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 2023.
Thanks. Um My name is Jake Buruk. I'm a medical oncologist here at Dana Farber at the Lang Center um for janitor urinary oncology. I'll be presenting the prostate cancer updates um from as 0 2023 with a um distinguished discussant Doctor Mary Ellen Taplin to uh provide commentary. At the end, I'm gonna try to get through six of the oral presentations. Um We'll spend a little bit more time on the first few. Um but uh I think some interesting points. I, I provided a few uh conclusions here up front um which, which I'll just briefly go through and, and um then go into a little bit more of the data in the slides. So the first was um the randomized phase three Tale Pro two study, which was initially um presented at Ogu earlier this year. Uh Looking at Ta Opera and Enzalutamide versus Enside and first line MC R PC. It showed in improvement in RPFS um in, in the HR R positive population. Uh The addition of Tazari and um spoiler alert, this led to uh a recent FDA approval for this combination in first line MC R PC for patients with hr altered prostate cancer. So really um a practice changing study. The second is uh updated results of piece one focused on the role of radiation in in addition to uh either double it or triplet uh therapy for patients uh with, with metastatic hormone sensitive prostate cancer, no improvement in overall survival. But there was improvement in a few um secondary outcomes or, or I should say other clinical outcomes which we'll go into uh was an exciting phase. One study of T MP S MA in combination with a lap rib that showed uh manageable safety and promising clinical activity with a um higher response rate than was seen with um Pluto alone. In the vision study. I think maybe one of the, the most exciting abstracts presented in prostate was uh data on arteria A I uh an pathology A I based biomarker um that showed really nice, not only prognostic but also strong predictive uh value for identifying men with localized high risk prostate cancer who uh do or don't benefit from hormone therapy. The ice cap um collaborative uh there was data presented from our very own doctor Praha Ravi, looking at the um prognostic value of PS A Nader greater than 0.1 in patients getting radiation and hormone therapy and or or with or without hormone therapy for localized prostate cancer showing that if the nader doesn't go below 0.1 that's strongly pregnant for poor uh MFS um prostate mortality and overall survival. And then finally, um some nice data from a consortium uh looking at um prognosis of, of MC R PC patients based on the presence of BRA or other HR R alterations showing that uh BRACO is associated with poor prognosis. Um uh followed by non BRCA HR alterations, followed by patients who don't have those alterations, go into a little bit more detail. I'm gonna go quickly for the sake of time. Um But open to questions at the end. So first, the, the Teller two study, as I mentioned, this was first line MC R PC patients uh were allowed to get prior Aaron or dose of tail in the hormone sensitive process in the metastatic hormone sensitive setting. Um And patients um were stratified by, by whether they received those uh in the charge gene status if it was known. Um patients received enzalutamide uh with placebo or with Tala opera and overall survival or uh radiographic progression survival was the primary end point. You can see here the list of hr gene alterations and I'll comment a little bit more on that. At the end T for two was initially presented at as OGU. Uh looking at the overall cohort, this presentation focused on the hr R mutant population. This cohort too. I'm gonna skip over. Um This for the most part, just mentioned a pretty low proportion of patients received uh avarado uh in the hormone metastatic hormone sensitive setting. About 30% received dose of tax. And then I think an important point is that pretty much, uh you know, 98 99% of patients uh underwent tumor tissue testing as well as liquid biopsy. You can see bracket two, the most commonly altered gene um pretty well balanced between uh the uh TAS opera in the placebo group. And here's the um top line results looking at RPFS in the HR deficient population. And you can see there is a uh more than 50% reduction in the risk of progression, radiographic progression in patients receiving tas operative in combination with an subgroup analysis is, is important. Um You can see for the most part uh a really consistent um benefit favoring the addition of Talas Opera um highlighted at the bottom is the subgroups based on BRACA 12 alterations versus other HR alterations. You can see um uh 80% reduction in RPFS with inpatient with BRACA 12, with the addition of Talas Opera. The uh hazard ratio is 0.72 for other hr alterations and the confidence interval did cross one, they did a little bit more granularity around the um specific alterations. Um We'll just uh point out um that um you know, the the magnitude of benefit is clear in the brea patients for the others. They're sort of a gradient with um a variant varying degrees of benefit with the addition of te opera. The