Activity Transcript

Neal Shore, MD, FACS: Hi, everybody, and welcome to Medscape Onsite: Prostate and Bladder Cancer Updates. We're here in San Francisco at ASCO® GU 2023. It's a great pleasure to be here. I'm honored to be with a great friend and colleague, Matt Galsky, from New York. I'm Neal Shore, I'm in South Carolina. We have urology and medical oncology perspectives on prostate and bladder cancer.

Let me kind of review quickly for you some of the really top exciting information in prostate cancer. We saw some data that came out from the ARAMIS Trial. This was a phase 3 study, the third phase 3 trial in nmCRPC. Previously, there was SPARTAN and PROSPER.

ARAMIS came along as an effective positive study meeting its endpoint of MFS and clearly a key secondary endpoint of overall survival. The rollover study that you're seeing the data here looked at the patients who were in the blinded portion of the trial and then ultimately who rolled over, so the control group as well as the open label. So it was a confluence of these populations.

What's really interesting is in the bars at the far right and you see nearly 30% of the patients went on to receive therapy for 4 years. This was a large phase 3 trial of over 1,500 patients. What was the take home here? The take home was really that when you look at those in the double-blind as well as in the open label and we look at their treatment, emergent adverse events continue to show very good tolerability with a low percentage of patients having grade 3, 4 reactions.

This is important because patients who are non-metastatic CRPC tend to really be asymptomatic with the exception of their side effects from T suppression. The rollover study that was presented here looking at patients who are on darolutamide, out to 4 and 5 years showed consistent tolerability.

Now here's MAGNITUDE. MAGNITUDE, an important trial that was presented a year ago at ASCO® GU at 2022 and interestingly combining niraparib and abiraterone, it was a positive trial in terms of the rPFS data and the biomarker or the HRR mutational positive group. The all-comers did not meet a positive finding.

In this presentation, we looked at the patients who had roll-in from less than 2 months or between 2 and 4 months who had abiraterone. So, sort of a layering or a sequencing to receiving niraparib poly(ADP-ribose) polymerase (PARP) inhibitor and you see the various gene alterations that are listed. Here's what we found here. It's in the embolden black. The less than 2-month exposure group to abiraterone, acetate and prednisone, they're small numbers. But even looking at the 2 to 4-month, what we're able to see is that there's a consistent rPFS in this data set for patients who had roll-in on abiraterone. These were a first line mCRPC patients who then received the PARP inhibitor, niraparib.

I think the take-home message here is that while you have a patient started on an approved agent such as abiraterone acetate with prednisone, you could be getting genetic testing during this time and making sure that the patient has an HRR mutation. At small numbers, but important to see that.

And then ultimately, we move to PROPEL another important trial combining abiraterone acetate with another PARP inhibitor, olaparib. The data that were presented today or really yesterday and here was the third data cutoff point on the prespecified final analysis for overall survival.

This was another important study because it looked at an all-comers population. MAGNITUDE was only positive for biomarker positive patients and their gene puddle of homologous recombinant repair alterations. What we see here is the third analysis and we see a 7-month difference compared to the control arm of abiraterone. Again, for first-line mCRPC patients, it has not yet reached statistical significance. It's trending that way. From the podium they announced that there will be additional overall survival follow-up.

And then looking at the mutation positive vs the non-mutation, both trending positive, clearly more robust in the HRR mutation positive. Again, nonetheless, the rPFS data is positive for both arms. Adverse event profile, yeah, there's a little more toxicity undoubtedly when you add a PARP inhibitor to an androgen receptor pathway inhibitor. The chief path adverse events of note, not dissimilar to the entire class of PARP inhibition, is myelosuppressive effects. You can see that here in this tornado plot.

And then a little bit increase in fatigue. There are some GI toxicities. Fortunately, the grade 3, 4's are low, but I think overall the consensus is that with monitoring CBC monthly, particularly in our patients with mCRPC, these are manageable and a multidisciplinary team of medical oncology and urology is vital.

And then let's switch over from, we talked about nmCRPC, first-line mCRPC, combination trials MAGNITUDE, PROPEL. What about first-line mHSPC? Low volume/high volume, and data were presented here, had been previously shown a year ago, the ARASENS, which was a successful trial looking at triplet therapy, ADT plus docetaxel and darolutamide vs ADT and docetaxel.

