Is ‘de-extinction' here? How gene editing can help endangered species
IMPACT
Gene editing's real value is not in re-creating copies of long-extinct species like dire wolves, but instead using it to recover ones in trouble now.
Red Wolves are seen at the North Carolina Museum of Life + Science on Thursday, November 8, 2017, in Durham, NC. [Photo: Salwan Georges/The]
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Have you been hearing about the dire wolf lately? Maybe you saw a massive white wolf on the cover of Time magazine or a photo of Game of Thrones author George R.R. Martin holding a puppy named after a character from his books.
The dire wolf, a large, wolflike species that went extinct about 12,000 years ago, has been in the news after biotech company Colossal claimed to have resurrected it using cloning and gene-editing technologies. Colossal calls itself a ' de-extinction ' company. The very concept of de-extinction is a lightning rod for criticism. There are broad accusations of playing God or messing with nature, as well as more focused objections that contemporary de-extinction tools create poor imitations rather than truly resurrected species.
While the biological and philosophical debates are interesting, the legal ramifications for endangered species conservation are of paramount importance. As a legal scholar with a PhD in wildlife genetics, my work focuses on how we legally define the term 'endangered species.' The use of biotechnology for conservation, whether for de-extinction or genetic augmentation of existing species, promises solutions to otherwise intractable problems. But it needs to work in harmony with both the letter and purpose of the laws governing biodiversity conservation.
Of dire wolves and de-extinction
What did Colossal actually do? Scientists extracted and sequenced DNA from Ice Age-era bones to understand the genetic makeup of the dire wolf. They were able to piece together around 90% of a complete dire wolf genome. While the gray wolf and the dire wolf are separated by a few million years of evolution, they share over 99.5% of their genomes.
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The scientists scanned the recovered dire wolf sequences for specific genes that they believed were responsible for the physical and ecological differences between dire wolves and other species of canids, including genes related to body size and coat color. CRISPR gene-editing technology allows scientists to make specific changes in the DNA of an organism. The Colossal team used CRISPR to make 20 changes in 14 different genes in a modern gray wolf cell before implanting the embryo into a surrogate mother.
While the technology on display is marvelous, what should we call the resulting animals? Some commentators argue that the animals are just modified gray wolves. They point out that it would take far more than 20 edits to bridge the gap left by millions of years of evolution. For instance, that 0.5% of the genome that doesn't match in the two species represents more than 12 million base pair differences.
More philosophically, perhaps, other skeptics argue that a species is more than a collection of genes devoid of environmental, ecological, or evolutionary context.
Colossal, on the other hand, maintains that it is in the 'functional de-extinction' game. The company acknowledges it isn't making a perfect dire wolf copy. Instead it wants to recreate something that looks and acts like the dire wolf of old. It prefers the 'if it looks like a duck, and quacks like a duck, it's a duck' school of speciation.
Disagreements about taxonomy —the science of naming and categorizing living organisms—are as old as the field itself. Biologists are notorious for failing to adopt a single clear definition of 'species,' and there are dozens of competing definitions in the biological literature.
Biologists can afford to be flexible and imprecise when the stakes are merely a conversational misunderstanding. Lawyers and policymakers, on the other hand, do not have that luxury.
Deciding what counts as an endangered 'species'
In the United States, the Endangered Species Act is the main tool for protecting biodiversity.
To be protected by the act, an organism must be a member of an endangered or threatened species. Some of the most contentious ESA issues are definitional, such as whether the listed species is a valid 'species' and whether individual organisms, especially hybrids, are members of the listed species.
Colossal's functional species concept is anathema to the Endangered Species Act. It shrinks the value of a species down to the way it looks or the way it functions. When passing the act, however, Congress made clear that species were to be valued for their 'aesthetic, ecological, educational, historical, recreational, and scientific value to the Nation and its people.' In my view, the myopic focus on function seems to miss the point.