overall survival data was immature 24% of the required events. Um but did trend in the right direction has a ratio of 0.69 with a P value of 0.068 time to PS A progression strongly favored Tazari as did time to cytotoxic chemotherapy and PFS two. The response rate was was impressively higher, 67% versus objective response rate compared to 40% with 38% of patients achieving a complete response compared to 18.5%. And um side effects were, were largely in line with what was um has previously been reported for the um uh independent drugs side effects were largely cytopenias. Um With the addition of talib and fatigue as expected and um patient reported um sort of this, this patient reported outcome of clinical deterioration also favored the addition of to operate. They concluded that um Taz Opera with Enzalutamide uh has the potential to become a first line treatment option for patients with MC R PC and HR gene alterations with the caveat if approved. Uh eight days ago, June 20th, um FDA did approve Taz and Enzalutamide for first line MC R PC and patients with HR gene alterations. I did note here um the specific genes uh that were included the FDA approval and just with the commentary that it does slightly differ from the uh list of genes that were studied in the profound study. Um I highlighted in bold the, the ones that are unique to um S A beam and the ones that are unique to a Arab in total. If you look at the two lists, there are 19 genes now where there is uh FDA approval for a Carp inhibitor, either alone or in combination with an A R inhibitor moving on to results of piece one study, this was again focused on um looking at the addition of radiation to standard of care, systemic therapy. Here's uh the, the study of design, we've looked at this before. So I'm gonna move on. Um prim endpoints were RPFS and overall survival with key secondary end points that they did comment on here. Um We will note that in the overall study, about 40% were low volume, 57% were high volume. Much of the results presented here focused on the low volume cohort. So here, here's the RPFS for the low volume population. You can see that um that in the group that received uh a the addition of radiation was associated with a significant uh improvement in radiographic progression for survival with a hazard ratio of 0.65 and A P value of 0.02. Um That's when looked at the, the subgroup independently and the patients who didn't get aberatt around. Interestingly, um there was no benefit with the addition of radiation. Uh When you look at the combined uh groups, whether or not patients received apparat, there was a uh significant uh improvement in radiographic progression, pre survival. There was no difference in overall survival. Um But if you do look at the curves, um the, the curve in black, the, the patients received Abbe and radiation um that those patients didn't seem to do the best but was not statistically significant. Another outcome they report on is, is serious genital urinary events um listed here, I'll note that um there were fewer in the group that did receive radiation, but that was really driven by um patients receiving less radiation or TP. And so, um I I, you know, um I I if if the patients getting radiation get less subsequent radiation, um that that doesn't seem like a, a terribly exciting clinical outcome to me. But um they, they did report that the addition of radiation um was associated with a significant reduction or improvement in, in the risk of uh serious genital urinary events whether or not patients received aone. And that, that's true in the, in the low volume population as well as the overall population. Uh the addition of radiation. Um whether or not patients received apparat was associated with the delay in the time to castration resistance in the low volume and overall population and radiation was associated with with minimal and unexpected toxicity. So they, they concluded that um you know, in patients uh who were undergoing standard of care, systemic therapy with AD T and there's a tax plus minus aone. The addition of radiation did improve um clinical outcomes, specifically pfsrpfs and serious genital urinary events. Um It did not improve overall survival. Um but they did conclude that it could be considered uh as a standard of care in men with Genova low volume disease in combination with uh systemic therapy, moving on to the loop study. As I mentioned, a phase one of of Pluto in combination with a lab just background on um the the pre prior clinical data and um preclinical data. The hypothesis was that the combination would um of a Lara would radiosensitizer to Pluto uh improve efficacy. The primary end point was safety um with secondary end points of uh anti Tuur activity. Here's the design, it was a um dose exhalation and three plus three design. I'll just, I'll just note here, Alain wasn't given throughout the entire six weeks. You can see depending on which cohort it was given either days 2 to 15 after treatment with Pluto up to in cohort nine day, starting days, day four before uh Pluto and continuing 18 days after they were looking at dose limiting criteria. Uh toxicity