So, we're going to talk about patient selection and treatment sequencing, understanding that we do not necessarily have level one evidence for a lot of the topics we're going to be discussing, but the truth is that's how we all have to practice. And radiopharmaceuticals are one of those areas that's really growing, and clearly an area that we need to learn more. So, Tanya, I'm going to start with you. How do you select these radioligand therapies in your practice, and when do you choose to think about that as the primary treatment choice?
Tanya Dorff: Yeah, it's an increasingly complicated question. The initial approval for lutetium PSMA was in the post-docetaxel setting, where we saw survival benefit, and although trials have been positive for progression-free survival with the radioligand therapy earlier, overall survival's been less of a signal, and we haven't really had a direct head-to-head against chemo. So, knowing whether chemo is the right choice or radioligand is really challenging at any given moment in a patient's trajectory. The thing I rely on most currently is really the PET scan. And so, I work very closely with my nuclear medicine physicians to really understand does this meet VISION criteria, but also does it seem like there's enough active disease and a good likelihood of response? A little more nuanced than simply VISION when possible. But I hope that we'll have better selection tools in the future because right now it takes a lot of discussion and shared decision-making.
Phillip Koo: Yeah, I agree, it's a very complicated decision and post-chemo, pre-chemo, and then obviously potentially hormone sensitive. Neal, what's your approach to RLTs in your practice, and how are you thinking about sequencing this given all the other treatment options that patients might have?
Neal Shore: Yeah, look, we had the approval of the first radiopharmaceutical, Radium-223 in about 2013, if my dates are correct, and then now we've had in the last several years, as Tanya nicely pointed out, the VISION trial, and in resistant biology post-chemo, the PSMAfore trial, and prior chemo there's the PSMAAddition trial that's in front of FDA now, which could bring us into hormone-sensitive metastatic disease. And I think that we're going to probably see other approvals and other particles, we'll probably go away from the beta on the RLT side to also alpha, particularly with Actinium. Many of our other colleagues in the world are trialing Terbium and Astatine. So, why do I mention that to our listening audience? Well, A, look, this is such a great panel that you've organized, you've got urology, medical oncology, radiation oncology, and nuclear medicine. And so, we're all learning together the importance of this.
The thing that I love about it, whether it's an alpha particle or a beta particle, it's a distinct mechanism of action different from a taxane, different from a PARP inhibitor, different from an RP, an androgen receptor pathway inhibitor drug, different from, in the US, Sipuleucel-T, or if you happen to be able to give a tumor agnostic indication for pembrolizumab, if you're MSI high or TMB high, those are uncommon. But the uniqueness of the MOA, and the importance of, as Tanya really aptly said, how do we bring that in front of the patient to help figure out is that patient optimizing his therapy? And it really boils down to getting the appropriate PET scan, which is another imaging... It's imaging, but it's a biomarker, like we do other biomarkers, with alterations, HRR, et cetera, I just think it's just such a fertile time right now for the multidisciplinary team to work together, tumor boards, research, decision making... And that's kind of how I approach it.
So, my tumor boards, my research team, we're constantly thinking about how do we optimize the patient's ability to choose? And then of course, we'll probably talk about the really remarkable ways to combine this whole field of radiopharmaceuticals really is very nicely positioned for combinations.
Tanya Dorff: Great. Well, I just want to bounce back to something Neal raised, which is biomarkers. And I think really important for us not to forget that even though we have this great radioligand tool with a novel mechanism of action, that we need to be doing sequencing, NGS, because when we do find a DNA repair alteration like a BRCA2, we know how powerfully that predicts for benefit from a different class of agents, the PARP inhibitors, and we just don't want to treat everyone the same. So, we need to be looking for those differences among our patient population so that we can put all the options on the table and the best options earlier rather than later.
Phillip Koo: Yeah, I think that's a great point. The biomarker testing, whether it be imaging, whether it be NGS, we need to learn more, there's so much more that we need to sort of uncover. Dustin, from your perspective, you're the one who's often administering this drug, giving it to patients, you've seen it used in the castrate resistance setting, or APMR setting post-chemo, you're seeing it move forward. What have you seen with regards to safety and tolerability for this drug? And what's going through your head as you see this shift towards earlier use?