Despite its insistence otherwise, Colossal's definitional sleight of hand has opened the door to arguments that people should reduce conservation funding or protections for currently imperiled species. Why spend the money to protect a critter and its habitat when, according to Interior Secretary Doug Burgum, you can just ' pick your favorite species and call up Colossal '?
Putting biotechnology to work for conservation
Biotechnology can provide real conservation benefits for today's endangered species. I suggest gene editing's real value is not in recreating facsimiles of long-extinct species like dire wolves, but instead using it to recover ones in trouble now.
Projects, by both Colossal and other groups, are underway around the world to help endangered species develop disease resistance or evolve to tolerate a warmer world. Other projects use gene editing to reintroduce genetic variation into populations where genetic diversity has been lost.
For example, Colossal has also announced that it has cloned a red wolf. Unlike the dire wolf, the red wolf is not extinct, though it came extremely close. After decades of conservation efforts, there are about a dozen red wolves in the wild in the reintroduced population in eastern North Carolina, as well as a few hundred red wolves in captivity.
The entire population of red wolves, both wild and captive, descends from merely 14 founders of the captive breeding program. This limited heritage means the species has lost a significant amount of the genetic diversity that would help it continue to evolve and adapt.
In order to reintroduce some of that missing genetic diversity, you'd need to find genetic material from red wolves outside the managed population. Right now that would require stored tissue samples from animals that lived before the captive breeding program was established or rediscovering a 'lost' population in the wild.
Recently, researchers discovered that coyotes along the Texas Gulf Coast possess a sizable percentage of red wolf-derived DNA in their genomes. Hybridization between coyotes and red wolves is both a threat to red wolves and a natural part of their evolutionary history, complicating management. The red wolf genes found within these coyotes do present a possible source of genetic material that biotechnology could harness to help the captive breeding population if the legal hurdles can be managed.
This coyote population was Colossal's source for its cloned 'ghost' red wolf. Even this announcement is marred by definitional confusion. Due to its hybrid nature, the animal Colossal cloned is likely not legally considered a red wolf at all.
Under the Endangered Species Act, hybrid organisms are typically not protected. So by cloning one of these animals, Colossal likely sidestepped the need for ESA permits. It will almost certainly run into resistance if it attempts to breed these 'ghost wolves' into the current red wolf captive breeding program that has spent decades trying to minimize hybridization. How much to value genetic 'purity' versus genetic diversity in managed species still proves an extraordinarily difficult question, even without the legal uncertainty.
Biotechnology could never solve every conservation problem—especially habitat destruction. The ability to make 'functional' copies of a species certainly does not lessen the urgency to respond to biodiversity loss, nor does it reduce human beings' moral culpability. But to adequately respond to the ever-worsening biodiversity crisis, conservationists will need all available tools.
Alex Erwin is an assistant professor of law at Florida International University.
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This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider. Ursula A. Matulonis, MD: Hello, I'm Dr Ursula Matulonis. Welcome to season two of the Medscape InDiscussion Endometrial Cancer podcast series. Today, we'll discuss antibody-drug conjugates (ADCs) and how they fit into the treatment of gynecologic (GYN) cancers, but also, importantly, we'll hear from our guest, Dr Leif Ellisen, about different aspects of ADCs that perhaps we haven't thought about in GYN cancer. It really is an honor to have Dr Ellisen here today. He's a professor of medicine at Harvard Medical School and Program Director for Breast Medical Oncology. He's also the clinical director of breast and ovarian cancer genetics at the Massachusetts General Cancer Center. He's also the co-leader of the breast cancer program at the Dana-Farber Harvard Cancer Center. Welcome to the Medscape InDiscussion Endometrial Cancer podcast. Leif W. Ellisen, MD, PhD: It's great to be with you, Dr Matulonis. I am looking forward to discussing this important and fascinating topic. Matulonis: As you know, there has been an explosion