2-Minute Drill: Experts Discuss 2022 Genitourinary Cancers Symposium

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Kristie Kahl: Hi, and welcome to 2-Minute Drill, a video series where no subject is off topic. We’ll talk about the latest clinical research—whether it’s good, bad or ugly—from the most recent cancer conferences. Either way, we’ll get to the point fast. Bringing together some of the leading and most engaging voices in cancer care, CancerNetwork®, home of the journal ONCOLOGY®, will offer unbiased, unscripted thoughts and opinions from our panel about the 2022 ASCO Genitourinary [GU] Cancer Symposium. I’m your host, Kristie Kahl, vice president of Content at MJH Life Sciences®. Today, I’m joined by Dr. Alan Bryce, chair of the Division of Hematology and Medical Oncology at the Mayo Clinic. We also have Dr. Tanya Dorff, section chief of the Genitourinary Disease Program at City of Hope. Let’s also welcome Dr. Benjamin Lowentritt, director of the Prostate Cancer Care Program at Chesapeake Urology. And last but certainly not least, we have Dr. Dan Petrylak, professor of medicine and urology at Yale School of Medicine.

Before we jump into today’s topics, let’s go over some ground rules. One, while many shy away from talking about themselves, on this show we actually want you to. If you have anything [such as] a trial you’re presenting, we want to hear about it. If you have a drug that you’re investigating, we want to also hear about it. If it’s more than 3 syllables, you might have to tell me how to pronounce it. Rule number 2, we don’t want or need your financial disclosures. We’re limited on time and we all know that some of those disclosure slides could take about 20 minutes alone, so let’s just skip it. Three, this is meant to be fun. Obviously, bullies are not welcome, but we agree to disagree here so speak up and tell us your thoughts fast.

Let’s talk points. I will be awarding points during each discussion. We have some friends here in the studio [who] are keeping track, in part because I can’t do math that well, but also because we will let you know who our winner is at the end. We don’t have a prize, but I think bragging rights is prize enough. Points will be awarded for originality, cleverness, humor, or any other attribute I feel necessary at the time of your response. But with that, please be mindful of the clock. The last thing I want to do is have to cut you off, but I will. Each question will be allotted a certain amount of time and answered, so please keep your eye on the timer. Points will be deducted from serial offenders. Alright, let’s jump into it. First topic: Each of you gets 1 minute to tell us what was the biggest surprise that came out of ASCO GU. Dr. Petrylak, we’ll start with you.

Daniel P. Petrylak, MD: The biggest surprise was the activity of ODM-208 [CYPIDES; NCT03436485] in patients with castration-resistant prostate cancer [CRPC]. We’ve all been looking for novel anti-androgens and this is a compound that basically aggregates all steroid synthesis. It was designed to be effective in those patients with androgen receptor [AR] mutations. What I think the biggest surprise was, yes, it does hit the target and in fact, you do see a significant response rate in those patients who have activating mutations—overall about 24%—but you also have seen responses in those patients who don’t have those mutations.The drug was designed to hit the target, but it’s hitting more than the target. So, to me, that’s the biggest surprise.

Kristie: Okay, and you had 8 seconds left. I’m going to give you 3 points for originality and [for being] under time. Dr. Lowentritt.

Benjamin H. Lowentritt, MD: [I’ll take a] bit of a different tack. Some of the discussion around what was released during the meeting surprised to me. Most notably, as a urologist, I was certainly outnumbered by my medical oncology colleagues [who] were there talking about cytotoxic chemotherapy for mCRPC [metastatic CRPC]. It was surprising how frankly open everyone was [to the idea] that it wasn’t the standard of care today, even though one of the bigger trials that was revealed—the [phase 3] ARASENS trial [NCT02799602]—used docetaxel as the standard of care because it was at the time of the enrollment. There [were] data showing that there is only 3% utilization of docetaxel in the mCRPC space. Frankly, it was just the openness with which everyone said we’re not really looking to prove that we need to add something to docetaxel. The question is, “does docetaxel add anything to the oral [regimens]?” So, I thought it was an interesting discussion and a surprise to me that people were so open about it. As a urologist, certainly that’s been our focus as well, but it was good to hear.

