all very reasonable and you can omit the dose of Paxil part. We're going to switch gears now to the castrate resistance setting. So I think the newest approval the newest kid on the block is loutish um PSM A. For metastatic castrate resistant prostate cancer. This was approved based off of um the data from the vision trial that will go over so just a little bit of background PSM A. Is prostate specific membrane antigen. It is highly expressed in prostate cancer. It's also expressed in non prostate cancer cells like salivary glands. Um Loutish in PSM A. Is basically a radio labeled small molecule. That what I how I explain to people is that there is basically like a homing device to these prostate cancer cells where it can deliver um you know high doses of this beta radiation so that you get targeted treatment to the prostate cancer cells. Um while limiting side effects to the surrounding tissues. Um So we'll go over the vision trial results. And then another trial that also looked at Leticia M. P. S. M. A. So the vision trial um was a phase three randomized trial. It looked at men with PSM A positive disease on gallium PSm a pet scam. They had to have received at least one hormonal agent and a taxing chemotherapy. And they added loutish in PSM A two standard of care versus standard of care alone. It's important to note that in this trial standard of care options that were omitted, patients couldn't be on chemotherapy, immunotherapy or any investigational agents. The definition that they used here for PSM A positivity was having at least one lesion that had uptake on their P. S. M. A. Pet scan that was above the liver. Their primary endpoints for radiographic progression free survival and overall survival. Again, the characteristics were pretty balanced between both arms, median age. Men were in their early seventies, they had good performance status. 50% of men had disease in the lymph node, 90 90 ish percent of people had disease in the bone. And about 11 to 13% of men had disease in the liver. This trial met both of its primary endpoints in terms of radiographic progression free survival. There was a little over five month benefits seen with the addition of Leticia psm. A. The median radiographic progression free survival with Leticia was 8.7 months compared with 3.4 months with a hazard ratio 0.4. And then overall survival there was a four month overall survival benefit with the addition of loutish iem as well, with a hazard ratio of 0.62 or like a 38% reduction in risk of death By adding loutish mps. Made a standard of care. Other important outcomes here are response rates. 9% of men who received Leticia had a complete response to treatment. Um And a larger percentage had a partial response around 42% versus standard of Carolina, which was 3%. Um And then men also, about a third of men had stable disease. Primary progression was seen 13% of the time in the loutish um group versus a little under half the time in the standard of care group. The other important thing and we'll touch on this as well as we talk about the next trial is the confirmed 50% decrease in P. S. A. And this trial was found to be 46% in terms of safety in general loutish um has been well tolerated. The biggest side effects that were seen were fatigue bone marrow suppression, particularly anemia and dry mouth which is not unexpected given the expression of PSM and the salivary glands. So in conclusion due to the prolongation of overall survival and radiographic progression free survival scene with the addition of loutish um to standard of care. Um this ultimately became FADA approved in March of 2022. Um for men with metastatic castrate resistant disease. After treatment with an anti androgen type medication and taxing chemotherapy. Next we're gonna talk about updates on the therapy trial which were reported at Osco 2022 this year. And this was looking at overall survival um After a median follow up of three years. This trial will go over the scheme on what they were looking at here but basically 291 men with metastatic castrate resistant prostate cancer were screened um to be either randomized to receive loutish mps M. A. Versus Taxol. The inclusion criteria is different in this study than in the vision trial. So in this trial patients had to get an F. D. G. Pet as well as a PSM a pet. Um They had to have an suv max of greater than 20 and there could be no discordance meaning you couldn't have an F. D. G. Positive um lesion and a psm a negative lesion. Um They had to be the same. So 91 men were ineligible because of this. So the loutish um was given every six weeks for up to six cycles. And the carbon Tax cell was given up to 10 cycles. And then on the right hand side here you'll see that post protocol treatments. Men who received loutish um often went on to receive is taxable and vice versa because in Australia loutish E. M. P. S. M. A. Was already approved. Men on the carbon tax alarm could then go on to receive um blue teaching PSM A. As well. So before we go into the three year update just to recap what was seen and presented or published in the