Dustin Boothe: Yeah, I would say that it's been fascinating to see it go from the post to pre-chemotherapy setting because in the post-chemotherapy setting, they didn't have a lot of options. And this is kind of what it was, all they had. Maybe at that point they could switch to cabazi, and sometimes as appropriate. But really our decision-making was a little more simplistic at that point. In the PSMAfore era, it became more challenging with more options. And we established a tumor board, and we'd look to one side, the first thing you see a patient, you think, okay, is this the right systemic medicine? Are there better systemic options? And that's what NGS helps us with. And that's what also looking at the scan and the clinical picture and the aggressiveness of it, sometimes the amount of visceral disease and the high-volume in younger patients dedifferentiated nature, we think maybe chemotherapy makes more sense.
And then, we looked to the other side, we looked at our nuclear medicine colleagues, and said, "Okay, let's talk about the scan now, and let's look at the heterogeneity and look at the SUV values. And is this a VISION or PSMAfore candidate based on the imaging?" And even if it is it still right? Does this patient have the right avidity and the pattern that this drug is going to do what we think it's going to do? And then we also, as a radiation oncologist, I selfishly bring up my own specialty, also, we say, hey, look, there's only two spots here. And this patient was castrate-sensitive for four or five years, let's use external beam in this setting. And to your question about toxicity, that plays into all these discussions too. It's like, well, in somebody who has large volume disease, and we know that the superscan is no longer a contraindication, but we also know that there's added toxicity when we treat those patients.
And we know that if we just burn through all of our therapies, and we've got this slow progression, a single fraction of external beam radiation can prolong the course for these patients significantly and benefit them toxicity-wise as well. But more towards toxicity, when we look at our patients and the experience that we've had, let's say that I've been really impressed in my experience, as moving from the beam to the systemic therapy, I was a little afraid, I think a lot of radiation oncologists are, that we are going to make these people super sick. And sometimes they do, and that's why we need collaboration with medical oncology.
But I've actually been impressed with how little I'm really having to push people towards getting transfusions, and really dose limiting toxicities. But certainly we have the dry mouth, we have patients with fatigue, and we sometimes do see these hematologic and renal toxicities. But I have been pleasantly surprised as we've gone from post-chemo to pre-chemo, that these are less sick patients and they do better, and it's really been a joy to be able to be involved in delivering these therapies in these patients.
Phillip Koo: That's great. Just to follow up on that. So, they're healthier, they're doing better, but on the flip side, they potentially might be getting radiation that is systemic. So, what's going through your head regarding long-term potential complications that we might need to think about?
Dustin Boothe: Yeah, it's a really important question, it's something that we don't take lightly. On one hand, we've been delivering radioactive iodine to patients in their 30s, and have followed them long-term, and we know that a targeted radiotherapeutic could be safely delivered if the target is narrow enough and the ratio between target and organ at risk is favorable enough. So, that gives me hope. At the same time, we do see MDS and we see leukemias in patients with NETs with LUTATHERA. And so, we're really, I think, early on the data and understanding whether they're going to be the long-term complications because before we are dealing with post-chemotherapeutic patients, these patients were living a year and a half, that's like the life expectancy of somebody with a GBM. And so, now we're seeing with the PSMAAddition data and we're moving earlier and earlier, time will tell if we see those changes that we're seeing at a biochemical level.
In some cases, if that translates to long-term worries about resulting in secondary malignancies and other bone marrow limiting toxicities and things like that. So, it's early to find out, but it's certainly something I worry about as somebody who sees secondary malignancies from external beam. You see patients that develop sarcomas after breast radiation, it's what keeps us up at night. But I am hopeful based on just what we've seen and what we've been doing with thyroid cancer for decades and decades.
Phillip Koo: Great. So, Tanya, this question's for you. Now , let's say we do have a label for RLT in the hormone-sensitive setting, and you're speaking to patients and we know how important patients' goals of care are, what are you hearing from patients about what outcomes matter the most to them, or perhaps what adverse events are most concerning to them? And how you fit in the current status of radiopharmaceuticals into the decisions to treat with this across the whole spectrum?