Kahl: Yes, great point, 2 points. Dr. Bryce.

Alan H. Bryce, MD: I hear Dr. Lowentritt. Urologists are all just surprised that the oncologists don’t want to do chemotherapy all the time, right? You know, we just want to do what’s best, whether it’s chemotherapy or anything else, so we’re not committed to [and don’t worry about cytotoxic agents]. The most surprising outcome was the confirmation that there was activity [with] the combination of abiraterone/olaparib [Lynparza] in the HR [hormone receptor]–negative setting. We saw that in the PROpel study [NCT03732820]. Even though we had seen that already in the phase 2 data that led into the phase 3 PROpel trial, it was still a signal that I don’t think we were very confident in and even now, as we digest those data, we’re still trying to understand why that is and can we apply it in a completely unselected fashion. [It will require] quite a lot of follow up and we’re still going to be thinking about it and talking about it 6 months from now.

Kahl: Absolutely, just on time. Two more points. Dr. Dorff.

Tanya Dorff, MD: I agree with Dr. Bryce that PROpel was the most surprising. I have designed a study where we’re using a PARP inhibitor up front in metastatic hormone-sensitive prostate cancer [mHSPC] based on some preclinical evidence of how it might have a completely different effect—maybe pruning some of the aggressive clones or maybe the crosstalk with the AR. What was surprising to me though was that the PROpel [trial] looked positive for PFS [progression-free survival], but the MAGNITUDE trial [NCT03748641] was negative for [niraparib (Zejula)]and one would have expected more concordant results. I thought that discussant Celestia S. Higano, MD, raised some good points about differences in study design. But there’s a biology question here that needs to be answered. We didn’t hear any correlative science; I hope that there will be some sort of evaluation of what might be happening biologically or not happening that might help us understand [whether] we are going to be using PARP inhibitors in an unselected population or not.

Kahl: I like your added points. Three points. Let’s move on to the next topic. You each get 2 minutes for this one. Tell us, what trial that you heard out of ASCO GU do you think will be the most practice changing. We will go in reverse order. Dr. Dorff, take it away.

Dorff: Alright, I’m glad I get to go first this time, so I get those originality points. We’ve already spoken about ARASENS. To me, this is immediately practice changing because I’ve been on the fence after PEACE-1 trial [NCT01957436] about whether we need to be adding AR-targeted agents on top of up-front docetaxel. But really the bigger practice change that needs to happen—and this was a call to arms, seeing yet another positive study—[is that] we’ll get the oncology and urology communities energized and motivated to not be doing just castration anymore for mHSPC. I get it, occasionally there’s a very elderly, frail, comorbid patient [then it’s] fine. That patient can just get castration for their first-line therapy. But the majority should be getting doublet therapy, and now there’s a question about triplet therapy. But when you looked at some of the real-world data that were being presented about how many patients are getting intensification up front, there’s been improvement, but we have a long way to go. Again, I hope that this will be practice changing just by waking people up, saying that the CHAARTED trial [NCT00309985] wasn’t a fluke, LATITUDE [NCT01715285] wasn’t a fluke, and STAMPEDE trial [NCT00268476] wasn’t a fluke in any of its multiple iterations. This is the real deal. We don’t keep things in our back pocket. We hit the cancer hard up front and that’s how our patients do best over the long haul.

Kahl: That’s a great explanation and great comparison. We’re going to go with 6 points there. Dr. Bryce.

Bryce: I always agree with Dr. Dorff. At least after many years of working together. Absolutely, ARASENS is going to change practice, right? We only have to wait for a compendium listing, which hopefully comes fairly quickly. But it’s confirmation that triplet therapy is a viable option in mHSPC. The key message over the last 7 years through now—[with] 2 chemotherapy trials, 2 abiraterone [Zytiga] trials, 2 enzalutamide [Xtandi] trials, apalutamide [Erleada], and now darolutamide [Nubeqa]—is that treatment intensification works. We haven’t seen a negative study in further intensification since CHAARTED in 2015. Vincent DeVita, MD, proved that intensification works in lymphoma back in the 1970s, right? It has taken the prostate community 40 years to catch up, but we’re doing it now. I think this trend will continue. You’re going to see further intensification for a long time yet. And yes, we’re already thinking about deintensification. But as much as we think about that prospectively, the default position for now has to be [that] every patient should be considered for triplet and then you back down and give a reason why we’re not going to do triplet in the individual patient. I agree with Dr. Dorff. I think most patients land on doublet, but nevertheless triplets should be in the conversation for every patient we see.