of different ADCs in oncology in general. These drugs are now making a significant impact in GYN cancers with FDA approvals for mirvetuximab in ovarian cancer. The tumor agnostic accelerated approval for trastuzumab deruxtecan for HER2, 3+ advanced cancers, which really applies to all GYN cancers. Then, tisotumab for advanced cervical cancer. There are also multiple phase 3 trials, as well as earlier phase 1 and 2 trials of ADCs in GYN cancers and in endometrial cancer specifically. These ADCs are targeting several different payloads, such as HER2, TROP2, and folate receptor alpha (FRα), CDH6. Some have the payload of topoisomerase one (TOP1), whereas some have anti-mitotic payloads. In phase 1 trials of TOP1 payloads, we are already seeing that previous exposure to previous TOP1 payloads are not allowed. We are eventually going to have to think about how to rationally sequence different ADCs and really understand the mechanisms of resistance and response to each of these drugs that we're going to be using. You and your team at Mass General are leaders in ADCs. You recently published a paper in Clinical Cancer Research identifying the emergence of TOP1 mutation as a resistance mechanism to TOP1 payload ADCs. I really want to focus on resistance mechanisms and ask you what you think are the most common and impactful resistance mechanisms that cancers developed to ADCs and some of the challenges to using ADCs, not just once but repetitively. Ellisen: Well, thank you again, Ursula. These are very important questions, and I think one thing that sets the stage for the discussion is that ADCs are quite complex molecules. When you think about an antibody binding on the cell surface, you think about delivering some kind of payload that's bioactive, and you think about how the antibody is linked to the payload, which determines how it's delivered. So, multiple and complex resistance mechanisms develop. One way to divide them up would be de novo resistance vs acquired resistance. Some of the work that we're doing in de novo resistance suggests that you can see a lot of intrinsic chemo resistance of the tumor cells, just like you would with standard chemotherapy as a mechanism. In some cases, low expression of the ADC target itself, although that doesn't seem to be a major contributor. More interestingly, we're learning that in de novo resistance, many features of the tumor microenvironment that may affect both the biology of the tumor cells and the penetration of the ADCs into the tumor are important and may confer resistance. When we look at the acquired resistance setting, we don't see a lot of loss of the target per se. However, we and others have demonstrated where loss or mutation of the target likely mediated acquired resistance. More commonly, we see some of the things that you might see with chemotherapy, such as activation of cell survival pathways in the tumor, upregulation of drug efflux transporters, and mechanisms of that kind. More interestingly, though, and specific to the ADCs, is a specific mutation of the target of the payload. For example, as you mentioned, TOP1. When administering systemic TOP1 inhibitors, you don't really see the emergence of these mutations, but we are seeing them now in the setting of the ADCs. This may have to do with the fact that we're delivering much higher doses. It's more potent, and the tumor is pressured to have an on-target resistance mechanism. Matulonis: That is very interesting, and as we step back as clinicians to try to navigate both the de novo and the acquired mechanisms of resistance, what are some of the strategies that you're pursuing — both from a laboratory standpoint, but also from a practical, clinical standpoint? How to overcome these ADC resistance mechanisms? Ellisen: My bias since we started working on ADCs a number of years ago was that, because of the complexity of these molecules, a lot of the work that we needed to do was going to be analysis of patient samples themselves to really understand among all the possible ways that resistance could occur, which are the ones that really occur importantly in vivo. For example, we've launched a number of preoperative trials in breast cancer, where this is a common method for treatment now, where we can profile the tumor before treatment and after treatment. We can identify, through things like single-cell analysis, these tumor phenotypes in tumor states that are chemo-resistant. Then, we can do things like spatial analysis to identify what we call cellular neighborhoods or ecosystems within the tumor that govern how the tumor cells themselves behave. Are they hypoxic and chemo-resistant? Can the drug make its way into the tumor, governed by things like angiogenesis, which may preclude effective delivery of the