Dr. Choudhury:
Welcome to Integrating Targeted Therapies in mHSPC: A Changing Treatment Landscape, an ASCO Post Roundtable. I'm Dr. Atish Choudhury. I'm a genitourinary medical oncologist at Dana-Farber Cancer Institute. Joining me today are two of my colleagues.
Dr. Autio:
Hi. I'm Karen Autio. I'm a genitourinary medical oncologist from Memorial Sloan Kettering Cancer Center in New York.
Dr. Wulff:
And I'm Libby Wulff. I'm a genitourinary medical oncologist and a palliative care physician at the University of Kansas in Kansas City.
Dr. Choudhury:
Thanks so much for joining. For our first case, we'll discuss the management of PSMA PET-positive metastatic prostate cancer. So, the first case is C.N., who's a 71-year-old man with no prior PSA screening history, who presented with hematuria and hematospermia. His past medical history included a myocardial infarction, hypertension, hypercholesterolemia, type 2 diabetes, ADHD, and anxiety. His PSA was 32 at the time of presentation, and CT of the abdomen and pelvis demonstrates multiple prominent pelvic lymph nodes.
So, MRI of the prostate demonstrates a large mass in the left peripheral zone of the prostate with extracapsular extension and invasion of the left seminal vesicle, as indicated in these figures. He undergoes transrectal ultrasound prostate biopsies, which reveal Gleason 5 + 4 = 9 prostatic adenocarcinoma with 9 of 14 cores involved.
So, what additional studies do you recommend at this time? I'll start with you, Karen, for this one. What additional studies do you recommend?
Dr. Autio:
Yeah. I mean, we know this patient has a Grade Group 5, a very locally advanced tumor with metastatic lymph nodes. So, I think, probably, the most important next step is going to be to get full staging. So, a PSMA PET scan would be my next.
Dr. Choudhury:
I agree that would be appropriate, and we'll discuss some other studies that we might do later on. So, this patient did undergo a PSMA PET/CT, and this shows heterogeneous uptake in the prostate gland and extending into the left seminal vesicle, mildly avid enlarged left internal iliac, left iliac, and retroperitoneal lymph nodes. Multifocal uptake in the axial and appendicular skeleton, which was a surprise, including pelvic bones, vertebrae, ribs, sternums, and scapula, highly suspicious for osseous metastatic disease. So, this is four or more bone metastases that are shown on the PSMA PET.
So, Libby, do you also recommend conventional imaging in these cases?
Dr. Wulff:
This is tough. I mean, I think, to me, it feels like there's a little downside, although my personal practice is that I try to avoid ordering imaging that I'm not going to act on, just for the sake of my own sanity and the patient's out-of-pocket cost. I think, in this instance, it could be helpful, just at baseline, to see, exactly, how are these lesions looking before they've had a chance to be treated and before we can see what a tumor flare would have the potential of looking like on the conventional imaging? I think it's helpful to have a baseline, even though I do trust the PSMA PET.
Dr. Choudhury:
And Karen, do you think that conventional imaging is useful here?
Dr. Autio:
I do. I find it very helpful just to have the baseline. Again, it's unlikely that it's going to change the determination of low- vs high-volume disease, but when I think about moving forward and comparing the next set of imaging to the baseline, it might not be that that next set of imaging is a PSMA PET. In which case, I find it helpful to have the bone scan there as a baseline. So, I do tend to repeat even if I don't think it's necessarily going to change the immediate next treatment steps.
Dr. Choudhury:
Yeah, this is a very, very controversial point. So, I think that, for teaching, that we'll often say that conventional imaging is recommended, but again, how much it's going to change your management is challenging. And then, in terms of monitoring, it also becomes very challenging because then, are you obligating yourself to repeat both sets of scans when you're following this patient, just the conventional imaging, just the PET?
So, these are real decisions that we have to make in our practice because every scan exposes patients to radiation and additional costs, as well. And I think that there are definitely good reasons to do additional imaging here. However, I think that, again, that point is very, very controversial.
