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Advances in prostate cancer treatment and prognosis

Expert-led insights from the 2022 ASCO Annual Meeting

Emerging data: Key phase II and III clinical trials

Recorded: Friday 15th July 2022, 12:30 CDT | 14:30 BRT | 20:30 TRT/SAST

Experts at the forefront of prostate cancer research will explore clinical outcomes of interest in the key ANZUP 1603, BRCAAWAY, ARESENS, and SALVENZA clinical trials that assessed patients with either:

  • Metastatic castration-resistant prostate cancer
  • Metastatic hormone-sensitive prostate cancer
  • High-risk prostate specific antigen-recurrent prostate cancer

The impact of prognostic tools on patient outcomes will also be evaluated.

[00:00:01.28] Well, hello, everybody. Welcome to this discussion in advances in prostate cancer treatment and prognosis. We are going to be talking about some highlights of prostate cancer from ASCO 2022, reviewing abstracts, and having some discussion about them, and also, hopefully, taking some great questions from you, the audience.


[00:00:31.25] So you’re going to be hearing from the three of us today, three GU medical oncologists. I’m David VanderWeele from Northwestern in Chicago, Illinois, and I’m also joined by Dr. Alicia Morgans from Dana-Farber Cancer Institute and Harvard Medical School in Boston, as well as Dr. Atish Choudhury from Dana-Farber also in Boston.


[00:00:58.86] So the program for today, we will be breaking our session up into four smaller sessions, and we’ll be taking turns, leading us through some abstracts that we’ve selected for each of those sessions.


[00:01:14.79] They are radioligand therapies, hormone-sensitive prostate cancer, genetic testing, and biomarker-driven therapy, and then a final one just trying to tie together a few other things. “And now for something completely different”, Dr. Morgans gets the pleasure of trying to lead that session.


[00:01:34.86] So each one will be set up with going through the abstracts, but then followed with some discussion and questions from you, prompting further discussion. In total, it will last about 90 minutes, and each session will be about 20 minutes each or so. Maybe a little bit longer for the first one’s. A little bit shorter for the later ones.


[00:02:02.55] Again, we’ll start off with presentations and some summary slides and snippets of what was presented at ASCO at the abstracts that we will be covering, and then this will be followed by discussion. Please, submit your questions. The questions can be posted at any time, but of course, if they are related to the session that we are working on now, that will help us to be able to answer them in real time.


[00:02:34.43] Dr. VanderWeele and Dr. Choudhury I would just love to hear your thoughts on being back together in person for ASCO. It was quite a memorable experience, I think, after being away for so long. Memorable in a good way for me. Perhaps, memorable in a less good way for others. I think a couple of our colleagues and friends got COVID, but do you have any thoughts on being back in person, good, bad, otherwise?


[00:03:03.26] Good question. It was great, and I was one of those who managed to escape getting COVID, although I too heard from many others-- well, from others who did. And it seemed like it was back to pretty close to prepandemic.


[00:03:23.33] I think a number I heard was 30,000 attendees or something, and I think we may have been up close to 40,000 in 2019 if my memory serves. So not quite all the way there, but yeah, it was really good being able to see people in person, folks I hadn’t seen in quite a while.


[00:03:44.62] It was a different experience. Sorry, go ahead.


[00:03:48.76] - It’s a much different experience in person than doing virtual meetings at home. When you do the virtual meetings at home, it is very academic. You’re listening to the talk. You’re seeing the questions. You’re browsing the posters, but you don’t really get the informal interaction with the other people where you can talk about what you just heard and make snide comments or make plans for things that you might consider next based on that. So there are definitely reasons why it’s good to get together.


[00:04:25.40] And so in this session, we’re going to be talking about two abstracts. The first is abstract 5000 from Dr. Hofman talking about lutetium PSMA-617 therapy versus cabazitaxel. This is an update on the initial presentation that was at GU ASCO this year. This is the ANZUP 1603 study.


[00:04:49.78] And then also sticking with the theme of radioligand therapy, an update on the VISION study, and so this is abstract 5002 and PSMA PET imaging, baseline imaging that was done as part of screening for the VISION study. And this was put together by Dr. Kuo, but presented by Dr. Armstrong. Next slide, please.


[00:05:17.24] So first up is the TheraP study. And hopefully, we’ll be able to advance that slide. And so the TheraP study is a phase II study, a rather small study. Phase II looking at the comparison between two different active therapies. So looking at lutetium PSMA-617 therapy in comparison to cabazitaxel.


[00:05:53.33] Items to note for this study is that there was two PET scans that were required for eligibility for this study, both a gallium 68 PSMA PET scan, as well as an FDG PET scan. They also had rather stringent requirements on the scan, and that you had to have at least one site that expressed PSMA quite highly in order to make it in.


[00:06:21.85] The initial presentation of the primary endpoint was done at GU ASCO this year. And that is summarized in this top line, and actually, it was pretty exciting data. So the primary endpoint was PSA response, that’s a response in at least 50% decline in PSA. And it met its primary endpoint, with lutetium PSMA causing a decline in PSA in 66% of patients compared to 37% with cabazitaxel.


[00:06:57.16] And in addition, there were many other positive outcomes in terms of secondary endpoints. This includes progression free survival at 12 months, 19% versus 3%, improve quality of life in some metrics that were measured, as well as more favorable toxicity profile. And so what was given as an update at ASCO, at this meeting is what’s noted at the bottom there, the 3-year overall survival with mature follow up. All right, next slide, please.


[00:07:37.62] And we’ll see the Kaplan Meier curve summarizing the comparison and overall survival. As that’s being brought up, you’ll see that actually, they’re very similar, and in fact, there is no significant difference in overall survival, with median overall survivals of 19.1 and 19.6 months respectively. Importantly, there were no additional safety signals identified.


[00:08:16.72] When looking at these overall survival curves, a couple of caveats. And that’s that 15 patients assigned to the cabazitaxel arm withdrew after randomization, and presumably, some of them or many of them went on to receive lutetium PSMA therapy off study.


[00:08:38.47] In addition, there was some crossover in post therapy as well or post trial, with additional patients on cabazitaxel receiving lutetium PSMA, and those under lutetium PSMA are receiving cabazitaxel. Those caveats in mind. Again, there was no improvement in median overall survival, and in fact, those curves look pretty similar. The next slide, please.


[00:09:09.84] As I discussed at the top, there were stringent eligibility criteria in terms of the imaging, and so I believe, it was in the [61] patients or so who were excluded from the trial based on imaging, either because there wasn’t a lesion that expressed PSMA at high enough levels, or there was discordance between the PSMA PET scan and the FDG PET scan, indicating that there was a tumor that did not express PSMA.


[00:09:41.56] But those patients were followed for overall survival, and so that’s shown on this Kaplan Meier curve. And so in fact, you can see that the patients who had a screen fail did considerably worse than those patients who made it on the trial, whether they got cabazitaxel or lutetium PSMA.


[00:10:02.35] So that’s interesting. That’s of note. I guess we don’t-- so these patients represented here for the screen fail, screen failed because of the imaging requirements. And so I think-- well, in the next abstract, but also as time goes on, I think we’re going to be hearing more about PSMA PET imaging and the implications of that on its own, as well as predictive marker for PSMA base therapy. All right, next slide, please.


