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Alicia Morgans: Hi. Welcome to UroToday in our online medical education program Beyond Androgen Blockade to new pathways and novel treatments in metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer.

My name is Alicia Morgans and I have the honor to moderate today's discussion, following a presentation by Dr. Dan George. The topic that he will be speaking about today is the biological basis of metastatic CRPC, the unmet medical need for new targets and treatments. Thank you so much, Dr. George.

Daniel George: My pleasure, Alicia, thank you so much for having me on the show. And it's a pleasure to be able to talk about what I think is an incredibly important and increasingly complex topic, and that's on our understanding, current understanding of the biologic basis for metastatic castration-resistant prostate cancer or mCRPC, and really how we're going to identify both new targets and treatments for this disease.

So to begin with, I think it's important for us to recognize that CRPC is not a monolithic disease. And how we get there is going to influence, to some extent, the driving biology in that particular patient. So what I mean by that is if somebody's getting just androgen deprivation alone in developing CRPC, that biology may look different than someone who's been treated with a chemotherapy like docetaxel, a AR pathway inhibitor like enzalutamide or any other host of treatments in the hormone naive or sensitive setting. So it's important to take that into a context.

But however you get there, CRPC historically, at least, has been associated with a number of different genetic alterations, and they're unfortunately are not mutually exclusive, so you can have more than one. And probably the bigger your tumor burden, the more of this you have. We'd like to break them down into the AR dependent mechanisms. Those are shown on the bottom here, things that will drive more engine receptor activity, despite the low androgen systemic androgen levels. So autocrine, endocrine pathways, AR variants, and RNA splicing variants, genomic aberrations in the receptor itself, fusion proteins associated with it, and glucocorticoid or other hormonal pathways that may cross activate, and even non-canonical AR signaling through other pathways like AKT and whatnot. And then above, you're going to have, what we're terming AR variable dependent mechanisms. We don't like the term completely AR independent because some of these may still interact, but they're not dependent solely on the engine receptor for activity.

So immune escape mechanisms, proliferative signals, like Myc and MAP kinase, survival signals, bone microenvironment alterations like SAR and neuroendocrine transformation or epithelial plasticity, stemness, even our DNA repair defects associated with sometimes germline, sometimes somatic alterations. We're all part of what can drive this resistance, and the heterogeneity within patients is likely to increase over time. That's this bottom message here, and it's something to bear in mind as we use multiple agents in the patients, not just in the hormone sensitive setting, but in the castrate resistance setting. So I know that was a mouthful. There's a couple other key, I think, important aspects to, now, castration resistant disease. And another is the phenotype, how we actually describe this disease. Because historically, we've used bone scan and CT scan, but head scan is fundamentally changing how we visualize the cancer, how we quantify the extent of this cancer, and to some extent, the biology as well in terms of PSMA as a target.

And it's important to recognize this both as a delivery mechanism for radio pharmaceutical or radio ligand therapeutics, but also potentially immunotherapy, other immune conjugated drugs and other approaches. So PSMA as a target is going to be useful. But just as an imaging agent, it's already changing how we think about the burden of disease, how potentially we can follow disease changes over time, and ultimately identify patients for targeted therapeutics. Genetic testing is critical. There's no turning back. Now, we have clear pathways to target. We absolutely need to be doing genetic testing. It has prognostic significance. Even things that we can't necessarily target are not actionable today. Things like P53 or loss of PTEN have prognostic significance. It's got predictive significance for responsiveness to certain targeted therapies, particularly around homologous recombinant repair and MSI high, but there's for sure to the others. And then it's got familial significance. Approximately 10% of our advanced prostate cancer patients have germline mutations that drive the cancer biology. And understanding that and the implications for next of kin is really critical. And really having genetic counselors and family testing available is important, particularly for that subset.
Lines of therapy are challenging in prostate cancer. And our clinical trial data really speaks to this. If we look historically at first line therapy in mCRPC, our median overall survival for our patients starting on our AR pathway inhibitors in this setting is about 35 months. That goes all the way back to PREVAIL and COUGAR-302 trials from 2013 and '14. And if you look at our most recent TALAPRO-2 and PROpel studies, their control arms, exactly the same. We in 10 years have not moved the needle on frontline therapy. It's about three year median survival. In the real world, it's even less, it's two years or less. Second line median survivals after patients have failed those therapies, 15 to 18 months. And third line, if you think of patients that have failed both chemotherapy and novel hormonal agents like our vision trial, our median survivals are a year or less.