ADC? And then, when we switch to thinking about how we can study mechanisms of acquired resistance. One very useful tool has been the increasing use of circulating tumor DNA analysis, that is, blood-based analysis, because we can do repetitive sampling in the setting of progression and really get an overview of the genetic evolution that gives rise to resistance. That was how we identified these TOP1 mutations. But it's also the case that we need to look at tissue; that can be challenging in the metastatic setting. And so, what we've done here is develop a number of patient-derived resistant tumor models that we can then take back to the lab, propagate them, understand resistance mechanisms, and then do things like really complex and comprehensive screenings to ask in an unbiased way, 'How might that resistance state be overcome?' I really think, fundamentally, it's going to take this kind of coordination between the laboratory and the translational work that is going to give us the best insights that will be most relevant to patients. Matulonis: Before we move on to biomarkers, given that you've identified — these TOP1 mutations and changes — I want to ask you the question: Do you think it's possible to overcome these different resistance mechanisms? Ellisen: TOP1 is a particularly fascinating one because, as we know, TOP1 itself is so essential to the fundamental processes in the cell transcription replication. What happens with a TOP1 mutation is the enzymatic activity of TOP1 is not lost, but it's substantially modified. That modification of the activity requires the cell to adapt in very complex ways, and we're just beginning to understand it. However, the adaptation that results from, for example, a TOP1 mutation is going to create additional vulnerabilities in that tumor cell. We're doing a lot of work, and others are as well, to try to understand those evoked vulnerabilities that occur after such resistance mutations that might lead to ways to overcome that particular state. Matulonis: That's really fascinating. I am going to move on to biomarkers and what we're seeing in GYN. We're not as far along as in some other cancers. We have a lot of work to do, but we really need to understand the heterogeneity of the biomarker expression in different patients and different sites of recurrence. And this certainly happens in endometrial cancer, where patients will sometimes have peritoneal disease resulting in ascites. They may have lung metastases, or they may have nodal metastases. How do you think about the biomarker changing over time within a patient and their different metastatic sites? Ellisen: This is the big challenge of advanced and metastatic cancer as a whole. Just to give you an idea of what we're facing, a number of years ago, we published a paper describing an individual breast cancer patient who had received a sacituzumab govitecan. They had a really fantastic response to the drug but progressed at multiple sites. We were able to do an individual sampling of those sites. In one subset of metastatic sites, there was a mutation in TROP2, which was the target of the ADC, which caused loss of expression and resistance to those particular sites. In another subset of metastases, there was a mutation of TOP1 resistance to the payload. We hope that this kind of phenomenon, you know, will not be occurring in all of the patients, and I do believe that to the extent that we can make ADC therapy more effective and more potent, we have a better ability to combat this heterogeneity that's intrinsic to the cancer. That might be through a better selection of ADCs. That might be through combinations that we might talk about momentarily, to really try to expand the way that the body responds and expand the ability to target the tumor, in particular through combinations such as immunotherapy, where you can then activate the immune system to combat the heterogeneity of the metastatic tumor. But there's no doubt that it's a daunting challenge for the whole field. Matulonis: I just wonder how we use ADCs in a patient's treatment and where that patient is at the start of their cancer journey vs later on. Obviously, resistance mechanisms are likely to increase as the tumor changes over time. One would think that the ADC that you use first has the best chance of response. Should we be thinking strategically about how to position the ADC sequencing? Ellisen: That's exactly right. There's no doubt that we have to be smarter about that. For example, coming back to these TOP1 mutations, it seemed to be quite clear from the relatively limited but quite compelling clinical data so far that, if you have one of these mutations, you're very unlikely to respond to a second ADC that harbors a TOP1 inhibitor payload. The more we