What you see here is not reaching yet in looking at definitions of high volume/low volume vs high risk. The high volume/low volume definitions were the classic charted. The high risk was more in the latitude schema. I think the bottom line is that in looking at subgroups, whether the patients had high volume vs low volume disease clearly benefit to the high volume/high risk. About 30% of the patients fell into the low volume/low risk classification in the subgroups.

Overall, really no significant differences in the amount of treatment-related adverse events in the triplet vs the doublet. Again, speaking to the tolerability of darolutamide.

Overall, I think what we have here today at ASCO® GU 2023 is really interesting and important considerations for our colleagues to have that shared decision-making conversation. Thinking about ARASENS' triplet vs couplet, undoubtedly value proposition is there in the high volume/high risk patients and then I think it's more of a case by case in the low volume. But at this point, let me hand it over to Matt.

Matthew D. Galsky, MD, FASCO: Thanks, Neal. Lots of excitement in prostate cancer. I'm going to talk about bladder cancer. For those joining us live, good morning to you. At ASCO® GU this year, we saw results for TAR-200. And TAR-200 is really interesting because we don't often talk about technology solutions in GU oncology in general and particularly in meetings involving medical oncologists.

But this is actually a device that's inserted into the bladder that leads to sustained release of gemcitabine through an osmotic gradient and continuous release of gemcitabine within to the bladder is certainly favorable from a pharmacokinetic standpoint. There have been a few studies so far with TAR-200 establishing feasibility and safety and even studies before with TAR-200 in the muscle-invasive bladder cancer setting prior to cystectomy showing that pathological complete responses can be achieved.

So, this was a study in patients with non-muscle-invasive bladder cancer with TAR-200, the devices inserted into the bladder by a urologist. This was a marker lesion study. So both to establish the safety and also to establish some preliminary evidence of activity in non-muscle-invasive bladder cancer and that indeed was shown.

There are complete responses observed with TAR-200 and the safety profile is similar to what's been shown in patients with muscle-invasive bladder cancer in terms of mostly low grade adverse events in mostly bladder related side effects as one might expect, little systemic exposure with this agent so little in the way of systemic side effects.

So, TAR-200 is being explored across multiple disease states and bladder cancer right now from the non-muscle-invasive disease setting to muscle-invasive disease in a trial that's using this in addition to immune checkpoint blockade in the neoadjuvant setting. And then a very interesting study in patients who are cystectomy ineligible comparing TAR-200 with programmed cell death protein 1 (PD-1) blockade vs concurrent chemoradiation. So, really trying to establish a new pillar of treatment for muscle-invasive bladder cancer beyond our conventional treatment strategies.

We saw results from TROPHY-U-01 at ASCO® GU involving the antibody drug, sacituzumab govitecan. You'll remember this is an antibody drug conjugate directed against Trop-2 with SN-38 as the payload. The TROPHY-U-01 program has multiple cohorts, both single agent and combination trying to assess sacituzumab govitecan in distinct clinical disease states.

So, Cohort 2 was presented and this cohort evaluates patients who are "platinum ineligible". Really if you look at the definitions that were employed here, this is more of a cisplatin ineligible population than a platinum-ineligible population. Really the intent of studying sacituzumab in this setting is that for a period of time, single agent immune checkpoint blockade in frontline treatment of patients with metastatic urothelial cancer was a common treatment strategy that still exists to some extent, although that has gone away a little bit based on emerging data.

So, what to do after patients with metastatic urothelial cancer have had frontline immune checkpoint blockade and then progressed has not been clear? And so sacituzumab has been explored in this space. And what we see is a response rate of 32% and this is somewhat in line with response rates that we've seen with sacituzumab in more heavily pre-treated patients. So, certainly an active drug.

Sacituzumab is approved in other malignancies as well, so there's a fair amount of experience with this antibody drug conjugate. The toxicity profile is consistent with what we're used to with topoisomerase inhibitors. And so certainly, this has become an important part of our treatment armamentarium for bladder cancer.

In terms of the treatment-related adverse events, really similar to what we've seen in prior studies with sacituzumab govitecan and importantly cytopenias, neutropenia does occur with this agent and the use of growth factors is required beyond cycle one in many patients, and many people practice using growth factors from the onset given the risk of febrile neutropenia.

To switch gears a little bit back to the muscle-invasive bladder cancer setting. We've known for some time that with neoadjuvant cisplatin-based chemotherapy, a subset of patients will achieve a pathological complete response. Paradoxically, we only know that a pathological complete response has been achieved after the bladder is removed and certainly that's associated with a highly favorable prognosis and that's a good thing for patients.