So it's important to recognize, despite all the options that we have for current therapy, patients are not living long enough and we're going to be adding more drugs into this space. So it's going to be challenging to do eight or 10 lines of therapy. We're going to need to be able to do more combinations, more precision medicine, more adaptive approaches, not waiting for progression for the next line of therapy, because the five-year survival is just not long enough. And you know who these patients are based on performance status, how many prior lines of therapy, PSA doubling time and other prognostic factors, really to help shape who we need to accelerate our treatment approaches.

Now, we have a pretty decent armamentarium... Sorry about that... Already. And we've got here, I think 11 drugs here shown here. For the most part though, we've got six different therapeutic groups. I mean, we have a pretty strong already armamentarium for metastatic CRPC with second generation AR pathway inhibitors, cell-based immunotherapy, targeted immunotherapy, alpha particles, taxanes, PARP inhibitors, and I don't even think I have Pluvicto on here as well. So we've got a number of therapies associated with benefits associated with metastatic CRPC. It's really our job to figure out where are the holes, what are we missing? And to do that, we need to understand the biology of mCRPC. And let's start with the best target of all in prostate cancer, the androgen receptor, because this is clearly a driver of disease biology for, I'll say the majority of patients early on and still for a key subset of patients even in the mCRPC pathway. And we traditionally block this by lowering androgen and by using androgen receptor antagonists, the receptor antagonist binding on that ligand, domain shown there on the far right, lowering androgen, also targeting that component.

But there's all these other aspects to the androgen receptor, the DNA binding domain, the internal domain that can also be altered and ultimately develop mechanisms for resistance to. So if we think about how to get around alterations and whether it's the RNA splice variance, whether it is at the DNA level with truncation or other formulations and alterations of the engine receptor, one way is just get rid of it completely, degrade the androgen receptor. And to do that, there's a new class of drugs hotly under development now that will target the androgen receptor for Ubiquitination. Ubiquitination is how our cells typically will degrade proteins shown over here through this schematic where the E3 ligase will buy the target protein, typically through some small molecule, activating that degrader, this case PROTAC. That brings in the androgen receptor in green here into this formulation.

Ubiquitination, the little purple tags are put on, and that's what signals it for degradation to the protein zone. Evidence of this working. Here's that ARV-110 molecule showing activity, PSA regression, in patients that have progressed through an AR targeted therapy. And you can see both phase one, phase two results here. It's early results, but we could see a number of patients showing different degrees of response. Some patients showing resistance, no evidence of response, but over half the patients have PSA declines. If you look at particular types of DNA AR alterations, the T878 alteration in particular, we can see pretty high rates of response. So maybe works in some mutations better than others, but definitely showing activity. Another approach is to target upstream, say, well, let's get rid of any signaling here to the engine receptor, not just lowering this from the testes, not just lowering this somewhat by blocking the actual androgen production like abiraterone, but upstream where we're blocking all kinds of androgens that could be altering this, including our progesterone, progesterones and other hormones.

So that's what this molecule, ODM-208, or what's now referred to as MK-5684, does. It's blocking very high up, right from the cholesterol conversion. And it's working at the adrenal gland, it's working at the testes. It's also working in the prostate cancer tissue. And importantly, that's more and more a source of this resistance, is that pericrine autocrine type formation of these hormones. So this is more kind of complete hormonal annihilation. And it works, again, not in everyone, but we're seeing about half of the patients, we're seeing some declines in PSA, sometimes pretty dramatic declines following prior progression on abiraterone or enzalutamide or both in some circumstances. And it's working even in those patients that have the ligand binding domain mutations.

What about PARP? PARP is something that it's a little bit controversial. I think everybody has agreed there's a BRCA two mutation, a BRCA one mutation. Adding a PARP, whether it's at the time of a novel hormonal agent or after has shown clinical benefit, has led to FDA approvals, it's uncontroversial. Where it gets a little murky is in patients that don't necessarily have a BRCA two mutation. If they've got an HRR mutation that's non BRCA ATM based, is there still benefit there? The clinical data says yes, it may not be as robust, but we are seeing it and the FDA has agreed. And we're seeing approvals both in the post novel hormonal agent setting as well as in combination with first novel hormonal agent. Where it gets a little bit more increasingly complicated is when we go beyond HRR. And could there be situations where just targeting androgen receptor inhibition is resulting in a genetic instability, a repair dependency on PARP that PARP inhibition can work?