can understand resistance, the more we can test for resistance at the time of progression on one ADC and the more likely we are to be able to make a better choice in the second ADC. ADCs are being tested in so many different settings, and there are going to be numerous ADC options in the future. We'll have many ADCs to choose from and making the smart choice hopefully will be informed by knowledge about specific mechanisms that arise in individual patients. Matulonis: That totally makes sense. What do you see as the differences and differentiators regarding the other parts of the ADC? You mentioned this before, but specifically the linker and then the type of the antibody. Ellisen: These are really important considerations and speak to the complexity of these ADCs. Linking the antibody to the payload is important, because it determines how much of the payload is released outside the tumor cell. If you take two examples on the extremes, sacituzumab govitecan has a pH labile linker, so it's quite labile and has a short half-life. You have a lot of payload, SN-38, a TOP1 inhibitor released into the circulation, and therefore, sacituzumab has a lot of chemotherapy-like toxicities. On the other end of the spectrum, you have an ADC, like trastuzumab emtansine, which has quite a stable linker that requires intracellular processing and lysosomal processing to release the payload. And so there, you can see how a very labile vs very stable linker controls the side effect profile to a large degree of these two drugs. It turns out that features of the antibody are also quite important. One of the particular ones that's coming into focus is the issue of once the antibody binds, whether it stays on the cell surface or whether it's rapidly internalized. With sacituzumab govitecan you have rapid internalization and no ability for the antibodies to stay on the surface. We know that antibodies that coat the surface of tumor cells attract immune molecules that can induce things like antibody-dependent, cellular cytotoxicity, and phagocytosis that can engulf and kill tumor cells. So you have this balance between rapid internalization, which can deliver more payload, and this staying on the cell surface, which can recruit the immune system. There's no perfect formula or a secret sauce for what everybody believes is the best way to design your antibody. These are things that are being tested systematically to see whether there really is a best practice or best design along those lines. Matulonis: It's really interesting, and there is a lot to learn about all these different ADCs and how unique they are. You just never know until you start testing them in patients and see that they're safe and effective. This is really exemplified in breast cancer, but there are some ADCs that really don't require minimum levels of biomarkers, as we've seen with HER2 and trastuzumab deruxtecan, TROP2, as you've mentioned, CDH6 and in certain circumstances, FRα as examples. Is the efficacy of these ADCs really about the presence of just tiny, low levels despite there being 0 or 1+? Or is there some other mechanism of action that these ADCs are imparting against the cancer cell? These are questions really around where the field is headed, because clearly, not requiring tissue, not requiring a biomarker, is much easier for clinicians and patients than requiring perhaps new biopsies, sending testing out for biomarker assessment, et cetera. What are your thoughts about that? Ellisen: This is a really fascinating aspect of ADCs. Currently, there's a debate in the field of ADCs about how much of the ADC activity is really related to this canonical ability to bind to the target and deliver into the tumor cell and how much of ADC activity relates to a slow and persistent payload release in the microenvironment, kind of what we might call a metronomic release of payload, in the tumor microenvironment that is going to be less target dependent or particularly less dependent on very high levels of target. I would say that, undoubtedly, most ADCs exhibit some aspect of both of these. You see this in clinical data where, at very high levels, there is a correlation with target expression and duration of response. But at lower levels, there's not a great correlation. So, both of those exist depending on the design of the ADC and the target itself. Which is better, high specificity and target dependence vs not screening? In the short term, it's certainly convenient that we have ADCs that don't require prescreening. But in the long term, particularly as we have more ADCs becoming available, it would be quite valuable to identify patients who are highly likely to benefit from a given ADC based on target expression. In other words, as more ADCs become available, it would