Kahl: Absolutely. I’m going to give extra points for cross referencing other cancer types outside of GU, so we’re going to go with 7 points there. Thank you, Dr. Bryce. Dr. Lowentritt.

Lowentritt: I’m going to lose points for originality here but the reality is that the ARASENS trial is the most immediately practice changing. Long term, the use of PARP inhibitors, and especially the use of PARPs in an unselected group, is really intriguing and exciting. But [there is] still more to come on that. We have to remember that maybe a year or 2 ago, I was afraid that this was going to be a negative trial. Most of us probably participated if not in this one, then in one of the similar trials. But this one was very different in that it did have an active comparator on top of [androgen deprivation therapy] with docetaxel. This idea that we were seeing that significant response that we got from adding darolutamide to docetaxel is an immediate eye opener to anyone who is not already using it. I agree that despite what I said earlier, the interesting thing is I’m referring patients for consideration for docetaxel. Before it was an either/or, and oftentimes the discussion came down to, [just giving an] oral anti-androgen. [Combination therapy is] what we always wanted to do or what we believe we want to do, especially for the younger patients with higher volume disease and better performance status [who] are going to have the opportunity for a longer-term outcome. There’s no question that this gives us the momentum to really push forward on that and build on PEACE-1 and what we’re seeing overall that triplet therapy for the correctly selected people is going to make sense. So, despite the lack of originality, I think that the ARASENS trial is clearly that most practice changing.

Kahl: I almost took away points for the originality, but I like that you put your personal spin on how you would treat [patients] so we’ll go with 6 points. Dr. Petrylak, finish out this topic.

Petrylak: We’re going to do something completely different and I’m going to boldly go where no discussion has gone before, namely a phase 1 trial in bladder cancer. We presented data on enfortumab vedotin [Padcev] for patients who are platinum-ineligible disease [NCT03288545]. Why am I saying a phase 1 trial is going to be practice changing? Number 1, for the population of patients that we’ve evaluated, platinum-ineligible patients with muscle-invasive urothelial carcinoma, there’s no standard neoadjuvant treatment prior to surgery that is considered to be effective and has been looked at in phase 3 trials. This takes away the ability to treat micro-metastatic disease prior to cystectomy and to downstage the tumor. In platinum-eligible patients, the CR [complete response] rate is about 30%, and in our trial with enfortumab prior to surgery as neoadjuvant treatment, it showed a 36% complete response rate with a 50% downstaging rate. That’s comparable to what we see with platinum-based therapy. Right now, there are phase 2 and phase 3 trials which are designed around enfortumab vedotin in combination with checkpoint therapy as well as with other forms of chemotherapy. This potentially could be practice changing because it’s going to open an area where we did not have a standard of care and potentially could benefit a group of patients that’s about 30% to 50% of patients with advanced urothelial cancer.

Kahl: We have originality, and a different cancer type. I’ll give you 10 points on that one.

Next up, we’re going to up the ante a bit for 1 minute each. We just heard about the most practice changing [research], but before all that, what trial is going to lead to the next FDA approval that came out of ASCO GU? Dr. Lowentritt, go ahead.

Lowentritt: When I think of an approval, I think of a drug that we haven’t had access to for prostate cancer before. That one new drug is going to be niraparib [Zejula]. The MAGNITUDE trial [NCT03748641] will lead to approval for the selected patients with HRR [homologous recombination repair] mutations and mCRPC in combination with abiraterone. It was powerful study for those patients. Once again, when you have those patients for whom you’re fortunate enough to find an HRR mutation and we want to intensify our treatment, that combination showed a really important difference. I look forward to having the opportunity to use that medication in the appropriate patients. That’s probably our first approval for a new drug, not an update.