[00:10:43.66] And so in conclusion, the lutetium PSMA therapy had a similar-- sorry-- had a very good safety profile and showed excellent response, both in terms of PSA responses, as well as progression-free survival, although with longer-term follow up, we see that there was similar overall survival with lutetium PSMA therapy and cabazitaxel.


[00:11:13.45] And so the authors conclusions are that lutetium PSMA is an alternative for patients with metastatic CRPC and whom the next treatment option would be cabazitaxel otherwise. Great. Next slide, please.


[00:11:33.07] So that was the TheraP study, and now moving on to the VISION study and a substudy in VISION that was presented at ASCO this year. Of course, the primary endpoint for VISION was presented last year with a lot of fanfare, I would say, and VISION of course, was also lutetium-177, PSMA therapy, radioligand therapy, although with a different trial design.


[00:12:02.73] In VISION, everybody received standard of care therapy, and then patients on the experimental arm also received the radioligand therapy in addition to standard of care. Again, PSMA-based imaging was a requirement as part of screening for the VISION trial, although the entry criteria were not quite as stringent as for TheraP.


[00:12:27.42] For one, only a PSMA PET was required. An FDG PET was not required. And in addition, the point of the PET was to exclude patients with significant PSMA negative disease, but there was not a requirement for at least one lesion with very high expression of PSMA PET.


[00:12:51.48] If we could advance the slides, please. We can see a schema from the VISION study. And as we’re pulling that up-- so we went on to look at-- so in this abstract or in this presentation, they looked at many metrics from that, screening PSMA PET scan, to see what was predictive or what was correlating with response and how patients did on therapy.


[00:13:35.88] So now up on the slide, we see the schema for the VISION study. Again, patients with advanced prostate cancer who had had a prior AR pathway inhibitor and prior taxane, randomized 2 to 1 to receive standard of care therapy alone or standard of care therapy plus the radioligand therapy with lutetium PSMA.


[00:14:00.16] Then on the next slide-- if we could pull up the next slide, after looking at many different metrics from the PSMA PET scan, what rose to the top actually was the SUV mean, that screening PSMA PET scan. And so looking at patients, at the average, PSMA expression is essentially what that is signifying, so the patients with high SUV mean, [actually] did better on study than those with lower SUV mean.


[00:14:46.24] And so to look at this, they basically divided patients into quartiles. And so the highest quartile had SUV mean of just about 10, and then the others had various cutoffs, 7.5, 5.7, and less than 5.7. And so shown on the right hand side is the progression-free survival. Actually, I believe on the right hand side is the overall survival of patients broken down by quartile, and so you see that the patients with the highest SUV mean, again, SUV mean greater than 10, had more favorable outcomes.


[00:15:30.13] If we could bring up the next slide. This will show us similar findings but here looking at progression-free survival. And again, those in the highest SUV mean had the best progression-free survival, the longest progression-free survival, although this time we did see more separation between each of the different quartiles separated by SUV mean. And so those with the highest SUV mean had a progression free survival of 14 months compared to all comers on the treatment arm of about 8.7 months or so.


[00:16:10.72] I think it’s interesting to note that even those in the lowest quartile, so less than six, the progression-free survival was 5.8 months, which does compare favorably with the median progression-free survival of the standard of care treatment arm in general, which was about 3.4 months or between 3 and four months.


[00:16:32.03] I think it’s also important to note that all the imaging that’s presented in this abstract is from the PSMA PET imaging, from patients who are on the treatment arm, and so we see differences in outcome, both in progression-free survival and overall survival. But we’re still awaiting the results from patients on the standard of care arm, so I think it’s a little bit early to say if this is predictive or prognostic.


[00:17:08.30] If we can have the next slide. And so SUV mean is the metric that rose to the top in terms of thinking about-- looking for a possible predictive biomarker, but not surprisingly, they also did find other features that correlated with how patients did, again, focused just on the treatment arm.


[00:17:34.31] And not surprisingly, these features go along with what we see on conventional imaging, and that’s looking at the location of the disease. So patients with bone metastases or patients with liver metastases do worse than those who don’t have metastatic disease at these sites. So the Kaplan Meier curve on the left, you see it’s a relatively minor fraction of patients in the light blue who do not have any metastatic disease in the bone, but those patients do have better outcomes, with a median progression-free survival of 11 months versus 8.7 months.


[00:18:11.91] And again, similar for liver lesions, just like on conventional imaging, if you have liver metastatic disease on PSMA PET scan, you also have worse outcomes. And here are significantly worse than those with lymph node-only metastases, so their progression-free survival was 4.4 months as opposed to more than double that if you don’t have liver metastatic disease. Next slide, please.


[00:18:40.78] So in conclusion, among men with PSMA-positive metastatic CRPC, where treated with lutetium PSMA therapy, a higher SUV mean is strongly associated with improved outcomes, and just like on conventional imaging, if you don’t have disease in the liver or the bone associated with improved outcomes, both progression-free survival and overall survival.


[00:19:12.14] So I think this data further supports the use of PET scans in evaluating our patients with metastatic CRPC, and I think we’ll probably continue to get more data that may more strongly indicate that the imaging may be predictive in terms of response to therapy.


[00:19:34.82] And I think, as we’ve seen this data, many of us have gone to our radiology departments and [nuclear medical] departments and said, hey, we don’t get a readout of SUV mean on our PET scans and the clinical scenario, is this something we should be looking at or something that we could be seeing?


[00:19:55.19] And so I think at many places, we’re in discussion, and maybe I’ll start things off by asking Alicia and Atish, what do you think of the imaging data? Why don’t we just start off there first? And I guess, especially getting your thoughts about SUV mean, is this something that you think about or is this something that you have available to you? What’s the scenario at your institution?


[00:20:31.96] So I actually talked to actually several nuclear medicine doctors about this because I think that the data is really interesting, and I would love to have that to be able to communicate with my patients what their prognosis may be in terms of the amount of benefit because I think as you said, all of the patients who are selected seem to show some benefit. It’s not that any of them didn’t have benefit as compared to standard of care as populations, but of course, it’s just maximum benefit with that SUV mean over 10.


[00:21:03.79] So the issue is that it can take hours to calculate an SUV mean, and there’s no-- I think you’d need data AI or whatever it is to make that calculation. And there are ways to do it, but right now it seems to be just a clinical trial type of a construct that is not feasible in our routine practice, although as the machinery and the software advances, my hope is we will have it or we’ll have something that is easy to obtain and can really serve as a crosswalk. But especially if you’re doing SUV mean over the whole body, it can take hours to actually get that data, and it’s not feasible in routine practice at this point.


[00:21:43.77] We were told that the Australians are very fast at this, and whether it’s partially due to this software or their experience. But yes, we’re at the same institution, Dr. Morgans and I, so we’ve got the same feedback. What is a little bit interesting to note is-- and this might be one of your next questions-- is there are very similar overall survival of the lutetium PSMA with the cabazitaxel.


[00:22:09.93] So if you’re making an argument that a high SUV mean is a predictive marker for benefit from the lutetium PSMA, does that mean a low SUV mean would be predictive for maybe better outcomes with cabazitaxel than lutetium PSMA, which was not discussion that was really had on that topic? So I don’t know David if you have any thoughts on using SUV as a potentially predictive biomarker to actually decision selection between the two.