But patients also look at us a little bit quizzically when we say that good news, there was no cancer in your bladder after their bladder has been removed. So, there's been an attempt to pursue treatment paradigms that try and leverage clinical data to identify patients who might not indeed not require cystectomy in order to achieve cure. And there are a number of programs going on trying to pursue this treatment paradigm.

These are the results of HCRN GU16-257, and in this clinical trial, 4 cycles of a gemcitabine cisplatin plus nivolumab were administered. After that, patients underwent clinical restaging, which was defined as cystoscopy, biopsies of the bladder, urine cytology, and magnetic resonance imaging (MRI).

And if all of those were normal, then patients were defined as having a clinical complete response and patients with a clinical complete response could opt to not undergo cystectomy and receive maintenance nivolumab, not dissimilar to what we do in the metastatic setting with switch maintenance therapy or undergo cystectomy immediately. If there was no clinical complete response, patients were recommended to undergo cystectomy.

The primary endpoints were clinical complete response rate because clinical complete response has not really been a defined entity. And so we really didn't know what the clinical complete response rate would be with this combination and then the ability of clinical complete response to predict long-term outcomes.

76 patients were enrolled, 33 patients achieved a clinical complete response of those patients. Only one patient opted for immediate cystectomy. In the swimmer's lane plots here, you see in the dark lanes patients who are alive without invasive recurrence in the bladder, so with an intact bladder.

In the light blue lines, these indicate patients who had a clinical complete response who then had a local recurrence in red, followed by cystectomy in yellow. The purple squares indicate patients with metastatic recurrence of whom there are 2 in this cohort of patients achieving a clinical complete response. I should say the median follow-up for this group is 30 months and the arrows at the end of the lanes indicate patients who are still alive.

You can see in the Kaplan-Meier curves, a landmark analysis at the time of clinical restaging stratified by whether or not patients achieved a clinical complete response or not.

The take home here is that a stringently defined and uniformly assessed clinical complete response does have significant prognostic value and really raises the question, can we move away from our current treatment paradigms from the outset deciding what the treatment path is going to be for all patients with muscle-invasive bladder cancer to a more personalized strategy where we use the response in situ in an individual patient to try and personalize treatment decisions?

There are more trials like this coming and I think we need to better understand where this fits and if we can integrate novel technologies like urine tumor DNA to help triage these decisions, I think this approach does have legs in terms of really becoming one of the treatments that we do offer our patients. We did identify in this study that high tumor mutational burden was associated with a higher likelihood of patients achieving bladder intact, durable metastasis-free survival as one might expect from a treatment regimen that integrates immune checkpoint blockade.

We saw results from the CheckMate 274 study at ASCO® GU this year. So, this is a phase 3 study randomizing patients in the adjuvant setting with muscle-invasive urothelial cancer at high risk for recurrence after radical resection to adjuvant nivolumab vs placebo. Patients at high risk in this study were defined by patients who had received neoadjuvant chemotherapy and had pathological T2 or higher disease in their surgical specimen, or patients who had not received neoadjuvant chemotherapy and had pathological T3 or higher disease in their surgical specimen and were cisplatin ineligible, so couldn't receive adjuvant treatment.

This is a bit different than adjuvant trials in the past that these patients really have not been included in adjuvant studies in the past, and really both of those populations are unmet need populations or have been unmet need populations. I'll note that this study and this generation of adjuvant studies was really the first to pool patients with urothelial cancers of the bladder and urothelial cancer of the upper tract.

The results of CheckMate 274 were initially presented a couple of years ago. Now the minimum follow-up at the time of the initial report was 5.9 months. The trial met its co-primary endpoint at the initial report with an improvement in disease-free survival and the intent to treat population and in patients with tumor programmed death-ligand 1 (PD-L1) expression greater than or equal to 1% leading to FDA approval.

This updated analysis is extended follow-up from the CheckMate 274 study now with a minimum follow-up of 31.9 months, and the median follow-up is 3 years now. What you see is that there's an improvement in the disease-free survival in patients treated with adjuvant nivolumab vs placebo in both the intent to treat population with a hazard ratio of 0.71 and in patients with PD-L1 expression greater than or equal to 1% with a hazard ratio of 0.52.