So, we'll talk about initial treatment strategies, and I'll go back and forth. So, Karen, when you see a patient like this, do you have a go-to in terms of LHRH agonists or antagonists?
Dr. Autio:
For the LHRH agonist vs antagonist, I mean, for a patient that has high-volume disease, particularly if they were symptomatic, then I do generally like to start with a medication like degarelix with a direct antagonist, and then we'll frequently switch over to something with more convenient dosing. In terms of injectable vs oral, I predominantly am using injectable forms, but for patients that have cardiovascular disease, for example, or other risk factors like that, then relugolix, an oral LHRH antagonist, is preferred for my patients.
Dr. Choudhury:
Is there a specific reason that you feel like an injectable is your default?
Dr. Autio:
I know I can get it on the spot. So, for a symptomatic patient, I can give degarelix in clinic the same day. So, I tend to go for that rather than waiting for a prior-authorization and approval, for example, for an oral.
Dr. Wulff:
That's a very real concern for our patients because out-of-pocket costs can be such a burden, depending on the patient population we serve. And waiting to get copay assistance, grants, that kind of thing, can take precious time when what they really need is relief.
Dr. Choudhury:
Absolutely. So, for symptomatic patients, I do agree that starting with an injectable antagonist, like degarelix, is very reasonable. This patient wasn't particularly symptomatic to start with.
And in terms of oral vs injectable, it's very interesting the pluses and minuses of the two different approaches because, at this point, the out-of-pocket cost for oral relugolix are not too limiting for most of our patients, especially those with private insurance, though it does often take some time to get the copay assistance there. So, I do tend to favor the oral for patients who I'm planned to discontinue treatment because the testosterone recovery tends to be more favorable. Also for patients with a cardiovascular history, I do think that there's some data that suggests that oral antagonists might be better than injectable agonists, though that point is also a little bit controversial.
Dr. Wulff:
Especially because that was monotherapy, and we're not looking... With treatment intensification, a lot of patients aren't going to be offered that. Although, I do think, also, even though this might be a patient for whom we would traditionally consider a lifelong treatment, with A-DREAM and some other trials, I think that we are going to be having more and more discussions about treatment holidays. Don't you?
Dr. Choudhury:
Absolutely. I totally agree that that's a consideration, and that's also a reason that I have started to use more oral antagonists in this particular setting.
The NCCN Guidelines do include combinations with relugolix in the guidelines. There has been PK data on abiraterone, enzalutamide, and apalutamide published. And we just presented our study with combining with darolutamide at ASCO this year, so we have PK data for all the combinations. So, I don't think that that's a reason to not give the combination other than the actual clinical efficacy, in terms of the randomized trials did use injectable rather than oral agents.
Dr. Wulff:
Yeah, all I meant was I think, the cardiac benefits, sometimes I've had a hard time justifying to patients if it were a high cost since that was... A lot of that cardiac benefit in HERO was with monotherapy, but it's really nice to have so many options.
Dr. Choudhury:
Exactly. And when you're combining it with something like abiraterone, that has its own cardiovascular toxicities, that, really, what are you doing? What's the big difference? So, Libby, getting into that, how do you then decide for an ARPI for a patient like this?
Dr. Wulff:
Yeah, this is tough. I mean, I think that, though, again, I'm a palliative care physician as well as an oncologist, so I'm very comfortable wading into these gray areas with patients and having multiple discussions. My personal practice is that unless there's one very clear obvious choice that a patient needs, then I usually don't decide their ARPI during the first visit. In fact, I choose not to, specifically, because I want to be able to have time to talk to them about some advantages and disadvantages.
So, that would be like if a person cannot possibly swallow pills, then apalutamide would be a great choice for that person because you can disperse that in water, or in applesauce, or something. But otherwise, I guess, my take on the data, my coloring book version is that I generally think that we're seeing the AR antagonist to be a little bit more efficacious in many settings. And also, for this patient, as to your prior point, who has a significant cardiovascular risk or has proven cardiovascular morbidity, I think I would favor one of the AR antagonists. But I'm one of those insufferable doctors who really talk to patients about all of them and talk about advantages and disadvantages with them. So, my approach is not as streamlined as some, I will admit.