[00:22:45.94] That’s a great question. So the data from that would come from TheraP. And we didn’t really cover it here, but they did do some looking at SUV mean. And it does look like my interpretation is that this may end up being both predictive and prognostic marker, and that it seemed like patients with high SUV mean, not only did they have better responses or higher percentage of patients with PSA response, which was the primary endpoint of TheraP, but also higher percentage of patients with PSA response to cabazitaxel.


[00:23:25.63] And so how meaningful is PSA response? Obviously, it’s convenient and a good endpoint to have for a smaller phase II study to give you some indication of activity, even though there were a lot higher PSA responses with lutetium therapy that didn’t bear out in terms of overall survival for the TheraP study.


[00:23:50.35] But from the data that I’ve seen from TheraP, it does look like the high SUV mean may just portend a better outcome in general or better response to therapy in general and not merely just a predictive biomarker for benefit from the lutetium PSMA therapy. And that goes along too with their data, capturing the data from patients that were excluded from the study due to the imaging.


[00:24:23.71] So on TheraP, it was a bit higher percentage than the VISION study. VISION study, I think was around 13% or something. TheraP, I don’t know the exact percent, but I think it was higher than 25%. And those patients had worse outcomes. So presumably they had PSMA low or negative, or maybe heterogeneous PSMA expression and were excluded from the study.


[00:24:50.30] And of course, they went on to whatever therapy they wanted or their physician decided on, but they did have significantly worse outcomes. I think it was markedly worse. And so, yeah, I think that would support the idea that the PSMA SUV might be both prognostic and predictive.


[00:25:16.92] One thing that I think is so interesting about SUV in this particular setting is that PSMA expression, which is what’s driving the SUV, is not static, and so we may be able to induce increased expression.


[00:25:30.51] And I don’t know if concurrent AR-target agents in this very advanced mCRPC setting might be able to increase expression. And so you might think of it as something that is useful in a sequencing situation because you can find, OK, my SUV mean is relatively lower, and if I do these maneuvers, I can treat in this way and then increase SUV mean and PSMA expression on the cell surface.


[00:25:59.47] So I think it’s really interesting to just think about where this is going, and that this is not a static biomarker and might be something that we could manipulate too.


[00:26:10.67] Yeah, that’s very interesting comment. And yeah, I think there’s been a lot of controversy or a lot of discussion, at least, about how PSMA expression is regulated by AR, both in the initial hormone sensitive or treatment naive setting, as well as now in the CRPC setting, later stage disease.


[00:26:38.93] And there was also, presented-- it’s not one of the abstracts that we’re covering but data presented from VISION on response with concomitant therapy what’s their differential response to lutetium PSMA therapy or differential benefit, I guess, based on what therapy you’re getting as your standard of care along with the luteum therapy?


[00:27:08.06] And there were some differences, but the general takeaway was that there was benefit seeing regardless of what category of therapy you had. But yeah, that’d be interesting to think about, now that this is available, how should we be sequencing it? Are there other things that we can do to modify that predictive biomarker or modify response more importantly to enhance or optimize your response to therapy?


[00:27:50.90] All right, let’s do a quick check in to see if we are able to get those questions coming in from the audience. I am not seeing them show up, so I think we will move along then to the hormone-sensitive setting. Well, actually I’m starting to see them come in.


[00:28:19.69] --see them if you want us to read them or Dr. Choudhury offered?


[00:28:25.06] OK. Yes, I guess you are ahead of me in seeing them, but I am seeing some show up here. So here’s a question. “When would you envisage lutetium PSMA becoming a routine part of clinical practice?” And I will open it up to you guys.


[00:28:48.60] So I say now, we are already referring patients for lutetium PSMA. So the way that we’ve set it up at our institution is that patients get Gallium PSMA PET. We then assign them to a tumor board. The tumor board reviews the images and make sure that they have PSMA-positive disease, and then the nuclear medicine team takes over.


[00:29:12.48] I think the VISION trial was very clear that this is an active agent. I think the FDA approval and the NCCN Guidelines definitely provoke the use of this treatment in its approved indication. Insurances are getting on board as well, so the future is now we’re using it.


[00:29:34.00] And the TheraP study wasn’t powered for overall survival, but it didn’t show a benefit or it showed similar overall survival to cabazitaxel. Does that dampen your enthusiasm or change how you think about sequencing lutetium therapy?


[00:30:00.46] It doesn’t really change it for me. So remember the interesting difference that was the initial primary endpoint was really on PSA progression-free survival and PSA responses, but honestly, we know that that doesn’t necessarily correspond with survival in prostate cancer. That’s not something that we would routinely use certainly as a primary endpoint. And that’s been very clear across studies for years in prostate cancer.


[00:30:26.59] I think that when you randomize an agent against an active control and you find that it’s similar, that doesn’t suggest that it’s not a helpful agent. It simply suggests that these are both options for treatment, and we can use things like the ease of administration and patient factors, of course, and patient preferences to make those decisions.


[00:30:47.30] And I think it’s also important to remember-- and you showed what happened to the patient population that was not going to be eligible for the TheraP trial based on the screening PET scans-- those patients certainly had a poor prognosis. And we don’t necessarily know how they were treated, but they needed treatment. They hopefully got some treatment. We do need to recognize not all patients are going to be eligible for lutetium PSMA-617, and so we do need to treat them as actively and aggressively as appropriate as well.


[00:31:20.68] I think excellent answer, and I would agree. Another follow up question is, “any patient subtypes in whom lutetium PSMA use would be contraindicated?” For example, certain metastases, I think is what was asked. I guess I would say it’s still unknown to me someone who would have a superscan.


[00:31:44.47] So one of the more significant adverse events that we do see is on bone marrow toxicity. And so patients that really have a high burden of disease throughout the skeleton, I’m actually not sure if they were allowed on the VISION study or not, but I know that expanded access.


[00:32:08.65] I think sometimes these patients were deemed ineligible because of concerns for bone marrow toxicity. And I don’t know if that’s based on data or just biology. I think the answer is still-- I think the jury is still out on that, and we don’t know a definite answer. Any other thoughts from you guys?


[00:32:35.57] Well, I have a-- so let’s say you have PSMA-positive brain metastases, those patients were not included in these trials, and what is the likely outcome? So presumably if the tracer gets to the brain, the lutetium would as well. And does it have therapeutic effect there? Does it cause excess toxicity there? I don’t think we know. I’ve not seen any reports on this particular topic.


[00:33:02.27] I think patients with superscan were also excluded just to make sure that that’s something that we acknowledge. So there is more work to be done on some of these populations with more poor prognosis disease, although liver metastasis is certainly a poor prognosis. And I’ve treated patients with- there were clearly patients on VISION with liver metastasis - so there were patients who had poor prognosis, but there were certain subgroups that were excluded.


[00:33:30.44] Great. All right, so that we don’t get too far behind, I think we probably should move on to hormone-sensitive prostate cancer. If we could advance those slides and allow let Dr. Choudhury take over.


[00:33:50.62] Great. So thank you for the invitation to talk about hormone-sensitive prostate cancer. I’ll be talking about three abstracts, and I’ll go through the titles as we go through them individually. So the first one is a phase III trial called CHART of an agent called SHR3680, which is a potent novel antiandrogen, and this is a randomized trial of SHR3680 versus bicalutamide in patients with hormone-sensitive prostate cancer.


[00:34:24.65] And this trial, unlike many of the other phase III hormone-sensitive prostate cancer trial selected for high-volume disease by charted criteria, which you might remember is greater than or equal to 4 bone lesions, one of which is outside of the axial skeleton or visceral metastases, and you can have had up to three months of ADT with or without first generation ARI to enroll on this trial.