listed there. This is a schema. Um really toxicity was, was in line with what we would expect. And actually this, this combination was really quite well tolerated across all nine cohorts. There were no DLTS observed. Um And here's the PS A response is waterfall plot, really nice. Um Waterfall plot in terms of, of of PS A response. And um here is a swimmer plot showing the uh both the PS A as well as radiographic responses and, and some patients with really nice um uh durable responses. The patients at the bottom here were in the most recent cohort with limited follow up. So they concluded that that these were really quite well tolerated. Um No DLTS observed and um there did seem to be promising clinical activity that actually exceeded a response rate, see vision. Uh And so it's a really exciting potential new combination. This was one of the abstracts that I thought was maybe the most interesting looking at this A I biomarker arteria A I um essentially asking the question of, can we identify men with high risk localized prostate cancer? Um with a low risk of metastasis, uh who who could benefit or who who would um where short term AD T would be suitable? Um Versus those who need long term AD T. I'm gonna skip over um a lot of the background just to say that Ogu 2022 Dan Scrat presented data with similar biomarker showing that in the intermediate risk population, they could pre identify patients who were biomarker negative, who did not benefit from the addition of short term AD T with radiation versus those who were biomarker positive and did benefit from the addition of short term AD T here, they were looking at the high risk population. So this is uh showing the trials that were included a little bit um of the features that were included in the A I model. Um This just shows that really the, the image, the, the H and E of the biopsy was the most um informative feature that went into the A I model. But there were additional clinical um and pathologic features that went in and the study design essentially um they included um several trials and, and then validated it in this NR RT OG 92 02 study of patients who are randomized uh with mostly high risk um but some intermediate risk are randomized, received long term versus short term A. So here are the results in the overall cohort. Um You can see that um this is the overall study um that that long term AD T reduced the risk of distant metastasis compared to short term AD T with a hazard ratio of 0.64. Now, here's with biomarker stratification on the left are the 474 107 patients who are biomarker negative and can see in that population, there was no benefit to the addition of or to the to to long term ad T versus short term AD T and preventing metastatic disease. However, in the biomarker positive group, two thirds of the patients, approximately there was a uh significant reduction in the risk of distant metastases has a ratio of 0.55. Um with the uh long term versus short term AD T and an interaction of uh value of peoples 0.04. Here, this shows that, that this um A I biomarker did a better job or, or was statistically significant and actually risk group, high risk, very high risk versus NCC and intermediate risk was not um significantly uh predictive of um of which patients benefit from long term versus short term AD T. Um This is now uh overall survival or, or death with distant metastases. And we see a similar result where the biomarker is able to identify um patients who benefit um or, or predict patients who who with long term AD T will have a reduction in uh death with distant metastases with long term AD T. Uh looking at subgroup analysis. Um This just shows that the biomarker um for, for all of these um clinical outcomes really trends towards um being predictive, not all of them reach so significance. But I think this is really neat, this um clinical impact with this, using this biomarker and this cohort. Um if, if this played out in real clinical practice, 29% of patients with NTC and high risk disease um would benefit from treatment shortening um to or or shortening ad T given the lack of benefit of long term AD T on just metastasis and death. Uh In addition, 43% of patients with intermediate risk disease could benefit from treatment intensification with long term ad t to reduce those um clinical outcomes. And then finally, um despite um long term ad t about 20% of men with high risk, low prostate cancer, um developed dys and metastasis and died of prostate cancer. So, um, could this identify patients for treatment intensification? So, I think, I think a really neat, neat study that could inform practice. Um, over the coming years, Doctor Praha Ravi, given time, I'm gonna, I'm gonna go um quickly through this, but our colleague, Dr Ravi prevented data from ice cap. Looking at the um prognostic impact of psan greater than 0.1 in patients with localized prostate cancer receiving um with or without radiation. I'm gonna cut to the chase. I think this um this uh slide nicely shows the results um of of this analysis that um ps a greater than later, greater than 0.1 really across metastases survival, prostate cancer specific