be valuable to have the means to select the best ADC among many for a given patient, either by the target expression or some other biomarker, the personalized, patient-selected cancer therapy that we all like to give, ultimately with a lot of ADCs available. I think that's what we'd like to do. Matulonis: As the ADC is nearing the cancer cell, what happens, either that internalization or perhaps the attraction of other molecules to, or other cells to that interaction, really would depend upon perhaps the target. So, maybe B7-H4 may have a more immune response vs also where the cancer is. Is it located nodally, or is it somewhere else where maybe there are not as many immune cells, or the immune cells just come regardless of where the cancer cell is? Do you have any thoughts about that? Ellisen: It's going to be important. I agree with you, and I think it's going to be particularly important as we think about some of these more novel combinations. For example, payloads that may activate the immune system combinations with immune checkpoint inhibitors. Site-specific tumor immune microenvironment and context are going to be even more important drivers of the responses that we see. Matulonis: Another one of my questions to you is what types of combinations of either ADC/ADC, or ADCs plus something else are you most excited about? Ellisen: It's a very exciting time because I think we have so many opportunities to combine ADCs with, as you said, with other ADCs potentially, but with other molecules and therapies and even established therapies that are mechanism-based and potentially synergistic and even potentially combinations which might have been tried in the past but didn't work because of prohibitive toxicity. One example is a clinical trial that we did with sacituzumab govitecan together with a PARP inhibitor. It was known that TOP1 inhibitors and PARP inhibitors were synergistic systemically. However, the problem was that there wasn't a great therapeutic window, because it was highly toxic to hematopoietic and other cells. But we reasoned that the specific delivery to the tumor cells might give more specificity and widen the therapeutic window. It turned out that was only partially true, and in fact, we had to do the sequencing of the true drugs, the sacituzumab and the PARP inhibitor, given sequentially, not at the same time. But still, the idea that this kind of combination, which, if you deliver it just systemic drugs, totally prohibitive, could be feasible. We were able to complete the clinical trial successfully with an ADC-based delivery. As I mentioned earlier, I do think that in the near term, there were already many clinical trials going on combining ADCs with immune checkpoint blockade. I think this is particularly exciting because we know that one of the major features that can stimulate the immune microenvironment is immunogenic cell death. We do know that ADCs are really effective in many cases at inducing this kind of cell death and potent tumor responses, which is a great stimulation to the immune system. Combining these with checkpoint inhibitors in the right context is a very exciting possibility, at least in context. And we're gonna be having more data emerging about that in the coming months and years. Matulonis: That's really exciting. I want to move to ADC payloads and focus on two questions. Obviously, the ADCs that we're using mostly clinically are either comprised of TOP1 inhibitors, or anti-mitotic agents. What do you think are some of the future payloads that are unique and different from these two? Much is discussed about drug antibody ratios (DARs). Everyone thinks higher is going to be better, but sometimes higher is toxic. What are your thoughts about the sweet spots of the DAR? Or does that not matter as much? Ellisen: Starting with payloads, I think we shouldn't overlook the ability to just try new chemotherapy payloads. One of the reasons I believe that in breast cancer the approved ADCs have been effective — these are all bearing TOP1 inhibitors, by and large — is because we've never used TOP1 inhibitors in breast cancer. Typically, no breast cancer has ever seen that drug before. Then we come in with an ADC and a totally new chemotherapy that can be successful — so leveraging on that paradigm and linking the ADCs to other chemotherapies, which we know can be successful in particular contexts, is certainly one thing that's being tried and that's reasonable. Others that I think are very exciting are things like immunomodulatory agents and immune agonists: for example, delivering those in a specific way. We know that, systemically, immune system agonists have been tried, but in some cases, they have prohibitive toxicity. When delivered selectively, they might be quite