Dr. Alicia Morgans:
Hello, and welcome to The ASCO Post Roundtable Series on Targeted Approaches to Metastatic Hormone-Sensitive Prostate Cancer. My name is Dr. Alicia Morgans, and I'm a GU medical oncologist at Dana-Farber Cancer Institute in Boston. Joining me today are two of my colleagues, and I will allow each of them to introduce themselves. Let's start first with Dr. VanderWeele.
Dr. David VanderWeele:
Hi, I'm David VanderWeele, also a GU medical oncologist, and I'm at Northwestern University in Chicago.
Dr. Alicia Morgans:
Great, thank you. And Dr. Ryan.
Dr. Chuck Ryan:
Hi, I'm Chuck Ryan. I'm also a GU medical oncologist and I practice at Memorial Sloan Kettering Cancer Center in New York City.
Dr. Alicia Morgans:
Well, thank you both for being here. Today we will be discussing the treatment and management of metastatic hormone-sensitive prostate cancer with three patient case studies. We will start our second installment with a focus on high-risk de novo metastatic hormone-sensitive prostate cancer. So, let's dig in.
Mr. J.D. is a 62-year-old gentleman with a history of hyperlipidemia, diabetes, and obesity, who came to his urologist for routine follow-up of his BPH. He had worsening urinary symptoms with increasing nocturia, and five to six episodes each night, and some urinary hesitancy that had developed over the last few months. He denied any dysuria or hematuria and had no flank pain, but his PSA was increasing over the preceding years. It had been around 5.5 and was in that range for a little bit, but was, on this visit, 9.3. He had a prostate biopsy that demonstrated Gleason 4+4 or grade group 4 prostate adenocarcinoma.
To better understand all of this, of course, the urologist ordered some imaging. He had conventional imaging with CT chest, abdomen, and pelvis with IV contrast, that was really negative for evidence of metastatic disease, but because it was high-risk disease based on the Gleason score, he underwent a PSMA PET-CT, and this showed multiple areas of vertebral body involvement and retroperitoneal lymph node metastases that were very clearly evident, even though the other scans were negative. And he underwent germline and somatic genetic testing, and these tests were negative for additional actionable alterations.
So, I think we're at a point where we need to think about what else we would need to think about adding for this patient. I'm wondering, and we'll start with Chuck on this one, what else are you thinking about? Would you need to get an FDG PET? Are you thinking about maybe doing somatic NGS testing to test for options for drug targeting? What else are you thinking about? Clinical trials, Decipher testing, often done in urology clinics? What do you consider?
Dr. Chuck Ryan:
Yeah, so good questions. It's interesting. He had a negative CT, but a positive PSMA PET, and I'm trying to determine whether or not he has oligometastatic disease vs high-volume disease, and then the issue is, is this a qualitatively different disease when the standard scans are negative? Well, a lot of the decisions we make are based on studies that enrolled patients using standard scans, so this person would not have been eligible, perhaps, for some of the old studies that were done that defined high-risk disease and what the treatments are. And so, we're in a little bit of a gray zone here, a little bit of a data-free zone almost. Having said that, I think I have all the information I need. I have his NGS, I have his prostate biopsy, and I have his imaging, and I have the patient in front of me to determine his performance status, his comorbid conditions, and things like that. I don't know that I need to put him through more testing at this point in time.
You bring up Decipher, which is a really interesting question, because there are data to demonstrate that patients with metastatic prostate cancer with a high Decipher score, for example, are those who are more likely to benefit from chemotherapy. And that may be something that we might want to consider. I'm not sure that that has risen to the gold standard of testing yet because, again, we're in a bit of a data-free zone here because this patient's volume of diseases is qualitatively different from the patients for whom the chemotherapy benefited based on the Decipher Score, based on those retrospective analyses and STAMPEDE and CHAARTED, et cetera.
Dr. Alicia Morgans:
Great. Yeah, thank you so much. That was a great discussion. I think, as we're considering all of this and really that disconnect between conventional imaging and PET imaging, David, I wonder if you have any other thoughts or comments there, because I feel like this is increasingly happening that... This patient had high-risk localized disease by all measures, so the urologist got a PET scan to complete staging and really understand whether there could be any bone involvement, even though the CT was negative, and then, clearly, multiple areas of bone involvement plus nodes. So, if you would go by PET, this is a higher volume than we would expect, though not defined on conventional imaging. Is this a patient... What systemic therapies are you thinking about for this patient? How do you rectify that in your practice? It's just a really practical question. It's not an easy answer.
Dr. David VanderWeele:
Yeah, so we talked about the patient getting a CT scan. I don't know that we said if they got a bone scan or not.
Dr. Alicia Morgans:
No.
Dr. David VanderWeele:
And I actually probably would get a bone scan. I know it's not going to highlight additional areas of cancer that you don't already know about, but I do think about the cancer a little bit differently if it's something that shows up only on PET scan rather than also showing up on a bone scan. And I don't think we have all the details about how many bone lesions there were. It feels like this is probably someone that I would put in a category of low-volume metastatic, whether or not, sort of regardless of what the bone scan ends up showing, unless I'm surprised and there ends up being a lot of things showing up on that.
So, in that scenario, I'm probably having a discussion about using doublet hormone therapies, so antigen deprivation therapy and an AR pathway inhibitor. We have many options for both of those categories of what agents to use, but probably discussion about using doublet therapy. And then, also, probably a discussion about radiating the prostate, probably a very strong recommendation if there isn't anything showing up on a bone scan. But if it ends up being low-volume, we have data to support that as well, both for better disease control as well as for symptom control. So, probably talking about doublet therapy and radiating the prostate.