[00:34:48.31] So there were 326 patients in the experimental arm, 328 patients in the control arm, and the primary endpoints were independent review committee assessed radiographic progression-free survival and overall survival. And after the primary endpoints were met, these patients were followed for survival next skeletal-related event and new antiprostate cancer therapy.


[00:35:14.62] So for rPFS, the median follow-up duration was 22.1 and 20.4 months in the experimental versus control groups respectively. And you can see that the SHR3680 plus ADT significantly prolonged the radiographic progression-free survival compared with bicalutamide plus ADT, with a 56% lower risk of radiographic progression or death. In patients with high volume mHSPC, the hazard ratio was 0.44, and the p value was highly statistically significant, at less than 0.0001.


[00:35:52.56] So updated data from the interim analysis, after the interim analysis was performed and was presented at the ASCO meeting, suggested a 54% lower risk of rPFS, and the hazard ratio became 0.46. And so clearly, it prolongs radiographic progression-free survival.


[00:36:13.58] Moving to overall survival, the follow-up duration was 30.5 versus 27.5 months in the two groups. While the US data was immature, there was still a strong signal for a survival benefit for SHR3680, with a hazard ratio for benefit for OS being 0.58 and a p value of 0.0001, and corresponding to a 42% lower risk of death.


[00:36:40.89] The frequency of adverse events of any cause or grade was very similar between the groups, and the weight increase was the most commonly reported adverse effects. So it seems that this agent, SHR3680, is both an effective and well-tolerated treatment for metastatic hormone-sensitive prostate cancer.


[00:37:03.63] So again, this agent with ADT significantly improved our PFS and OS versus bicalutamide. SH plus ADT showed a comparable safety profile, and this data certainly support the use of this agent, plus ADT as a standard treatment for patients with metastatic hormone-sensitive prostate cancer.


[00:37:23.92] Next, I’ll be talking about an update from the ARASENS trial, which was a phase III trial of darolutamide, plus ADT, plus docetaxel compared to a matching placebo with ADT and docetaxel. Key inclusion criteria were mHSPC with a ECOG performance status of 0 to 1.


[00:37:41.94] And this trial did not necessarily require the presence of high-volume disease by charted criteria, but these are patients who the investigator felt were appropriate for ADT and docetaxel as their upfront treatment, and so it wound up enrolling a fairly high-volume group. And so the exploratory endpoints from this trial included time to PSA progression and undetectable PSA at 24, 36, and 52 weeks, and any time during treatment.


[00:38:16.23] And so as you might expect, among the patients who received darolutamide, achieving an undetectable PSA of 36 weeks, was associated with an improved overall survival. So you can see this top curve is if you had undetectable PSA at 36 weeks. Whereas the gray line is anything that is detectable, and the hazard ratio for death between these two groups was 0.37. And the risk of reduction of death was 63% by stratified Cox Regression.


[00:38:49.14] If you look at the frequency of the percentage of patients who achieve an undetectable PSA, it is higher for the patients who receive darolutamide versus placebo at each of the time points that were looked at, so even if you didn’t get there by 24 weeks, you could still get there by 36 or 52 with darolutamide.


[00:39:12.72] And certainly, the frequency of an undetectable PSA at any time post baseline was significantly higher for darolutamide compared to placebo. And again, the OS was improved for patients who achieved an undetectable PSA. And the incidence of AEs were generally similar in patients achieving and not achieving an undetectable PSA by treatment groups.


[00:39:34.72] So it’s not that if you didn’t achieve an undetectable PSA, you would also get less side effects from the drug due to pharmacokinetic or pharmacodynamic reasons. The drug is there. You’re just not responding quite as well.


[00:39:51.40] So this is a very busy table, but I’ll just highlight that when you look at the patients who achieved an undetectable PSA in the darolutamide group versus the placebo group and those whose PSA remain detectable in the darolutamide and placebo group.


[00:40:10.11] It was certainly higher for darolutamide across the different characteristics at baseline compared to placebo, but the main things to look at here is that patients with a higher baseline PSA level, so the patients who achieved an undetectable PSA on darolutamide had a median PSA of 17, whereas those whose remain detectable had a median PSA of 81.


[00:40:38.94] And similarly, for placebo, it was 6.8 in the undetectable group and 36 in the detectable group. And the alkaline phosphatase was also higher in patients who did not achieve an undetectable PSA compared to the patients who did for both the placebo and the darolutamide.


[00:40:57.46] So again, the conclusions are that more patients with hormone-sensitive prostate cancer who received darolutamide in combination with ADT and docetaxel achieved an undetectable PSA and had significant delay in time to PSA progression than those who received placebo, and that the achievement of an undetectable PSA was associated with an improved OS, with the reduction of death reduced by more than 50% compared to those who did not achieve an undetectable PSA.


[00:41:24.46] But again, a lot of the reason you would not get an undetectable PSA is a high PSMA and high alkaline phosphatase reflecting a very high disease burden to start with.


[00:41:39.76] So next, to move on from metastatic hormone-sensitive prostate cancer to biochemical recurrent prostate cancer. So this is the SALV-ENZA trial, which is a phase II study, where patients with PSA-recurrent high-risk prostate cancer, after prior radical prostatectomy, who are planned for salvage radiation treatment were randomized to receive enzalutamide monotherapy, again, without testosterone lowering once daily for six months, versus a placebo.


[00:42:12.07] And again, placebo means no active treatment. There is no ADT in that arm also for six months, stratified by the central surgical margin status PSA value and Gleason score. All patients received prostate bed radiotherapy at the dose as shown, and then these patients were followed for progression. And the primary endpoint of the study was freedom from PSA progression.


[00:42:39.02] So over a median follow-up of 34 months with a range of 0 to 52 months, you can see that the freedom from PSA progression was significantly longer for enzalutamide, with salvage radiation compared to placebo plus salvage radiation with a hazard ratio of 0.42.


[00:42:57.14] Certainly, this would make sense purely from a pharmacodynamic perspective as well because enzalutamide as an AR antagonist will by itself bring PSA down, whereas placebo without ADT will not bring PSA down, so certainly, you would expect a freedom from PSA progression to be favored with enzalutamide.


[00:43:19.68] And there were not secondary endpoints in terms of metastasis-free survival or overall survival presented because those data-- there were not enough secondary endpoint events to analyze any of the secondary endpoints.


[00:43:36.72] If you look at the first plot, just simply for failure from PSA progression, you can see that, again, the confidence intervals for all of these are extremely large because this is a small trial, but there does appear to be a better benefit for the patients who had T3 disease compared to T2 and for the patients who were greater than or equal to 65 compared to less than 65 and for the R1 compared to the R0. But again, these are not statistically significant. This is just exploratory, again, given the small trial and the large confidence intervals.


[00:44:18.45] The common AEs were grade 1 to 2 fatigue, 65% with enzalutamide compared to 53% with placebo, and urinary frequency, which were similar between the two groups. And so this trial demonstrated that enzalutamide plus salvage radiation following prostatectomy delays PSA progression relative to salvage radiation alone. Again, whether this improves downstream clinical endpoints, we really don’t know.