mortality, overall survival, regardless or what patients receive radiation alone, short term ad T or long term ad T really. Um this uh this biomarker is associated with poor prognosis. So um really uh quite helpful for understanding prognosis in the clinical setting as well as thinking about um trial design intensification um potentially for patients with this poor risk factor. And I believe finally, um this was a study looking at clinical outcomes for patients with MC R PC receiving first line treat uh treatment by RACA status. Again, I'm gonna cut to the chase here. Um But what they found is that um overall survival um was significantly worse for patients who were, had BRCA alterations um compared to non BRCA and BRCA compared to HR R uh other HR alterations. Um this was actually independent of whether the BRAC alterations were somatic versus germline or whether there was monolith or bio loss. Um And, and here they show the outcomes from first line MC R PC on, you can see that the BRCA patients do worse with first line, second line and um treatment and, and overall survival followed by the HR R non braca altered patients um followed by all comers. And then patients without BRAC alterations have the, have the best um outcomes. And again, this is showing that that um no difference. The, these, these observations told whether patients got tax or a RSI first germ, whether the alteration was germ antic bi or BRCA one and BRCA two. So, in conclusion, I think we have a, a um uh a study that led to a new FDA approved um first line therapy uh of Enzalutamide with Taz Opera and patients with HR altered um MC R PC. Uh We need to see uh or I think it'll be important to see the overall survival data um as that matures. But, but I think uh an exciting new option for those patients. Um The addition of radiation to systemic therapy and MH S PC uh improves some clinical outcomes. But not overall survival. Um And so I think um supports that this is an option for, for some patients but, but maybe not mandatory, given the absence of an os benefit. The blue part combination of glut and lab um looks really promising. Um And I imagine it's gonna go on to uh further uh phase two, if not phase three study. And then um I, I really think this A I biomarker um has potential to inform how we uh to decide on which patients get systemic therapy, get hormone therapy in the localized setting. And how long um where, where we really lack um great clinical biomarkers to, to make that determination with that. I will uh open it up to Doctor Taplin for any commentary and uh feel free to put any questions in the chat. Thanks, Jake, wonderful presentation and congratulations to all the presenters. Really, this meeting is one of my favorites and I always learn a lot uh regarding the prostate cancer work. Um I agree with Jake, the Taro study gives us another option uh in first line MC R PC C of uh Anza plus A Park inhibitor. And that will need to be um considered in light of the abbey data from uh propel with a Park inhibitor. So now there's two choices FDA approved in uh hr mutated patients. It's a more controversial issue and wasn't FDA approved in, in non altered patients, but that may come up in conversation with some of your patients. And I think the underlying messages here is you need to be consistently testing these patients um for germline mutations. And when you're able for somatic mutations, either by tissue as was done in this study in a remarkable high percentage of patients. As Jake noted, um which was not always the case in some of the other studies. So this this data is very believable and should now be considered in your standard of care treatments for prostate cancer patients. Uh For me, the piece, one data didn't really change standard of care because we've been given prostate radiation with low volume uh MS uh hormone sensitive prostate cancer and I'll continue to do that. And I don't think it really changed my mind to give prostate radiation for high volume patients. Although the discussion at as o was along those lines, but as Jake pointed out, I wasn't totally convinced that the improvement in the, the, the g related um consequences was, was that significant? Uh I'm also excited about the possible combination of Pluto in a park um that may be in all comers as opposed to just the DDR altered patients. And that combination has um really very good biologic rationale compared to a lot of combinations that get, get moved forward. So I think, I think with this early phase one data, it's, it's very promising. Um I agree with Jake about the terra um biomarker work and we'll just point out if you saw those curves, they were coming apart at five years, there is almost no data in localized prostate cancer where any curves come apart at five years or anything. So, it's really strong data very well done. I think the biomarker itself is quite a mystery. Like there's very little uh that's been published probably because of prote proprietary information about what they're actually measuring, which I'm very interested to learn more about. Um But I think that, you know, has the potential to really help us um personalize