Kahl: We’re going with 75 points there. Dr. Bryce, you’re up.

Bryce: The first session at ASCO GU led off with conversations and data around PSMA imaging and theranostics. Clearly, lutetium Lu 177 dotate [Lutathera] should be fairly close [to approval] now. Data were presented with regards to the SUV [standard uptake values] and the genomics of responders, let’s say poor responders to lutetium, which is very important. ASCO GU gave us some good guidance on how to use lutetium and hopefully we’re going to see that within the next several weeks.

Kahl: Absolutely, 100 points. Dr. Petrylak.

Petrylak: I’m going to go with darolutamide [Nubeqa] as the next trend for being approved. Darolutamide is approved for nonmetastatic castration-resistant prostate cancer, but unfortunately, it is not approved in the hormone-sensitive state even though many of us would like to use it because of its favorable toxicity profile. Right now, its wedded to docetaxel and the approval would have to be in that group of patients. However, there is a second trial which is very similar to the trials that have been done with apalutamide and enzalutamide as well as abiraterone. That will be the second piece in the FDA approval. My bet would be on darolutamide for castration-sensitive prostate cancer.

Kahl: I like the introduction of 2 studies, so that’s 125 points. Dr. Dorff.

Dorff: I’m going off the rails here and go pie in the sky. What do I want to see the FDA do? I want to see them take action that allows our patients access to genomic testing because we now have the potential to use PARP inhibitors—maybe not in unselected, maybe only in selected [patients]—but how will we select if our patients are not allowed to have genomic testing [or] PSMA/PET scans. We’re about to have lutetium PSMA as a theranostic where you’re supposed to do the PET scan first. As Dr. Bryce mentioned, there are different cut offs that might have implications for who’s going to benefit, but what if my patient can’t get a PSMA/PET scan? Today, my patients are getting rejections left and right from their insurance companies. I don’t think the FDA can do this, but that’s what I would love for them to do.

Kahl: Original and you know that the patients have my heart, so 150 points, Dr. Dorff.

Again, 1 minute each. What trial requires the most follow-up out of ASCO GU? Dr. Bryce, let’s start with you.

Bryce: I talked about PROpel earlier, but there are a lot of data in there that we’re going to have to dig into very deeply. Some of the data just couldn’t be discussed in the time allowed at ASCO GU, but it came out in the Q&A afterwards and in the conversations that many of us had on the sidelines after the fact. There are a lot of data that we have to see out of PROpel. Overall survival is still pending, and that’s going to be very critical. We really want to know, what does the survival benefit look like in the HRR-negative population? We feel pretty good that it’s going to be there in the [HRR-]positive population, but what about the [HRR-]negative? There’s a lot of follow up data to come out of that study.

Kahl: Absolutely. That’s a great point, 115 points. Dr. Lowentritt.

Lowentritt: What else would need to be followed up? PROpel is, without question, the thing that we’re all going to want to know what’s underneath the hood and how are we going to follow it? I’m going to say the same thing for MAGNITUDE, as well. Understanding and starting to get down to [whether or not] we have specific biomarkers that are going to be better if we’re going to put them on longer-term therapy with PARP in addition to abiraterone [is important]. Is there a sub population that’s better? Frankly, when we get into these discussions, how many of the patients are able to stay on therapy or have to come off of the PARP inhibitor or even come off of abiraterone because of AES [adverse effects] or other problems? We need to understand what we’re putting patients through with PARP inhibitors in combination. I’m looking forward to getting more information on what that means.

Kahl: We’re going with 125 points. Dr. Petrylak.

Petrylak: We’re seeing more and more TKIs [tyrosine kinase inhibitors] combined with checkpoint inhibition therapy for first-line metastatic renal cell carcinoma. We have ipilimumab [Yervoy] plus nivolumab [Opdivo], we have axitinib [Inylta] plus pembrolizumab [Keytruda]. There was a trial that looked at axitinib plus nivolumab which showed promising activity of a 41% response rate [NCT03172754]. Of course, we need more long-term follow up to see if that has the same duration of response, phase 3 trials, and evaluate this in a randomized fashion. It’s well tolerated, and we need to see whether the efficacy on a long-term basis is going to be the same as what we saw on the promising phase 1 and phase 2 trial.