[00:44:48.91] Enzalutamide plus salvage radiation has a favorable side effect profile that in this study was similar to placebo salvage radiation. Of course, we know from other trials, for example, their recently reported ENACT trial in active surveillance that enzalutamide monotherapy does certainly have toxicities that are relevant.


[00:45:10.13] And so salvage radiation with enzalutamide, they believe should be explored further in a phase III trial, and potentially also comparing it against actual testosterone suppression to know what the differential benefit might be. And that is the end of my presentation. We can get to questions.


[00:45:38.25] Great. Thanks, Atish. That’s great. And I think there are some questions coming for all the abstracts that you are presenting, but I think some that a lot of people have been talking about-- and maybe we can discuss a little bit-- is ARASENS adding docetaxel or adding darolutamide to ADT and docetaxel significantly prolongs outcomes. What extent does docetaxel really contribute to this response? And then following up right after it, could darolutamide and ADT be used without the docetaxel?


[00:46:16.14] And more broadly, what are your thoughts or approaches to triplet therapy, doublet therapy? What do you do in this space where we have lots of options?


[00:46:26.76] Sure. I would like to hear Dr. Morgans thoughts on all of this and then I can respond after if that’s OK.


[00:46:33.82] Sure. I’m always able to talk. So I think that in my clinic at least, I use a fair amount of triplet. I would say though, that every clinical practice is different, and you may find patients in your specific practice who are more or less willing to use chemotherapy. I think that as I heard my friend Fred Saad said, “it’s not chemo now or never. It’s actually chemo when.”


[00:47:01.05] And so when you think about it that way and you think about still 6 cycles for 10 cycles, six cycles now when you have this new diagnosis, and many patients are really revved up and ready to do something really pronounced against their cancer, and they may be in a better physical situation to get chemotherapy now than they will maybe in the next line or the next line.


[00:47:24.63] And we do know that as patients continue on lines of therapy, they do become more frail, and certainly, the average number of treatments in mCRPC is maybe one or two lines of therapy. So we may lose the opportunity to use docetaxel if we don’t incorporate it upfront. That being said, do any of the trials that we have available at this time tell us what docetaxel adds? No.


[00:47:46.59] So these trials were not designed to answer the question of whether or not we add docetaxel to an ADT and AR-intensified backbone. They only talk about patients in whom we think it’s appropriate to give docetaxel, for example in ARASENS. They were chemo fit. Maybe they had more de-novo metastatic disease, high-volume metastatic disease.


[00:48:05.91] We thought as an oncology organization that these were the right patients to give docetaxel. We know that if we add their darolutamide to that, they have improved survival, and we know that darolutamide improves PSA responses, as we just heard from Dr. Choudhury. But we can’t answer the question of how much docetaxel adds. But to go back, again, to what Dr. Saad said, it’s not chemo now or never. It’s really chemo when for fit patients, and that’s why I do use a fair amount of triplet therapy.


[00:48:38.05] I certainly agree, and I’ll add an additional few points. Another question that did come up was about using darolutamide with ADT without docetaxel. So right now, darolutamide is actually not yet FDA approved for use in metastatic hormone-sensitive prostate cancer. We presume that it will be based on this data, and we presume that when that approval comes, that it will be approved in the context of ADT with docetaxel.


[00:49:05.68] Now, would it be predicted to have activity without docetaxel? Certainly it would, based on the mechanism of action and similarity of clinical outcomes in the non-metastatic CRPC space. But that question is being asked formally in a trial called ARANOTE that is currently enrolling, so we should have that data later on as well.


[00:49:27.53] But in addition to Dr. Morgans important clinical points around using upfront docetaxel, I will also make a biological argument that certainly, there is evidence that upfront cytoreduction reduction in hormone-sensitive prostate cancer, whatever the tool that’s being used, whether it’s an AR-targeted pathway inhibitor, radiation to the prostate, the use of chemotherapy drug, seems to be associated with an overall survival advantage.


[00:50:03.95] And I think that a lot of the reason that’s the case is because the mechanisms of resistance to one agent like ADT or an AR-pathway inhibitor often leads to cross resistance to these other agents. And we know this because if you test abiraterone or enzalutamide in a post chemo setting compared to a prechemo setting, the benefit from abiraterone and enzalutamide is far higher in the prechemotherapy setting.


[00:50:31.97] So using a triplet therapy to site or reduce as much as possible, get rid of as many potentially-resistant clones as much as possible early in the process is absolutely a compelling idea, even beyond the clinical trial data that we have in addition to the clinical features that Dr. Morgans presented.


[00:50:55.12] And one topic, one network meta analysis that I would like to refer our audience to, the first author is Dr. Soumyajit Roy who compared the strategies of triplet therapy versus ADT plus docetaxel versus ADT plus pathway inhibitor versus ADT alone and in a ranked list analysis did find evidence that that triplet therapy was the best among those options.


[00:51:24.73] Now the overall survival did not meet statistical significance compared to the ADT plus the pathway inhibitor, but that to me suggests that for our patients with the most aggressive disease, that triplet is a favorable treatment strategy.


[00:51:43.69] Great. Thank you. I think some really good points there. Maybe one last question on this topic before we move on to the next session. Thoughts on the CHART study SHR3680. This is compared to bicalutamide. We have lots of different options in this space. Do you see a role for this in your practice or globally, I guess? What are your thoughts on that study?


[00:52:14.20] So we’re not going to know the answer to that question because they weren’t included in the trial, so presumably, if it acts similar to the other agents, it probably would. But again, if it were assigned an FDA label, if it were put up for approval here in the United States, probably if the FDA would only approve it in high-volume patients.


[00:52:35.25] Now my perspective is that this is probably more of a global oncology study in that I don’t know how much of enzalutamide, apalutamide, darolutamide are available and exist in places like the Pacific Rim or sub-Saharan Africa where China has a very big economic footprint.


[00:52:56.61] So if this agent is available and affordable and accessible from a global oncology perspective, I think that there’s huge advantages from that side of things, but I don’t know if this agent will make it to the United States or to other Western countries. I don’t know what the company’s plan is there.


[00:53:18.76] Great. Thanks. All right, and now in the interest of time, we probably should be moving on to the genetic testing and biomarker-driven therapy. And unfortunately, not have a chance to get to all of the great questions that were submitted for that session. And so in this next portion, we’ll talk about two abstracts, one germline genetic testing and then the next on biomarker-driven therapy based on genetic testing results.


[00:53:54.35] And so starting off with abstract 10500, this is presented by Dr. Shaw. And this is a study of about 1,000 patients doing germline genetic testing I think it was 84 genes mostly in neurology practices, both community and academic centers, although I think community practices were pretty well represented. If I could have the slides advanced, I don’t think I’m getting control.


[00:54:30.60] And so yes, 84 gene panel. Interestingly, in the trial by design where patients who met criteria or indication for germline genetic testing by NCCN recommendations I think per 2019 or so or when this study was being designed, as well as 50% of patients who did not meet criteria. And then really what they’re looking at was clinical decision making following this germline genetic testing.


[00:55:11.34] And so of note, there were 10% of patients-- higher than I would have expected-- 10% of patients who did have a pathologic genomic variant-- I believe that’s what PGV is standing for-- Pathogenic Germline Variant-- and 34% of them were from patients that did not meet the NCCN criteria. The genes that were most frequently altered were CHEK2 and BRCA2. And 2/3 of clinicians reported that they felt that the genetic testing positively impacted the patient’s health.