Lancet in 2021. So the primary endpoint of this phase two trial was looking at 50% P. S. A decline. So in yellow here that was the primary endpoint. This is the loutish um group. The 50% P. S. A decline was sorry 66% of people when the loutish um group as opposed to 37% in the carbon tax cell group. Um you know we just talked about in the vision trial that that number for loutish um when it was given in addition to standard of care was only 46%. Which in my mind begs the question did they have better selection criteria in this trial? They looked at F. D. G. Pet In addition to the PSM a pet, they had a different suv cut off the vision trial just said it had to be gallium uptake greater than the liver as opposed to this one had to have an S. U. V. Max of greater than 20. Um So those are some notable differences. And then this trial also met some of its secondary endpoints such as progression free survival was improved at 19% at one year as opposed to 3% in the carbon tax alarm. There was also a higher response rate. So about 50% of men responded to loutish. Um as opposed to about a quarter of men in the carbon tax alarm. And it was also well tolerated. There were less um adverse grade 34 adverse events, less fatigue, less diarrhea, less hair loss. So quality of life was improved for these men. So this was part of the ASCO 2022 update. So in terms of progression free survival both P. S. A. And radiographic um they found that there was an improvement in by about two months with giving Leticia PSm A. Versus carbon tax cell. Um You can see here there was kind of around the media and a pinching of the curves. and then at 12 months you can see that there is an improvement in the um radiographic and P. S. A. Progression free survival. So the way that they reported out their survival numbers um was using this restricted mean survival time which is basically the area under the curve here. Overall survival between the loutish um group and the taxi group were very similar 19.1 months and those who got loutish um versus 19.6 months in Cuba's. Taxol. Um and that had a hazard ratio of 0.97 to me, what this really means is there's no overall survival benefit with one drug over the other necessarily. But I think it's also important to note when we looked at the first slide is that most men received both treatments. It was just the sequence was flipped for many of them. Um So it's a little bit hard to say that there was no overall survival benefit because of those confounding factors. So I think the conclusion from this trial is that when you are looking at someone in the castrate resistant setting who has the option of Leticia and PSM and Carbon Tax, it's reasonable to grab the loutish mps M. A. First because of the higher P. S. A. Response rates. The PFS benefit similar survival and better quality of life. But really how do we choose when that person is sitting in front of you and you have to make a decision how to sequence things. So in the vision trial will go over very briefly now um you know, they found that the pre treatment suv on the suv mean on the PSM A pet was prognostic and predictive for response to treatment. So if you look here, Men who had an suv mean of about 10 or higher had the highest median radiographic progression free survival of 14.1 months. And as you go down in SVV you also find you go down in radiographic progression free survival. But it gets a little bit complicated because when you look at overall survival only those who had again an suv means of about 10 or higher really derived this survival benefit with a median os of 21 months. The bottom three court tiles here All had very similar survival of about 12 to 14 months. How do you reconcile a radiographic progression free survival benefit? That doesn't necessarily translate into a median overall survival benefit. I'm not sure we really know. Lastly the therapy trial also looked at the pre treatment P. S. M. A. Um Suv means as a marker as to see if this was a predictive biomarker. And just like in the vision trial, they also found very similar results. They were looking at the odds of A P. S. A. Um decline of 50% or more. Um And what they found is that the higher the suv mean greater than or equal to 10. There was a higher odds ratio of having that P. S. A response to 50% decline or more. So take home points here in the metastatic castrate sensitive setting. Um We know that A. D. T. Alone is no longer standard of care. Obviously there's exceptions in all of our clinics. Um But some form of A. D. T. Intensification is important if you're considering dos attacks on one of those patients then you should be adding in my mind based on the data from Garrisons in Peace one either abiraterone or dare allude. Um I'd in the metastatic castrate resistant setting. Loutish mps M. A. Is a great option to offer to our patients. Should it be available? Um But I think we need to do more work to figure out who's going to benefit most from this, What's the best selection criteria? Um And really, who's going to benefit from sequencing Leticia before taxes and vice versa. Thank you.