Kahl: I’m happy we got some kidney cancer discussion, so we’re going to award 140 points for you, Dr. Petrylak. You’re up, Dr. Dorff.

Dorff: I’m going to go with something that’s not a drug, but Alicia Morgans, MD, MPH [of Dana-Farber Cancer Institute] presented these fascinating results from an international trial looking at patient experiencing in prostate cancer. This is essentially a whole new way of doing research, a whole new field. Quality of life has been [studied] very rigorously but has been hard to translate to what a patient is going to expect day to day for the next years that they’re managing a prostate cancer journey. [Morgans] did a wonderful job of presenting some preliminary data, but I hope there’s going to be so much more to come on that front.

Kahl: Absolutely, we’ll [give] 140 points there. Studies aside, this next topic can be on anything out of ASCO GU. This could be trials, data, a certain drug, presenter, the meeting itself, you name it. Thirty seconds each on who or what was the biggest winner out of ASCO GU? Dr. Dorff, we’ll start with you.

Dorff: I’ll be boring here and go with a drug. I thought the ARV-110 data looked exciting. I love the idea of an androgen receptor degrader. I think that’s a win right there. Because we all just want to annihilate the androgen receptor for what it does to our patients with prostate cancer.

Kahl: Okay, 100 points. Dr. Petrylak?

Petrylak: I think all the participants who came to San Francisco [are the biggest winners], because for the first time we’ve been able to sit down face-to-face, talk about studies, think about the disease, and just enjoye being in the presence of our colleagues. I’ll go with that as the biggest winner. Zoom meetings are wonderful as a patch, but they’re not as good as face-to-face discussions, designing trials, and other things.

Kahl: Great, we can’t wait to be back in person, 125 points for that. Dr. Lowentritt?

Lowentritt: The biggest winner to me was Ceslestia Higano, MD, for her role both as a discussant for PARP inhibitors, but also how she fiercely shot down some questions and it brought the whole energy of the room up. It was the one of the best moments where we had to recognize the hard work that was going into what she was doing. She was demanding of her colleagues to ask good questions. I thought that to me was the best moment and certainly the most memorable moment of the meeting.

Kahl: That’s a good call, 140 points to you. Dr. Bryce?

Bryce: Yeah, I agree with Dr. Petrylak, the biggest winner was that the science, the meeting itself, and the community. The fact that everyone was finally back together again [created] a palpable energy at the meeting. I think the entire community deserves tremendous credit for completing these studies, continuing to [practice] good science over what’s been a very challenging couple of years, and to the patients who have hung in there with us through all the extra challenges and burdens placed upon them throughout the last few years of COVID.

Kahl: Absolutely, 125 points. I’m going to up the ante again. Before I mentioned that we encourage you all to talk about yourselves. One minute each, give us your shameless plug from the meeting, the higher you boast, the more points you get. Dr. Bryce, go ahead.

Bryce: Well, I’m not good at this, honestly not my natural inclination at all. There’s ongoing work on treatment intensification. We’re involved with others in the CASCARA trial [NCT03934840], which would be a 4-drug first-line regimen in metastatic hormone-sensitive prostate cancer combining carboplatin, cabazitaxel [Javtana], and abiraterone ADT [androgen deprivation therapy]. I’m also very happy to say that the TRITON3 study [NCT02975934] has finished its accrual of 400 plus patients. This would be the most robust definitive study of PARP inhibitor monotherapy in patients who had abiraterone or enzalutamide [Xtandi] already for mCRPC and an HRR-gene mutation. To reflect on many other conversations, we’ve heard in the literature recently that study is randomized against an active comparator that includes docetaxel. I don’t believe there’s any other such study in the space, so we didn’t shy away from going with the active comparator.

Kahl: Okay, great point, 400 points. Dr. Dorff.