successful. So, conceptually, it is very interesting. And then other classes of target inhibitors that we know have efficacy in the right setting. But again, it might have been shown to be relatively toxic systemically, such as various DNA repair inhibitors, DNA damage checkpoint inhibitors, all these things, given our ability to deliver them in a more specific way with ADCs, I think now can be considered and reconsidered. That's a very exciting potential, I'd say. Matulonis: It's really quite impressive to think about this field moving forward. Ellisen: I will make a comment on the DAR because I think — that's a drug-to-antibody ratio — I think that's another fascinating one. The field has not settled on an answer. Because when you think about it, if you increase the drug to antibody ratio, what it does is mean that you're actually infusing fewer molecules of antibody, right? Because if you have more drug per antibody, you're infusing fewer molecules of antibody for a given toxicity that can be tolerated. And what that means is that there's a consideration called the saturation front where, if you have a lot of targets in a certain part of the tumor, if you don't have enough antibody molecules there, they get saturated. And so you never get the tumor penetration to actually kill all of the tumor, and that leads to a generation of resistance. On the other hand, with lower DAR, and more antibody, you can overcome that saturation front. You can get into the tumor, but maybe not as potent per ADC molecule. So, there is a sweet spot there. Whether it's gonna depend on the individual payload and target or the individual tumor type, I think, remains to be seen. But, there's gonna be a lot of investigation of that area, and it's going to be a really fascinating one to watch. Matulonis: Tell us about some of the ADC research that you are working on right now that you're really excited about. Ellisen: The real excitement in ADCs comes from their complexity. It's the opportunity to really merge what we're seeing in patients about how response and resistance are governed with what we can learn in a systematic way in the laboratory. When we think about de novo resistance, neoadjuvant studies understanding evolution in microenvironmental determinants that we typically don't think of when we're thinking of drug resistance. We think of the tumor cell but thinking about how the individual cells are arranged into a neighborhood within the cell. Maybe it is not at the top of our list for determining whether we're gonna give a drug or not, but I think it may be in the setting of ADCs. Secondly, this idea is that we can really think about mechanistic and rational combinations with ADCs that might not have been possible before for toxicities or other reasons. Then, we can allow the selective delivery that we can get with ADCs to make this possible and really get potent and synergistic tumor cell killing in the way that we always hope to do. Matulonis: What an exciting field. Congratulations to you, Leif, for all you and your team have done. You're pioneers in this field. Once again, GYN cancers are learning from breast cancer. And you're leading the way on this. Thank you so much for being here today. Today, we've talked to Dr Ellisen about ADC resistance mechanisms, ADC sequencing, and the different components of the ADC, including what's exciting in the field and novel payloads. Thank you so much for tuning in. Take a moment to download the Medscape app to listen and subscribe to this podcast series on endometrial cancer. This is Dr Ursula Matulonis for the Medscape InDiscussion Endometrial Cancer podcast. Listen to additional seasons of this podcast. Endometrial Carcinoma The Clinical Landscape of Antibody-Drug Conjugates in Endometrial Cancer FDA Grants Accelerated Approval to Fam-Trastuzumab Deruxtecan-nxki for Unresectable or Metastatic HER2-Positive Solid Tumors Mechanisms of Resistance to Antibody-Drug Conjugates TOP1 Mutations and Cross-Resistance to Antibody-Drug Conjugates in Patients With Metastatic Breast Cancer Single-Cell Analysis Technologies for Cancer Research: From Tumor-Specific Single Cell Discovery to Cancer Therapy Spatial Transcriptomics for Tumor Heterogeneity Analysis Exploring Circulating Tumor DNA (CtDNA) and Its Role in Early Detection of Cancer: A Systematic Review Current and Emerging Prognostic Biomarkers in Endometrial Cancer Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer Antibody-Drug Conjugate Sacituzumab Govitecan Enables a Sequential TOP1/PARP Inhibitor Therapy Strategy in Patients With Breast Cancer Antibody-Drug Conjugates as Targeted Therapy for Treating Gynecologic Cancers: Update 2025
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IRONMAN: Can PSA Guide Metastatic Prostate Cancer Care?