And so really stable effect in terms of disease-free survival despite the fact that this is adjuvant treatment. Remember, this is a fixed duration of treatment up to 12 months of treatment, but even after discontinuing treatment, the effect is sustained over time. I'll point out that there is an enrichment in the magnitude effect in patients with tumor PD-L1 expression greater than or equal to 1%.

But remember that this is using the PD-L1 assay that's associated with this program. So this is the 28-8 antibody clone scoring tumor cells only. This is not necessarily synonymous with the PD-L1 assays that you might be obtaining locally or with commercial testing. So, it is important when we're making treatment decisions based on a biomarker to use the biomarker that was employed in the study.

Here's distant metastasis-free survival with extended follow-up and you'll see in the intent-to-treat population hazard ratio of 0.74 in patients with tumor PD-L1 expression greater than or equal to 1%, a hazard ratio of 0.58, so also an effect in this important exploratory endpoint. With extended follow-up, the safety profile of adjuvant nivolumab looks pretty similar to the initial report.

Grade 3 or greater treatment-related adverse events occurred in 18% of patients treated with nivolumab, 7% of patients treated with placebo. Those adverse events are what one might expect with immune checkpoint blockade. So, really not different in the adjuvant setting than what we see in the metastatic setting.

This slide summarizes efficacy outcomes over time with successive database lock. So, I mentioned the initial report was 5.9 months minimum follow-up. Now, we have 31.6 months minimum follow-up. Really the point of this slide is to show how stable the effect size is over time in the intent-to-treat population and in patients with tumor PD-L1 expression greater than or equal to 1% across all of the primary, secondary and exploratory endpoints, so consistently hazard ratios in the 0.7 range in the intent-to-treat population and in the 0.5 range in patients with "high" PD-L1 expression.

Moving now to the metastatic setting. Several years ago, platinum-based chemotherapy was all we had for metastatic urothelial cancer. It had been the standard treatment for decades. And then immune checkpoint blockade came along initially demonstrating activity in patients who had received platinum-based chemotherapy and then progressed leading to FDA approvals in that space, and then rapidly moving immune checkpoint blockade to the frontline setting in patients who were cisplatin ineligible and that was recognized as an unmet need at that time leading to FDA approvals in that space for 2 drugs, atezolizumab and pembrolizumab based on accelerated approval from single-arm phase 2 studies.

The most important question then several years ago when IMvigor130 was designed was what should we give to patients with metastatic urothelial cancer? Platinum-based chemotherapy like we had been doing for decades, single-agent immune checkpoint blockade, which was an emerging therapy, or should we give the combination which had shown promise in other solid tumor types?

And so this large international phase 3 study with 3 arms was designed to address this question. Now, like most large phase 3 studies, one can only ask a limited number of questions with statistical rigor. And so the initial, the primary endpoint here was really comparing platinum-based chemotherapy with immune checkpoint blockade with atezolizumab vs platinum-based chemotherapy alone first for progression-free survival, and then there was a hierarchical analysis plan.

So if that met, then overall survival with that comparison could then be assessed and then only if that showed statistical significance could one test the survival between arm B and arm C, so atezolizumab monotherapy vs platinum-based chemotherapy. I'm going to show you results for all of these analyses because this is quite a mature study at this point, but recognize that I'll show you arm B vs C. And that ended up being an exploratory analysis based on what happened with the hierarchy of the statistical analysis plan.

So, here's the take home message, platinum-based chemotherapy plus atezolizumab vs platinum-based chemotherapy alone, a hazard ratio of 0.85, upper bound of the confidence interval at one. You'll see the P value. The log grade P value is .023. Seems like it's significant, but remember this was a hierarchical plan and so the prespecified threshold for significance was 0.21. This barely missed statistical significance.

But if you look at the curves, there's some separation of the curves, but maybe not what we're seeing in other solid tumor types where chemotherapy plus immune checkpoint blockade has become standard. And so based on these results, giving combination concurrent chemotherapy with immune checkpoint blockade in urothelial cancer is not standard of care.

Now there's an interesting hypothesis generating portion of this study because remember, these were the first generation of phase 3 studies in the metastatic setting to pool patients who were "cisplatin eligible and cisplatin ineligible".

The chemotherapy backbone could be GemCis or could be GemCarbo, both on the standard arm and the experimental arm. We've been a little bit, I think, naive about the fact that combining all chemotherapies with immune checkpoint blockade is going to behave the same. We know at least in the laboratory there are different immunomodulatory properties to different cytotoxic agents. And so this certainly might carry over into the clinic.