[00:55:52.25] And on the right is a chart showing how often changes were made or changes were recommended based on what kind of variant or what kind of outcome there was from the genetic testing, whether it was a pathogenic germline variant, a variant of unknown significance, or essentially a negative result.


[00:56:20.47] One thing that I found interesting and speaks to us in the health care field I think is that, if you look on the right hand side of this chart, if you look at the variants of unknown significance, that percent increases significantly if you go from the white to the non-white population, from 44% to 67%. And I think that’s probably a reflection of just who’s represented in our databases and what we have the most information on in terms of categorizing these germline variants.


[00:56:56.85] And so I think that’s very interesting little tidbit that probably wasn’t something that they were looking at initially but that came out of this study. And then they also broke down the recommendations from the clinicians based on the results of the testing. And so all the different changes or recommendations are on the left hand side. It’s a pretty busy slide.


[00:57:31.18] The axis on the bottom is recommendations, so it’s specific events that’s out of 1,000 patients, a hundred of whom had a pathologic germline variant, and so that’s what the denominator is out of for the most part here. But I thought what was pretty interesting here, well, for one, not a lot of patients had major changes in therapy, which is what you would expect.


[00:58:00.94] This is all in a urologic setting, so patients with newly diagnosed presumably mostly localized prostate cancer. But in terms of changing clinical follow-up, referring to genetic counselors, or even also referring family members for genetic counseling and genetic testing, though certainly these things are most common if patient has a positive result, this also was pretty frequent for patients who had a variant of unknown significance, which-- so I think is very interesting to note in this setting of community urology practices.


[00:58:48.35] So the authors conclusions is that germline genetic testing influences the care of patients with prostate cancer, and appropriately, patients with pathogenic germline variants received a greater number of recommendations for change than those with VUS or a negative result.


[00:59:09.29] They point out that germline genetic testing can identify potential treatment options, although in this particular setting, it’s probably more planning for the future than a change of treatment that is going to happen at that moment. But they did find that a lot of these variants were found in patients that were outside of the typical criteria that we think of for doing the germline testing.


[00:59:33.74] And their general conclusion is that this is a relatively new area for providers and perhaps an opportunity for more training for providers, educational opportunities, and thinking about how we’re incorporating genetic counseling into the practice.


[00:59:54.28] All right, moving on to the BRCAAway study, so this was an interventional study. It’s a small investigator-initiated study. And I guess I should add in a disclosure that we at Northwestern are the primary institution for this study.


[01:00:08.60] And I think the context for this is coming on the heels of MAGNITUDE and PROpel which are presented at GU ASCO in February and were large phase III studies looking at first line metastatic CRPC, combining abiraterone with a PARP inhibitor and MAGNITUDE that was niraparib and in PROpel that was olaparib.


[01:00:33.76] And so here is BRCAAway, a much smaller study but a similar setting combining abiraterone and olaparib, and a little bit different design here, which I think is something that we as clinicians are looking for. There are three arms, and patients were assigned to either combination therapy or abiraterone or olaparib with the design that there would be crossover in the monotherapy arms at the time of progression.


[01:01:14.72] And so I think part of what was missing from PROpel and MAGNITUDE, we saw that there was improved radiographic progression-free survival in the combination arms, but what we didn’t see is any indication or way to determine if combination therapy was better than sequential.


[01:01:37.94] So enter in BRCAAway, a small study, only 60 patients, but with a slightly different design. And so here are the initial results. And so this is looking at radiographic progression-free survival. It’s still an early time point, but you can see in the table of the bottom left that the 12-month progression-free survival is pretty strikingly different in that there’s 95% progression-free survival in the combination arm versus 40% and 49% in the monotherapy arms.


[01:02:15.35] And so that point is right at 12 months. Looking at the Kaplan-Meier curve, you can see that-- actually, if you look further out, there is a bit of a tail on the curve for abiraterone. And so the abiraterone and combination arms do come closer together. But initially, at this 12 months time point, there is pretty marked separation between those curves.


[01:02:44.73] And so the authors’ conclusions were that, in patients with metastatic CRPC and mutations, alterations in BRCA1, BRCA2, or ATM, the combination of abiraterone with olaparib was well tolerated and resulted in a longer progression-free survival and better PSA responses than either agent alone.


[01:03:13.30] And so I think this is an interesting trial. Even though it’s small, I think it could be impactful. I think it’s still too early for that. I guess I would ask the two of you, if we had more data or more time, do you think this data, on top of PROpel and MAGNITUDE, could that sort of nudge you in terms of your own practice? Or do you think it’s just kind of too small, that regardless of what the results look like, that it would do enough to really be contributing too much to our understanding of our landscape of options or practice pattern?


[01:04:04.53] I think one of the really neat things about this study, and this is the first data point that we’re able to hear about, but I know that this study is actually quite a complicated one. Dr. Hussein put together a very, very thoughtful design. And so there are other cohorts that we’ll be hearing about, I think. I think one of the neatest things, though, about this, in one of the next iterations, is that we might see crossover information.


[01:04:32.32] So for patients who are treated with either olaparib or abiraterone, and then we see how that sequencing may affect patients, I have to say that the PFS data is so strikingly different. I mean, that hazard ratio was pretty intense and so small that I would be surprised if there is not something synergistic going on. But that’s obviously a guess.


[01:04:59.58] We will see the sequencing, and even though numbers are small, we might see a signal to help us understand what happens in a stepwise fashion versus a combination fashion. And especially taken in context with MAGNITUDE and PROpel then, that might help us understand whether we should be considering these combinations as a first line.


[01:05:21.94] The other thing to think about, and this, of course, came up in PROpel and in MAGNITUDE, is that if we are using intensified AR strategies in the hormone-sensitive setting, how are we going to then implement them in mCRPC settings? So if there is success here, do we want to move that into a hormone-sensitive setting? Or do we want to think about a trial where we continue an AR agent and add on something like olaparib at the time of progression?


[01:05:46.38] Could we get synergy there that’s beyond a single agent olaparib, for example? So I think there’s a lot of questions that come from this. I think it’s really useful data. And even though it’s not powered to be a registration trial, I do think that it definitely will inform over time.


[01:06:03.67] Yeah, so presuming that PROpel and MAGNITUDE lead to some form of regulatory approval for a combination in mCRPC, I would say that this trial has very compelling data around doing them together, rather than sequentially. So if you have a patient who has not already started an AR pathway inhibitor while in hormone-sensitive prostate cancer, and they’re relatively high volume, and you know that they have one of these alterations, I would say that there’s quite compelling data to do that combination.


[01:06:41.26] The things that come up is that when you do sequential studies, you don’t know if you really made that switch very early in the process. Would you really have the same PFS2 as if you did the combination together? And you also don’t know if you started with one and layered on the second if you could, again, maybe save the toxicity of the cost from the initial run-in with the combination that you might not need if you can just layer on the second.


[01:07:10.09] And so I think Alicia’s trial idea of progressing on abiraterone and randomizing to abiraterone plus a PARP inhibitor, versus the PARP inhibitor monotherapy, is actually probably one of the more important studies that really needs to be done in this space.


[01:07:27.10] Yeah. Yeah, a great point. I think in the interest of time, we should probably move on. I think we did address at least some of the questions in some way that were coming up in the chat, but we should move on to something completely different. Dr. Morgans, do you want to take it away?