Dorff: We shared our phase 1 first-in-human results from our CAR T clinical trial targeting prostate stem cell antigen. This was designed by a City of Hope PhD scientist, and I’ve watched the trials and tribulations. There’s been some toxicity, it doesn’t work for everyone. The day we had a dramatic response in our fourth patient with 95% PSA [prostate specific antigen] reduction, disappearance of his soft tissue metastasis, and major improvement in the bone metastases, it just felt like such a breakthrough moment since we are working so hard to bring cellular active immunotherapy to patients with prostate cancer. Concurrently, I was second author on the Poseida PSMA CAR T [NCT04249947] poster because we’re also treating patients there, we don’t want to put all our eggs in 1 basket. We don’t know what the best target is, and we’d like to have as many options as possible. This is hard work. I am grateful to the patients and I’m grateful to be participating.

Kahl: Absolutely, 100 points. Dr. Petrylak?

Petrylak: Ten years ago, Craig Crews, PhD, walked into my office asking me whether we needed a new drug for prostate cancer. One of his closest friends who helped develop carfilzomib [Kyprolis] for myeloma had just recently passed away. Craig was the founder of the company called Arvinas that had this new technology for PROTACs [proteolysis-targeting chimeras]. We could come up with a prototype for the androgen receptor. Since that time, the laboratory has developed a drug, and that drug has moved into phase 1 and phase 2 trials. I’m proud to say that, and hopefully we can get that drug approved by the FDA in the next couple of years. Not only is that approach being used in prostate cancer, but there’s also a PROTACs that’s being developed for estrogen receptors, and it’s now actively being involved in breast cancer. This is really the first drug in this new class of drugs that will basically destroy proteins and potentially cause biological effects. I’m proud to be part of that.

Kahl: Great. I like the personal story at the beginning, 450 points. Okay, Dr. Lowentritt, bring us home.

Lowentritt: I was proud to present some real-world evidence that came out of both my group and another number of other groups about what is happening with patients who are getting apalutamide and enzalutamide for mCSPC [metastatic castration-sensitive prostate cancer]. It was the type of research we need to supplement what we’re getting from our registry trials and what’s coming out of pharma-sponsored trials. This was trying to look at what happens after approval, and what can we understand from what our actual use is. This was abstracted from our EMR [electronic medical records] data. It’s certainly not perfect data, but I think it gets us so much more insight into what’s happening after approval. I look forward to refining the data technique and exploring some other questions with what we can get out ofa large cohort of patients in the community setting.

Kahl: Thank you Dr. Lowentritt. We’re going to go with 400 points there. We touched on so much today. Thank you all. We really do appreciate it. But before we get into the points, 15 seconds each on closing thoughts. Dr. Petrylak, we’ll start with you.

Petrylak: [It was a] great meeting with result of clinical trials over the last several years. However, because of the pandemic, I’m a little bit concerned that we’re going to have a drop in some of these great presentations in the future. We must find ways of overcoming that [by] potentially accelerating trial accrual and getting these drugs to patients quicker.

Kahl: Great point. Okay, Dr. Lowentritt?

Lowentritt: Thanks again for having me here. The patients hopefully are the biggest winners. After all this, I was really impressed with how far we’re coming in so many different avenues. Even what we’re hearing today. I’m really excited for the next 5 years.

Kahl: Absolutely. All right Dr. Bryce?

Bryce: Now the dam has broken. We have rapid studies coming out in urothelial [cancer] after 5 years, when we had almost nothing. Renal continues to be gangbusters, prostate is gangbusters. There’s every reason to be optimistic and we just can’t take our foot off the gas. We [must] keep going.

Kahl: Absolutely. Okay, Dr. Dorff?

Dorff: We absolutely need people to look for clinical trials, not as their last line but early in disease because that’s where some of the most exciting trials are, and we need to make sure we’re recruiting a diverse population so we get a full sense of how these drugs work.

Kahl: Our winner of today’s 2-Minute Drill is Dr. Dan Petrylak with 853 points. Congratulations Dr. Petrylak. Thank you all again. We really appreciate it. That’s all we have time for today. Thanks for joining CancerNetwork® for 2-Minute Drill, where we offer unscripted, rapid insight on the most recent cancer conferences. I’m your host, Kristie Kahl. Have a great day!