And this preclinical data suggested, the clinical data is, I think, I, the beholder. Some people are convinced, others, less so. And I think we're going to need more data, more studies to really completely clarify that, those results. And those are coming in earlier disease settings of advanced prostate cancer. But in the meantime, where we currently use our PARP inhibitors, we do our genetic testing late into late castrate resistance. We're seeing more and more resistance. We're seeing more patients having brief responses to PARP inhibitors or not at all. Even though they've got a genetic propensity, an HRR or BRCA mutation, we're not seeing a durable response. How come? There's a lot of mechanisms that can drive PARP resistance, and these are present in our patients. And just to run through four of the most common ones, we can see increased drug influx. We saw this with our taxanes as well, upregulation of protein transporters, p-glycoprotein and others. We can see decreased PARP trapping, so loss of PARG or other proteins involved in the mechanism that allows PARP to be trapped on DNA so the DNA can't be repaired.

That comes off, DNA repair can happen again. Restoration of homologous repair even in the setting of these alterations, reactivation of BRCA or loss of other signaling pathways that are critical in this process that can bi step, bypass some of the HR resistance. And then stabilization of the stalled forks, the mechanism by which loss of BRCA really results in this double strand of DNA breaks and loss of EZH2 and other mechanisms. So it's important to recognize that the later we use our PARP inhibitors, the less effective they're going to be, the more likely we've got genetic heterogeneity for resistance. And there may be ways around that too, because BRCA and BRCA. And two and PLAB2 and many of these other key, rare, but key genetic alterations are pretty low down in the process of homologous recombinant repair.

But higher up in this process are ATM and ATR. And alterations that can target these may have sort of a rescue, if you will, for alterations of resistance down below. And it's been shown pre-clinically here, that loss of ATM confers greater sensitivity to ATR inhibition. And so ATR inhibitors are a way of getting around that. Many of our ATM patients aren't that responsive to PARP inhibitors, but they could be responsive to ATR or a combination of these two. So I think these are where we're going to see, this is where I think when there's loss of PARP inhibition, thinking about how can we, if there's loss of ATM, how can we also target ATR in order to see greater treatment effect? There's other targets within prostate cancer, particularly in castrate resistant where the cell cycle is going faster. And we've seen as our castrate resistant prostate cancer patients progressing at a much faster natural history than they were in a hormone sensitive setting.

What's driving that? Cell cycle. And blocking cell cycle can help to destabilize, create greater DNA damage and apoptosis. So causing a cell cycle arrest, a G1 arrest, particularly at youth targeting cyclines is something we've seen in breast cancer work time and again. It should work in prostate cancer. And so there's CDK4, there's CDK6, there's CDK2. And agents that can block these should have a treatment effect. It hasn't worked yet. We've seen now several studies done where we've used these drugs, and we've used them with ADT and we've not seen the effects. Now we're beginning to combine with novel androgen receptor pathway inhibitors. So abiraterone or enzalutamide, those trials are ongoing. That may be a key, just like the PARP inhibitors seem to work better when we combine them with AR pathway inhibitors, not just ADT. That's where I think we might be able to see benefits.
So those studies are ongoing. It'd be important to look for that. This is not off the table, but it's going to have to be contextual. By itself, it's not necessarily a driver. In the right context, these could really help to accentuate the treatment effects of other ages. What about immunotherapy? Bi specifics are a particularly popular idea right now, particularly in cold tumors where we can deliver more T-cells to the tumor using CD3 and then targeting the tumor. And there's a number of ways I've mentioned PSMA. Here it is again, coming up as a way of targeting T lymphocytes into the tumor microenvironment, creating those infiltrating lymphocytes, activating them, maybe with cytokines or other approaches, and seeing that treatment effect. There's this cytokine release, there's a lot that needs to be understood about this process, but there's a lot of promise here as well. And I think STEEP1 is another target that we've seen.

And I think you're going to see these results, these agents kind of moving more into a scalable setting as we figure out how to get people out of the inpatient into the clinic with those approaches. Novel antibody drug conscience, ways of delivering toxic chemotherapies, specifically to tumor using antibody drug conjugate. This has worked fabulously in bladder cancer, breast cancer. We need these agents in prostate cancer as well. And again, there's a number of targets that are under development right now. There's a number of different warheads. The linkers are the key. The more specific we can get this delivery, the more effective, the greater the therapeutic index, the more effective it can be.