Tanya Dorff: I have to say, it makes me nervous to think about treating someone whose life expectancy could be a decade, I just don't think we have long-term safety data yet. And I still have patients in my practice who have been on their upfront doublet for well beyond seven, eight years, and that's just a long time. And as Dr. Boothe mentioned, the early experiences with this radioligand were in patients with a much shorter life expectancy. So, that being said, what do patients want? Patients are scared of chemotherapy, and I think it's really important to educate them about the differences between intravenous or systemic radiation versus chemotherapy. Because for instance, we do get some nausea and vomiting with the radioligand, I have to prescribe an antiemetic as I'm prescribing my first dose of radioligand, I actually don't even do that anymore with docetaxel because people just don't get a lot of nausea vomiting.
So, people have these preconceived notions, oh, if I have chemotherapy, I'm going to be vomiting, and if I get this thing that's not chemo, I'm not. So, you have to level set and just explain each one has a different side effect profile. And I talk through some of my concerns, what we know, what we don't know, patients want treatment-free survival, right? They want a lower symptom burden, and we all know that suppressing testosterone creates a lot of toxicity in and of itself. So, I think the biggest impact will come if we're able to show that, and obviously we don't know that yet from our existing data sets. But if there's some combination of treatment that could get a patient the ability to have time off treatment, I think that's what patients are really asking us, as a prostate cancer research community, for, and we're not able to say that any more treatments really get us there yet.
We're just exploring this idea of treatment holidays, so it's still not considered very standard. So, there's upfront toxicity, and then that longer term gain. For some patients, it's not about living as long as possible, it's really about quality of life, and we have to really set that expectation for short-term side effects versus long-term side effects. So, obviously with docetaxel, a big concern being the neuropathy, which can be permanent.
Phillip Koo: Great. So, Neal, this topic comes up all the time, overall survival versus quality of life, your experience taking care of thousands and thousands of patients, what endpoints, what resonates the most when you're having these conversations with patients and their loved ones?
Neal Shore: Well, if I had to just pick, it's probably the safety toxicity profile more than anything. Am I going to have challenges? Am I going to end up in the emergency department? Will I be hospitalized? And then, will it preclude me from getting any other therapies? And more and more, and I really like Tanya's point, that I really promote, is this notion of being treatment-free. And I think for a long time, and some even feel it's a bit heretical to, oh, I've got advanced cancer, I've got to constantly be on a therapy. And so, now we talk about, we use words like intensification, deintensification, or escalate and deescalate, and I was at a meeting recently and we said, "Well, maybe we should just use the word optimization to encompass all of that."
So, the optimization could be doing all sides of that, intensifying, deintensifying, because you want to optimize and you want to offer the patient a therapy that's not going to preclude another therapy that has a different mechanism of action. And so, yes, that's probably more of a clinician concept that the marrow has become really a thing that we all are now very careful about. So, if somebody has a high tumor burden in their marrow, and then we're also giving them taxanes and arguably PARP inhibitors and radiopharmaceuticals, how do we protect the marrow so that we don't end up with somebody hopefully never getting an MDS or an AML, but it's perpetually thrombocytopenic so that they can't really handle any of these other therapies that they've not received?
So, I try to very carefully have that conversation without overwhelming patients, but in terms of the, just maybe make this comment, Phil, the radiopharmaceuticals bring in some very interesting... A, there's the marrow issue, but there's salivary gland, less so on the... We don't see the neuropathy like we might see with other therapies. But we have to get better in the community and the uro-oncologic community for sure, maybe some of our radiation oncology colleagues, as well as understanding salivary gland baseline measurement, understanding how to really look at the monitoring and dose holiday, dose interruption, optimization...
Do all patients need to necessarily get six cycles or four cycles, if it was an eight-week duration, so that we can protect patients? And so, the question that the patients frequently, the more informed patients is, what else do you have in your toolbox? Do you have something for me? And then the less educated who are just, hey, just keep me from feeling poorly and keep me out of the inpatient facility.