What you see on subset analysis here is that in arm A vs arm C, platinum-based chemotherapy vs platinum-based chemotherapy plus atezolizumab, in patients who received cisplatin, you seem to see a larger effect with the combination than in patients who received carboplatin. And this gets even a little bit more complicated because then you look at these subgroup analyses and added the PD-L1 story here.

It gets interesting because the group that's the outlier are patients who receive cisplatin and have high tumor PD-L1 expression. This is not just patients who get the combination. This is patients who get cisplatin-based chemotherapy alone.

If you get cisplatin-based chemotherapy and your tumor expresses high PD-L1, you actually do much better than if you get cisplatin-based chemotherapy without immune checkpoint blockade and have low PD-L1 expression suggesting that there might be some immunomodulatory effect of cisplatin, which we've known for some time. And then if you get atezolizumab on top of that, really small numbers, but the median survival in that group certainly is the longest of all these subgroups.

Some food for thought, this is hypothesis generating, but there is some translational data to support these findings, and so this concept is being brought forward for formal testing in subsequent studies.

Here's the response rates if you look across treatment arms. I think one of the take-home messages here is that the overall response rates are pretty similar among these treatment arms. You do see a higher complete response rate when you combine cisplatin-based chemotherapy with atezolizumab. But overall, the objective response rates are pretty similar, so we might not be seeing the full effect of combination treatments with response rate alone. And certainly some of the time-to-event endpoints, the durability of the responses, the depth of the responses might be where the action is here.

The safety of these combination regimens have now been well established in other solid tumors and in these large phase 3 studies in metastatic urothelial cancer. What you see when you combine platinum-based chemotherapy with immune checkpoint blockade is the side effect profiles of both of those classes of agents. You don't necessarily see synergistic toxicities when you combine these treatments, but as noted, this has not really become standard of care based on the results of this study and KEYNOTE-361.

What has become standard of care, however, is giving platinum-based chemotherapy with immune checkpoint blockade just in a sequential fashion instead of a concurrent fashion. And of course, I'm referring to switch maintenance treatment. So, patients who have at least stable disease after initial platinum-based chemotherapy moving on to immune checkpoint blockade immediately is now a standard strategy based on an improvement in survival.

Let's look at the exploratory analysis, which compared a platinum-based chemotherapy with atezolizumab. What we see here is that based on where this analysis is in the hierarchy as mentioned because overall survival was not met with platinum-based chemotherapy plus atezolizumab vs platinum-based chemotherapy, we can only look at this in an exploratory fashion.

Here's the results in the intent-to-treat population, and these curves look almost identical to other phase 3s that have asked this question in which you see the initial portion of the curve favoring chemotherapy and then the curves cross at about 9 to 12 months. And then later portions of the curve may be favoring immune checkpoint blockade and really speaking to the profile of these drugs, the different profiles in terms of efficacy.

Chemotherapy works in a larger proportion of patients, but the depth of response and the quality of response differs. Immune checkpoint blockade working in a smaller proportion of patients, but when it works, it can work really quite well.

How about PD-L1 expression? Well, here we see something interesting and when you look at patients with high PD-L1 expression in the all-comer group, now you start to see the curves favoring atezolizumab. You take this one step further, which was in line with the most recent label for atezolizumab before it was withdrawn, which was frontline atezolizumab in patients with metastatic urothelial cancer were cisplatin ineligible with high PD-L1 expression. These curves, despite being exploratory, really do support that last label. You see the curves favoring atezolizumab.

Here you now start to see this carryover into response rate where you see the atezolizumab response rates rival GemCarbo in patients with high PD-L1 expression, whereas you don't see that in the unselected patient group.

Dr Shore: Wow, fantastic, Matt. A lot covered, a lot of great take-home points. I think this has been fantastic. We could have gone on for a lot more time. Bladder sparing options, combination options, adjuvant therapy for bladder cancer, when to do the various assay testing, thinking about patients being chemo eligible or ineligible and how we sequence therapies, neoadjuvant adjuvant, prostate cancer, monotherapy in mCSPC, no longer the standard of care and mCRPC benefits. And now the looking at first-line mCRPC combinations of PARPs and ARPIs.

Thank you very much for your attention. To get credit for this, please go to this link. You can get your credit. Again, great pleasure working with you, Matt, as always. Thanks everybody and I hope you enjoyed the update.

This transcript has not been copyedited.