What about radio particles? I mentioned Pluvicto, and it's been a huge change for our field, and we're seeing that move up from the post-chemotherapy to the pre chemotherapy. We'll see that data later this year. And I think we're going to see these agents even in the metastatic hormone sensitive setting read out and hopefully in just a year or two. But it's a classic agent. It's different from the gamma rays that we use. These are beta particles, these are heavy particles. They emit a lower energy and they can cause greater damage. They can travel further than our alpha particles, so we get a further range, but it's still relatively targeted. And that's the beauty of it. Alpha particles are the ultimate smart particle. There are very high energy, very few particles needed for cell damage, very potent, double stranded DNA breaks, very limited exposure, just a few cells deep.

You think how on earth can that work in a high volume metastatic setting? But it does. And we see this. We saw it with radium. With these now more tumor directed, targeted alpha particles, they should be even more effective. So understanding how we use alpha particles, how we still use beta particles, where in some cases a little bit of a slightly dirtier bomb is worth it in order to get a greater bystander effect, and maybe a combination of these in the future. So fantastic tools for us to be able to sort out, and again, work with. So in summary, I would just say that metastatic CRPC, it's characterized by both the AR and the non AR dependent pathway alterations in the heterogeneity and duplicity of these. This is not going to be a biology driven typically by just one pathway. So novel agents that can target, specifically, and even some that are non-specific can improve outcomes.

How we develop these drugs is critical. Because the historical one drug at a time approach is not going to work anymore. We have too much already available in the field, too much to build on. We're going to need to understand selection of patients, subsets of patients and sequences, and combinations that are more adaptive, meaning not waiting for progression, but building on success, treating to minimal disease burden, especially in the castrate resistance setting. The combination of adaptive approaches like that I think ultimately will really change the survival for frontline mCRPC that hasn't changed in 10 years. Thank you very much.

Alicia Morgans: Thank you so much for that, Dr. George. That was truly fantastic. And what a whirlwind we've been through in terms of novel mechanisms of action. So I'd love to hear your thoughts. It sounds like a lot of the new approaches that you're suggesting and that we're testing in the field are novel mechanisms of action. How important is it to try to capitalize on something that's different maybe from simply having an AR targeted approach? And what are your thoughts on the potential synergy there between these novel mechanisms and are tried and true things like ARPIs?

Daniel George: Yeah, Alicia, this is a really important point because I think there are certain points in the field where the field has pivoted. Docetaxel was a pivot for metastatic castrate resistant disease. And then the development of novel hormonal agents, in particular, abiraterone and enzalutamide were a pivot. And we still fine tune those drugs and use them earlier and everything. But I think we're at another inflection point. I think we're at a potential inflection point now with our radioligand therapeutics. And I say that because again, I think Pluvicto is one of those watersheds. And we'll see other agents improve upon that or combine with that. I think immunotherapy is poised to be another inflection point. It's going to probably take a few years because of the complexity of some of the bi specifics and whatnot. But I think that can represent another inflection point. And then I think the precision medicine approach, we have the BRCA story.

We have the MSI high. I think you're going to see maybe there's going to be an ATM story that's specific to that. Maybe there's going to be a subset of the cell cycles that are specific to that. And I think you're going to find some additional targets. I didn't get a chance to talk about AKT and other approaches that, again, certain genetic subsets may be more prone to susceptibility. So I think we're going to sort of start recognizing it's not a all comers type approach to CRPC for those kinds of agents. And then there may be some agents where the target is just so prevalent, STEEP or PSMA where the selection really is 80%, 90% of the cancers that have it. It's not necessarily a precision approach from that standpoint of selection. It's a precision approach in terms of targeting the tumor, it's tumor directed approaches.

So not a subset, but something that I think we can use broadly, but hopefully as a new platform. So like docetaxel was a platform that unfortunately for many years we couldn't combine with, now we can. I think we'll start to see our radioligand therapeutics be a platform. I think you are going to see the AR pathway inhibitors be a platform. And maybe with this first PARP data, we're starting to buy into that, at least for HRR. I think there'll be other platform technologies that continue to shape the field. And then I think the real promise is can we, the adaptive approach, can we build on that, not just replace one drug with another, not replace docetaxel with Pluvicto, but begin to build these into a sequence or algorithm that shows the greater survival associated with a certain pattern.

Alicia Morgans: Great. I certainly could not agree more. And I wonder if you could comment a little bit, to your point, on targeted therapies. There are some targeted therapies that require testing because the target is not ubiquitous, but we are certainly using the medications to target the target. But there are other targeted therapies that don't necessarily have the same scarcity of target that requires testing. And at least in some data series, it looks like it's not always easy for us as a community to do the testing that we need to do to really launch drugs that require that testing. What are your thoughts around that? What are the barriers and how do we overcome that? And how might drugs that don't necessarily require that testing have an opportunity to help us help patients more effectively?