CHICAGO — Prostate-specific antigen (PSA) levels could help guide treatment decisions for patients with metastatic hormone-sensitive prostate cancer, according to real-world findings from the IRONMAN study. Specifically, an undetectable PSA nadir — defined as PSA level < 0.2 ng/mL — predicted a good prognosis and a PSA level ≥ 0.2 ng/mL predicted poor prognosis among patients receiving androgen deprivation therapy (ADT) or androgen receptor pathway inhibitor (ARPI) therapy for 6-12 months, according to Michael Ong, MD, who presented the findings at the 2025 American Society of Clinical Oncology annual meeting. In other words, this real-world study found that absolute PSA at 6 and 12 months is prognostic in this patient population, said Ong, a medical oncologist at Ottawa Hospital Research Institute, Canada. Patients with a poor prognosis could then be considered for clinical trials offering therapy escalation, whereas those with a better prognosis — particularly those with PSA < 0.1 ng/mL — could be considered for de-escalation, said Ong. Ong explained that prior phase 3 studies have demonstrated that PSA > 0.2 ng/mL is associated with poor prognosis in patients receiving ADT and ARPI. However, data in real-world settings remain limited. Some patients with rapid PSA decline never progress, whereas others develop early resistance despite intensive therapy, he explained. The IRONMAN study set out to answer two main questions: When should PSA cutoffs be interpreted for prognostic significance? And how may PSA cutoffs differ in real-world patients? To this end, Ong and his colleagues included 1219 patients from the prospective IRONMAN cohort with metastatic hormone-sensitive prostate cancer who had received ADT and ARPI therapy, with or without docetaxel, and had PSA data available. PSA was stratified into three groups: ≥ 0.2 ng/mL, 0.10-0.19 ng/mL, and < 0.10 ng/mL. The research team constructed a 12-month landmark population to assess conditional overall survival (OS) and progression-free survival (PFS) at 6 and 12 months across each PSA level. The 12-month analysis was the primary study outcome. Patients were a median age of 70 years, 58% had Gleason score of 8-10, and 75% had de novo metastatic disease. Overall, most (74%) were White and just over half were enrolled from centers outside US or Canada. ARPI agents included abiraterone acetate (44%), apalutamide (21%), enzalutamide (22%), or darolutamide (13%), and 12% of patients received docetaxel in addition to doublet therapy with ADT plus ARPI. PSA levels shifted across the two time points. At 6 months, 52% of patients had a PSA < 0.2 ng/mL, whereas 48% had a PSA level ≥ 0.2 ng/mL. At 12 months, 68% had PSA levels < 0.2 ng/mL and 32% had levels ≥ 0.2 ng/mL. Both the 6- and 12-month landmark analyses showed that PSA ≥ 0.2 ng/mL was associated with worse conditional OS and PFS compared with PSA < 0.2 ng/mL. Ong broke down conditional OS and PFS at 12 months — the primary study outcome —by absolute PSA levels. Absolute PSA 3-year overall survival 3-year progression-free survival OS mortality risk (adjusted hazard ratio) ≥ 0.2 ng/mL 45% 41% 4.85 (3.36-7.01) 0.10-0.19 ng/mL 79% 62% 1.34 (0.82-2.20) < 0.1 ng/mL 84% 80% Reference After adjustment for confounders, PSA ≥ 0.2 ng/mL was associated with an almost fivefold higher risk for death at 12 months (adjusted hazard ratio, 4.85). Ong noted that PSA was prognostic of overall survival regardless of ARPI class or whether patients received doublet or triplet therapy with docetaxel. Invited discussant Rahul Aggarwal, MD, agreed that a PSA nadir between 6 and 12 months 'is strongly prognostic for progression-free and overall survival.' However, Aggarwal cautioned, although 'it is tempting to use PSA nadir to guide treatment decisions in clinical practice,' the approach has not been validated. Plus, other factors and biomarkers may play a role in treatment decisions and help optimize outcomes, including quality of life, treatment and financial toxicity, and the role of the tumor suppressor gene PTEN , added Aggarwal, of the University of California, San Francisco. 'We await randomized trial data to know, in fact, whether we should use this to guide treatment decision-making,' said Aggarwal. Such trials are underway. Ong is co-chair of a phase 3 study assessing survival after treatment escalation for patients with PSA ≥ 0.2 ng/mL after 6-12 months of ADT and ARPI therapy. Another phase 3 study will assess treatment de-escalation in those with PSA ≤ 0.2 ng/mL at 6-12 months after treatment initiation. This study's principal funder was the Movember Foundation; the Prostate Cancer Clinical Trials Consortium was a trial sponsor, plus Amgen, Astellas, AstraZeneca, Bayer, Janssen, Merck, Novartis and Sanofi provided funding support. Ong disclosed relationships with AstraZeneca, Bayer, Bristol-Myers Squibb, EMD Serono, Janssen, Merck, Novartis/AAA, Pfizer, Sanofi, and Ipsen. Aggarwal disclosed relationships with Alessa Therapeutics, Amgen, AstraZeneca, Bayer, BioXcel Therapeutics, Boxer Capital, Curio Science, and others.