[01:07:46.75] Sure. Thank you. And we’ll get the slides up, and we’re going to be talking about something a little bit different now. And hopefully, I will have control here. Let’s see. Looks like I’ve got it, OK. All right. And as it’s titled, “And now for something completely different”.


[01:08:07.88] So we’re going to be talking about a really interesting and a novel approach in a neoadjuvant setting to a new target, B7-H3. And then we’ll talk about frailty and geriatric assessment and whether we can do something a little less cumbersome than the traditional geriatric assessment.


[01:08:26.11] So this first study is by a really, I think, wonderful young Investigator at Johns Hopkins, who, I think, just has a powerful personal story and a real sincere investment in prostate cancer. So I just love to see his work coming out and being recognized. This is looking at an agent, enoblituzumab. Sorry about that. I’m going to learn as it becomes, hopefully, something that we use on a more regular basis. But neoadjuvant enoblituzumab in a phase II study design.


[01:09:01.81] And it’s really, because of its design, meant to assess safety and then early PSA responses. This is not, of course, a registration trial. And so this is a drug that we’re going to be giving, or was given in this study, to patients who had a Gleason 7 or higher disease in at least two cores. And patients were screened to make sure that they had this, and had this, of course, diagnosed on their pre-treatment biopsy.


[01:09:29.80] Then they were treated for six weeks with the enoblituzumab and underwent a radical prostatectomy. And they were followed at the 30 day, 60 day, and six month, one year, and three-year time points, with these earlier time points being what we’re going to be talking about today. And there were serial sections and assessments that were happening here along the way looking at biopsy specimens, prostatectomy specimens, and frozen PBMC and serum specimens.


[01:09:57.31] So really trying to understand how this particular agent affected the immune environment and the microenvironment for these cells. Which we could do because it was given in a neoadjuvant setting and then we had the prostatectomy specimen to really kind of make these assessments, which is, I think, really kind of a unique and special thing about neoadjuvant studies.


[01:10:19.19] So what they found is that before prostatectomy, they did see PSA declines of about 10% in a third of patients. And at a year post-op, they had a PSA that was undetectable in 66% of patients. And this is, of course, a single-arm study, so we’re not comparing against standard of care.


[01:10:40.09] On the right, you can see a waterfall plot showing that some patients had a change in grade group, so the histology pattern, between biopsy and radical prostatectomy, suggesting that perhaps there was a downgrading happening for some of these patients. The median time to PSA recurrence was not reached. And there were, as you can see, downgrades in about 50% of patients. Some patients did have an upgrade, which we know is something that can happen between biopsy and prostatectomy, but those rates were lower.


[01:11:11.83] And the immune effects that I mentioned before were, I think, really some of the more interesting effects. We saw that there was a post-treatment upregulation of CD8 T cells, PD-1 and PD-L1 expression, and immune activation in the prostatectomy specimens. And there was an association between CD8 T cell increase and Gleason grade group decline. So at least some indication that perhaps there was an immune response against the prostate tumor that was leading to this downgrade because we did see the infiltration of these T cells.


[01:11:45.72] I think in any neoadjuvant study in particular, understanding the adverse event profile is going to be something that’s of high interest. Of course, if patients are treated and then not able to make it to prostatectomy, that’s a red flag and not something that we would necessarily feel comfortable with, especially for patients who have a Gleason 7 disease. And for many of those patients, we do expect they’ll get to prostatectomy, they’ll be cured, and hopefully be long-term survivors.


[01:12:10.11] In any event, we did not see strong, concerning safety signals in this setting. We actually saw that things seemed to go relatively well, with grade 3 adverse events in about 12% of patients. I would say that there was a patient who had an immune, or an infusion reaction, and one patient who had an immune myocarditis. I think that is something that we will need to keep an eye on as this moves forward. That patient was treated, improved with steroids, but always something to be aware of.


[01:12:35.26] Again, in a pre-prostatectomy population, these are going to be key. But there were no grade 4 adverse events related. And you can see all of the AEs reported in at least 10% of the patients, listed to the right here. Things like flu-like symptoms, GI symptoms, fatigue, which is common for many of our treatments, are listed here. Mostly grades 1 and 2.


[01:12:56.29] So in conclusion, enoblituzumab appeared to be potentially active in this neoadjuvant setting in these patients with prostate cancer prior to their prostatectomy. There was this intratumoral induction, or upregulation, of immune checkpoints and T-cell activation, myeloid inflammation that looked like it could be associated with downgrading of Gleason scores. And really, there was also a peripheral expansion of T-cell clones that, again, might be related to tumor control. So this is, I think, an interesting novel approach for us to consider and something that we have not seen yet in this particular setting.


[01:13:38.24] So as we move forward, we have the ELCAPA cohort study. And here’s the study design. It looks a little bit different than our normal designs. This is really an assessment that is done within a larger cohort study that includes about 50% of prostate cancer patients. These are all patients who are older adults, over 70 years old. But there are other solid tumor types in this particular setting-- so patients who have breast cancer, colorectal cancer, and lung cancer are also included.


[01:14:07.18] And the purpose of this was to really understand if there were patients who needed a geriatric assessment to be done, if that was really the best way to assess their fitness or frailty as it relates to future treatment, or if we could use a more brief and basic screening tool like a G8 questionnaire that might be a little bit easier, faster, simpler to give, not necessarily by a trained higher level clinician, but could be maybe done more simply by even a medical assistant in the office. So just trying to see if we could reduce burden, but have the same outcomes in terms of understanding fitness or frailty.


[01:14:45.50] So here you can see that there were about 1,600 patients who were in this entire cohort. They went through a geriatric assessment, and then also did these G8 assessments and modified G8 assessments. And the team, again, tried to understand the sensitivity, specificity, positive and negative predictive values for these as they looked at the cohort.


[01:15:07.52] And here we can see that sensitivity and specificity were 85% and 59% for the G8, 86% and 60% for the modified G8. And here we can see these thresholds. Really, if you just focus on the sensitivity analyzes and these bars on the figure here, we can see that the GA, Geriatric Assessment, was better on pretty much everything that we can see here.


[01:15:33.24] So the GA, Geriatric Assessment, held its own, really is more intensive in terms of labor and in terms of time, but is probably the way we need to go if we really want to understand the fitness of patients, and we don’t want to miss patients who are frail or unfit for more aggressive treatments.


[01:15:53.39] So ultimately, frailty screening demonstrated good diagnostic performance, but a lower benefit for detecting these unfit patients. So using the G8 or modified score were not as-- they weren’t sufficient. They didn’t replace the GA, a full geriatric assessment. Frailty screening did not provide a reduction in unnecessary geriatric assessment.


[01:16:12.62] Again, in English, geriatric assessment is necessary if we don’t want to miss these unfit patients. And so performing this geriatric assessment is really going to help provide a higher clinical benefit to patients as we’re trying to understand their fitness or their frailty. Passing it back to you, David.


[01:16:31.87] Great. Thank you, Alicia. And sort of bringing into our world, where we have a lot of older patients, and having a discussion about triplet therapy. Should we be adding chemo? How aggressive do we need to be for everybody? This is another side of that same coin. We also need to be identifying those patients that are more frail.


[01:16:56.64] And interesting, that just easy screening, which is probably what I do or think I’m doing, but clearly probably not effectively, and really need to get better training in how to do a better, full geriatric assessment and be incorporating that into our management decisions and who should be getting how intensive a therapy. That’s great.