Daniel George: I mean, this comes down to that field of biomarkers, where even drugs that we might say, well, gosh, 90% of patients have this target, there's still variation. Some have it more than others. Some have it maybe in some tumor settings or sites of disease and not in other sites. So I think it requires a certain degree of humility to recognize that this isn't going to be an off the shelf one size fits all. We're going to have to think, really going to have to think about the patient's context and the context of that target. Some of these targets are going to be rare, and you're going to be just, "Do I really need to look for something that's in 10% of patients?" But you do because it can make a huge difference. And I think our immunotherapies may continue to fall into some of those lines.

So how we test, when we test, and when do we repeat testing are all going to be important lessons for us to learn together. I mean, this isn't going to be, "Gosh, the academic sites figured it out and no one else knows." We're all going to learn this together. I mean, PSMA imaging is, we need to learn from PSA imaging, the prognosis, the predictive significance, and the repeat value of imaging. So there's humility when some of the new technology comes along to recognize what we don't know and to remember what we do know. PSA doubling time, really important prognostic marker.

And to know that that's an indication that we need to accelerate our transitions in treatments. We can't afford to have patients go three months off, no treatment when the disease is rapidly accelerating. Same thing with tumor burden. High tumor burden, we have to be sort of like the hurry-up offense in football. We just can't take three months in the huddle. We have to go. So these kinds of things will help us. But when you have situations like that, just knowing that the testing needs to be proactive, we need to be thinking ahead, is really important. And the more we can educate and hold each other accountable to that, have some QI benchmarks and things, so we have some consensus on what's important, what scenarios are important to do these testing is critical, because this is complex, and it is only going to get harder.

Alicia Morgans: Absolutely. I think that's a great way to segue into my last question, which is holding ourselves accountable, but across disciplines. Because as we think about these different treatments, the novel mechanisms of action, some of these are oral, some of them are delivered with partners in nuclear medicine or perhaps even inpatient strategies with some of our bi specifics and other approaches. How do we work together optimally? And how do we recognize that even when things are oral, they may actually still have toxicities that require us to monitor patients and again, collaborate together to make sure patients are safe?

Daniel George: Alicia, this is a really critical thing, because I think 10 years ago maybe there was some turf battle over who's going to treat the patients with this drug or that drug. In my mind, that's a moot point now. We all need to be advanced prostate cancer clinicians, every radiation oncologist, urologist, medical oncologist. There are so many patients now living with advanced prostate cancer. We've doubled the time, maybe not at this very last castrate resistant disease setting, we haven't doubled the time, but all the treatments up till then and all the impact we've had on metastatic hormone sensitive disease, and now this kind of influx of more patients with advanced prostate cancer because of some decreased screening that's happened, we're inundated with a higher and higher burden of prostate cancer. People are living longer, just naturally. So now we're getting more men diagnosed with prostate cancer in their eighties that we're treating.

And there are unique challenges to that population of patients. So this is not a time to be fighting over who's going to do what. This is a time of coming together and informing multidisciplinary standards, consensus on quality. Everybody needs to get these things done in terms of bone health, in terms of genetic testing, in terms of tumor burden assessment and discussions of chemotherapy, hormonal therapies, targeted therapies, and at what point. And then we can figure out how can we deliver those things collectively. So I'm not going to give radio therapies, and I may give chemotherapies, but there's lots of people that can give hormonal therapies.

And so we're going to have to divide and conquer this because there's more patients, more treatments, more disease and burden of patients management than any one profession can handle. So that's where I think the centers can come together. In your own community, you can come together. Because medical oncologists are getting bombarded out there on the general side from all cancers, not just prostate cancer. That's proliferating and options and survival. It's all these cancers. So we all need help, and we've got to band together for that.

Alicia Morgans: Absolutely. I think to really overcome what has become such a complex disease, we have to work together. We have to understand our own strengths and weaknesses, understand the pros and cons of each of these treatments, work with our patients to make those shared decisions, and ultimately do what's right for that individual patient as we try to do what's best for his cancer.

So thank you so much for taking the time today and sharing a huge amount of knowledge with us. We really appreciate your expertise.

Daniel George: My pleasure, as always, Alicia. Nice to see you.