the duration of AD T for our prostate cancer patients, which is very important. I'll just congratulate Praful on his presentation. It was excellent and I don't have really too much to say about the Elena Castro data except continue to test all your patients uh for um germline mutations and prostate cancer. And a controversial area is whether patients with localized prostate cancer should be. Germline tested low risk prostate cancer. I am a strong personal believer that they should be. It's not currently in the NCN guidelines because I don't think patients with especially BRCA, two patients are very good candidates for active surveillance. So I just went down a pet peeve path. But um you know, that's gonna come up and um II I personally do it and recommend that you think about Drumline test and low risk prostate cancer patient. And that's all I have to say. Thanks, Mary Ellen. So many good pearls there. Um Can I follow up on something that you brought up, which I think is really important. Um Pushing testing, the importance of germline somatic testing with, with now the approvals in the first line MC R PC setting, I I don't want to put you on the spot, but I'm I'm going to um when are you gonna be doing somatic testing now? I mean, should knowing that, that this is now approved for first line MC R PC. Should we be moving our practice to doing somatic testing at the time of metastatic diagnosis? Um So that we have that information lined up to know about the somatic braca the somatic pal B two. when they're progressing on first line therapy to, to be able to give tells opera be. Yeah, I think it's very easy to say that we should be doing it. I think in practice, it's very difficult to do. Um just because of the uh bone predominance nature of the disease and half the time even in a very experienced place like ours, when you do a bone biopsy, it does not go all the way to sequencing. Um So I think yes, like we should put extra effort into doing it. I think a bigger question is, should we be s somatic? We seek sequencing all the tissue from the prostate prostatectomies. So I wasn't previously doing that because it was such a long number of years before they got to their metastatic disease. But I think since that she is available and is useful information, I might start doing that more than I have traditionally been doing. Um, 11 question from the, the chat. Um, any from, from Henry Cornelius. Thank you, Henry. Um, any therapies coming online for patients with somatic P 10 mutated prostate cancer. Um I think we're, we're familiar with, with Doctor Sweeney's had assertive study and, and that, that was unfortunately not, you know, moved forward. Um despite I think promising clinical activity in, in P 10, deficient MC R PC. But curious, Mary Ellen, any, anything you know of in the works? Um That's been my biggest frustration. I came to Dana Farber 20 years ago to develop therapeutic in, you know, P 10 mutated patients with Bill Sellers and others and, you know, 20 years later, there's nothing. Um I don't know of anything. I know there's some phase one trials that are going on with um you know, other compounds. I, I don't know what's gonna end up with them. It's been a, a very um disappointing um um you know, area and prostate cancer. Thanks. And then uh Doctor Sri put a question in the chat, chat about treating with parp outside of BRACA. Um ne hr R. What about CT DNA? So, II, I think the evidence just is, is overwhelmingly, you know, again and again, clear that BRACA patients drive the most benefit. Um So, you know, I think testing early to find those and, and treat with parp actually, as soon as patients develop CR PC um is how I'm gonna approach it for, for other alterations. I think, um it's more of a case by case, you know, a germline pal B two, I think probably with a second, you know, with loss of heterozygosity, I think has a high chance of responding. I would probably prioritize doing a in the first line MC R PC setting for a, you know, um random ATM or, or, or sort of a mutation, one of the long list of genes without a second copy loss, I maybe wouldn't rush to it when, if, if I had do Taxol and Pluto and maybe other treatments that, that might have a greater benefit, certainly, you know, I'm gonna give at some point. But I think um how, how much I'm prioritizing depends on the alteration. I think CT DNA, we see. Um it certainly um as Mary Ellen was saying, is an alternative when, when we can't get tissue, which is true for a lot of our patients with metastatic prostate cancer, given bone predominance, but self free DNA, unless there's a an exceedingly high amount of tumor circulate in circulation, which isn't um most patients, it's gonna miss to copy um deletions, which are probably the most predictive of part response in some of the creative studies. So I think CT DNA and, and tissue are, are, are complementary if you can get tissue. I think that's probably preferable in cases where you can't get tissue. Um I think CT DNA is a great alternative but know that that uh a negative may be a false negative in a subset of patients.
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