[01:17:24.37] So a couple of other patients-- sorry, a couple other questions coming up especially for the B7-H3 study that you presented. I’m not even going to attempt to pronounce the name of the antibody. So any potential benefits of novel antibodies in combination with more traditional therapies? Are there specific patient types who may be benefiting? And does T-cell, sort of along the same lines of T-cell modulation, represent the future of prostate cancer treatment? That’s the prompt, take it away.


[01:17:59.23] I was going to say, I think Dr. Choudhury should take this one. Because I think he’s been thinking about these pathways for a long time.


[01:18:09.67] I was so certain that Dr. Morgans would punt this to me. But I would say that we’re just so early days with really understanding how the immune system and prostate cancer really interact. Like, what are the reasons why prostate cancer does not seem to respond as well to checkpoint immunotherapeutics? Are there other checkpoints that are relevant? Should we be using combinations?


[01:18:36.70] Is this even a strategy that is worth the time and effort and the amount of money and resources that are going into immune approaches? And really, should we be focusing more on antibody drug conjugates and radiopharmaceuticals? I think that remains, actually, a pretty active debate, and we had a pretty fun one about that at one of our SPORE retreats that we had in LA.


[01:19:00.16] So what I would say is that I think it’s going to be a while before anything along these lines becomes something in routine practice. Sipuleucel-T is an approved agent and has been shown to prolong survival. And I do use it in my practice even though the cytoreduction is pretty much modest or nonexistent. But everything else will probably have to be in some way biomarker directed and probably will work best in combinations. But I think we’re very early days.


[01:19:37.11] Yeah, I agree with that. Although I do think that the downgrading seen in this particular study-- and what a lot of parameters are looking at, including thoughtful analysis of the immune reaction-- but that downgrading kind of stood out to me as perhaps a signal of activity. But the right setting, the right combination, still early days and more to come about that.


[01:20:03.78] Maybe trying to sum up a couple last questions in the bit of time that we have left. So are there clinical situations where frailty screening may still prove to be useful in patients with prostate cancer? And what are the overall benefits of geriatric assessment? Can I direct that one towards you, Dr. Morgans?


[01:20:26.13] Sure. So I think that the study that I presented, the cohort study, was very interesting, but I do think that we need to keep in mind that this study was done by a group that is very facile with geriatric assessments and thinks a lot about the care of older adults. I think using this information to show that a geriatric assessment is maybe better in terms of positive, negative predictive value, sensitivity, specificity, that’s great. But something like a G8, which is actually potentially more feasible in our practices, might be better than nothing.


[01:21:01.24] And so I would advocate that if we want to do something, but we don’t have the staffing to do full geriatric assessments-- and in many places, that’s actually geriatric oncologists who partner. And so it’s not the medical oncologist in GU who’s doing these assessments herself or himself. It’s really these partners who see our patients. If we don’t have access to those individuals, but we are OK doing a G8, I think that’s fantastic. And I would say that’s actually going above and beyond what we’re doing for most of our patients in most of our practices anyway.


[01:21:34.65] The International Society for Geriatric Oncology actually recommends a G8 as their screening tool for older adult patients, specifically for patients with prostate cancer over the age of 70. So if that’s all you can do, you are actually, again, going above and beyond, and you are meeting recommendations for actually excellent care, not just minimal care. So thank you for thinking of this. And we can use these to identify patients who are especially frail.


[01:22:02.19] And we do know that a G8 with a score that is 14 or less is actually associated with increased mortality in cancer patients. So if we find that and are using that, perhaps as we’re thinking about things like chemotherapy or other stressful, strenuous therapies that we know patients may be not able to endure or may not have the social supports to endure, may have comorbidities or drug-drug interactions that may make it challenging, understanding that score and knowing that they’re above or below 14 actually could really inform your decision-making.


[01:22:36.92] Great. Thank you. Yeah, I know that you are much more thoughtful about this than I am. And I think that-- well, thank you, first of all, for presenting this abstract. But I think it just is a very good reminder that time and resources are limited to do the best job. You need a lot of both. But even if you can’t quite meet very much the gold standard, then continuing to keep this front of mind and what’s the best way that we can really be evaluating, assessing our patients, and using that information to inform what’s going to be best for them. Just very thankful, very helpful.


[01:23:22.04] All right. And that is time for us. Thank you, Dr. Morgans, Dr. Choudhury, very much for joining me in this session. Hopefully this was helpful for people, hopefully informative, maybe modestly entertaining, maybe thought provoking. We enjoyed getting your questions. We enjoyed having the time to have the discussions. And thanks for answering those questions.


[01:23:49.89] And, once again, also, please give your feedback. That’s very helpful. Let us know about the speakers. Let us know about the format. Help us to know how we can improve these kinds of things for the future. And that’s it. Thanks, everybody.

Dr. David VanderWeele, MD, PhD

Northwestern University, Illinois, USA

Dr. David VanderWeele is an Assistant Professor of Medicine (Hematology/Oncology) at Northwestern University. His research efforts have focused especially on altering the course of potentially lethal GU cancers using targeted therapies and translating discoveries made at the bench into improved therapies in the clinic. He practices in the GU clinic and is the GU lead in the Early Phase Therapeutics clinic, and he is the Interim Director of the OncoSET Precision Oncology Program. He is the Principle Investigator for multiple biomarker-selected studies for newly diagnosed prostate cancer.  He is active in the Alliance and SWOG cooperative groups, where he is on the leadership teams of multiple phase III studies, both on-going and in development.  He collaborates with basic and translational scientists to develop tissue and liquid biomarkers to identify and characterize aggressive disease. In the clinic, Dr. VanderWeele manages patients with prostate, bladder, or testicular cancer.


Dr. Alicia Morgans, MD, MPH

Dana-Farber Cancer Institute, Boston, USA

Dr. Alicia Morgans is a Genitourinary Medical Oncologist and the Medical Director of the Survivorship Program at Dana-Farber Cancer Institute. As a clinician and investigator, she has expertise in clinical trials and patient-reported outcome measures, as well as incorporating patient preferences and beliefs into clinical decision-making. Her research has investigated complications of systemic therapy for prostate cancer survivors, including the study of skeletal, cardiovascular, diabetic, and cognitive complications, and has been funded by grants from the Prostate Cancer Foundation and the Department of Defense. Since 2016, she has been the President of the Medical Advisory Board for ZERO, a non-profit organization dedicated to supporting education and research funding for prostate cancer research.

Dr. Atish Choudhury, MD, PhD

Dana-Farber Cancer Institute, Boston, USA

Dr. Choudhury is a medical oncologist and clinical/translational investigator within the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, and Assistant Professor of Medicine at Harvard Medical School. He received a BA in Chemistry from Johns Hopkins University and received his MD, PhD from Columbia University. He currently serves as Chair of the Gelb Center for Translational Research, and his research interests include: investigation of genetic and epigenetic biomarkers from circulating free DNA from patients with metastatic cancer; biomarker studies conducted using biobanks of patients participating in clinical trials; and the clinical investigation of novel therapeutics for genitourinary malignancies.


This independent medical education meeting has been funded by Astellas. Astellas has provided funding for speaker fees, organisational costs, plus the venue. The views and opinions expressed in this independent presentation belong solely to the author. The contents of this presentation do not constitute an endorsement of the use of any product by Astellas or necessarily represent the views of Astellas.