Dr. Alicia Morgans:
That's really helpful. And I just want to follow up on the comment about the bone scan. I think that's a really interesting and potentially overlooked aspect of this and may be really helpful for you, because one thing we don't have is a defined method for defining response to treatment or progression on treatment by PSMA PET, so we still do that when we're in a metastatic setting based on conventional imaging, or we should still be doing that, because that's where we really have the best data and we really understand when progression is meaningful, such that we should change treatment and not just a fluctuation and expression of PSMA protein on the cell surface, which is essentially what is being measured by a PSMA PET.
So that, I think, is really useful and does help you to define the disease by the conventional strategies that, as Chuck said, those are the studies that have led to our knowledge base. And so, I think that was a great suggestion and something really important for us to consider doing, even as we increasingly sort of mistrust our bone scans and I think, in some practices, are phasing them out. So thank you for that.
Chuck, let's shift gears a little bit. If this patient had an HRR mutation... I know in this hormone sensitive metastatic setting, we don't necessarily have an approved combination, but there was some data presented relatively recently that suggests that this may be on the horizon, and certainly we have combinations available or single agents available in the metastatic castration-resistant prostate cancer setting. So, if this patient had an HRR mutation, and imagine that approvals existed, would you review some of the data that might inform some of the decision-making in this metastatic hormone-sensitive setting?
Dr. Chuck Ryan:
Sure. So we don't have an approval in this space, as you point out, but very encouraging data came from the AMPLITUDE study, which was with niraparib at ASCO, and it looked very good in terms of rPFS, in terms of delaying progression when a PARP inhibitor is added early on. And this allays some of the concerns that people have had about the potential for high response proportion, but perhaps inducing resistance that might emerge later. I don't think that is a concern so much with these agents anymore.
We have, of course, several PARP inhibitors that are approved for prostate cancer, olaparib, talazaparib, niraparib, and rucaparib, and this, niraparib, is the first one to be studied in this hormone-sensitive space. So we're very quickly going to have crowded options for patients in this hormone-sensitive space, but for HRR mutations, it's going to be pretty limited to the PARP inhibitors. I think one of the questions would come up, which is, would we avoid chemotherapy in that setting in place of a PARP inhibitor? If capivasertib is approved in that space, what will we think about in that space, as well? So, lots to think about.
Dr. Alicia Morgans:
Absolutely. It's definitely a shifting landscape. That is for sure. David, I'd love to hear your thoughts. We have lots of options available for AR pathway inhibitors. This patient was 62. There was some data relatively recently from the STOPCAP study that suggested we might make different decisions for younger patients rather than older patients. I don't know if you have any thoughts or comments there in terms of choosing an AR pathway inhibitor, or any other thoughts about how you might differentiate between these drugs. Certainly, I would imagine approvals, insurance, pathways also always coming into play.
Dr. David VanderWeele:
Yeah. When I have these discussions with patients, we talk about how there are many options. I do think of them as all being pretty similar in how effective they are, also pretty similar in their side effects. But there are some differences in the side effect profile, also some differences in terms of convenience and different things. Patients have different values and things that they're concerned about more or less.
And so, I think this patient actually has a history of diabetes. That might be a reason to try to avoid abiraterone and the prednisone that comes along with it. It seems to have a bit worse effect on glucose control. Our AR agents, in general, are going to affect glucose control anyway, but I think with the prednisone it seems to make it a little bit worse.
We don't have a lot of head-to-head comparisons between these agents. I tend to like darolutamide, in terms of the side effect profiles seem to be pretty similar to placebo across multiple trials. But it does require twice a day dosing with food, and so that's sort of extra convenience concerns. So I think you have a lot of options, and it's a discussion about... There isn't a clear, better one, compared to the others, so it often comes down to side effect profile, convenience, and often cost, since abiraterone is the only one that's available as a generic and thus much, much more affordable than all the other agents.
Dr. Alicia Morgans:
Yeah, I think that's so important. I think one of the things that I tell all of my patients is, "If I can't get you this one, I can get you a different one. I can get you one of them. We have four options." And I think it's really reassuring for patients to hear that, and it's also reassuring for me, because usually we can get something, and having abiraterone as a generic is great.
I think both of you were involved in a study that we did looking at abiraterone vs enzalutamide, specifically looking at fatigue and cognitive function, and one of the big take-homes over a year of follow-up is that patients actually felt pretty well, and they felt pretty well regardless of the treatment they were on. And that is another reason that I know, in real-world populations, although the patients were enrolled in this clinical trial, they were essentially just being monitored. No real deep interventions there. They felt pretty well, and there were no real differences between these agents.
I so appreciate the two of you talking through this case. Let's review some key clinical takeaways. Germline and somatic genetic testing are really important parts of the workup of patients with metastatic hormone-sensitive prostate cancer, as we have seen. And imaging with PSMA PET scans has caused stage migration for patients who were previously classified as high-risk localized prostate cancer. And now, in this patient's case, really a metastatic hormone-sensitive prostate cancer case will get that bone scan to define high- or low-volume, based on conventional imaging, which is what we still do. But this is an area of influx.
Patients with HRR mutations may soon be eligible for treatment with ADT, niraparib, and abiraterone, based on the AMPLITUDE trial. Of course, this is something that we are just learning about, so we're going to have some longer-term data. We'll have survival data that becomes more mature, but right now we know that this combination does prolong radiographic progression-free survival, as compared to ADT and abiraterone alone.
And additional options for treatment of patients with de novo low-volume metastatic hormone-sensitive prostate cancer include ADT and AR pathway inhibitors, with or without radiation, as we heard. So this brings us to the end of the case. Please see the other segments for further discussion about the latest research in metastatic hormone-sensitive prostate cancer or visit ascopost.com. Thank you.