Dr. Choudhury:
And Karen, how do you approach this conversation?
Dr. Autio:
Yeah, I also do tend to not do it on the first visit. I mean, I talk on the first visit about how we're going to add on a second agent, but I don't get too much into the weeds about what exactly that first agent is going to be because I like to have some sense of tolerance with just ADT alone and PSA response before I go into it.
I mean, I use all the AR inhibitors as well as abiraterone, so I don't have one that's a particular go-to. I think, ultimately, there's probably relatively... I have equipoise in terms of their efficacy across them. And then there's just nuances of side effects, and drug interactions, and patient preferences that factor into the mix of which one I ultimately end up using. As well as whether or not it's going to be used in combination with chemotherapy, in which case then we are sort of drilling down to two agents.
Dr. Choudhury:
So, you would favor abiraterone or darolutamide if you're planning for a patient for docetaxel?
Dr. Autio:
Yeah, if I'm planning for docetaxel, then I do tend to stick to those two, just based off the data.
Dr. Choudhury:
So, if based on the PSMA addition study the lutetium PSMA is approved, how are you going to decide between that agent and docetaxel? I'll start with you, Karen. I feel like the lutetium is going to be in the water in Manhattan. Are there going to still be patients that you're going to give docetaxel for?
Dr. Autio:
I'm a big believer in triplet therapy with docetaxel, so I will still be using that. It's going to be tough because we will have no head-to-head data, and it's going to be a lot of discussion with patients about the pros and cons to each approaches. And then I'm sure we'll get more data that, hopefully, helps us to understand who's better served by on approach rather than another. If I had a patient whose PSMA expression, at baseline, was maybe not so robust, that might be somebody that I'm thinking about with high-volume disease. That might be somebody that I would prefer docetaxel for.
Dr. Choudhury:
So, what is your default around docetaxel over lutetium PSMA? Why was that your first instinct that you favor triplet with docetaxel?
Dr. Autio:
Probably, in part, comfort level and in part, just with lutetium PSMA, knowing that the bulk of the benefit is probably coming from those first couple of doses, but the FDA approval will be for six doses. And I do sometimes think about how much additional benefit are those patients getting from the subsequent third through sixth and long-term toxicities associated with that.
Dr. Choudhury:
Absolutely, because there is some concern about late-term MDS and AML that can come up maybe 3 to 4 years after treatment. So, in patients who are going to live for a long time, I think there are some concerns about upfront lutetium. Libby, what are your thoughts between the two?
Dr. Wulff:
Yeah, this is so tricky. And it's, again, such a privilege to have these difficult decisions to make. I do think, for myself, even though I really tend to be a trial purist, I do think that some of their somatic testing might help me with that. Like if we're seeing that they have a tumor suppressor loss or if we're seeing HRR mutations, that might push me in one direction or another. And my understanding about the data and my clinical experience, it would dictate that in those patients who have a lot of those tumor suppressor gene loss profiles, I just haven't seen very encouraging results from patients getting lutetium PSMA.
So, while it doesn't mean I wouldn't offer the treatment to the patient, I just have a little bit less confidence and think it can be important to debulk. Now, this patient had high-volume disease by criteria, but not verging on medical crisis levels, but it's hard. And we're all very hungry for additional data from these studies to help guide us because we really need some more objective criteria.
Dr. Choudhury:
Absolutely, so biomarkers are definitely going to be helpful in making that decision. And speaking of biomarkers, we'll talk about the BRCA mutations in PTEN-deficient in the next two segments. So, we can hold off on that for this one, and we'll talk about the role for radiation with this patient. So, he was started on degarelix, as Dr. Autio had mentioned, and was transitioned to leuprolide, and was started on abiraterone and prednisone by the outside oncologist. I was not part of that decision, but he did present to me for a second opinion to discuss the role of docetaxel. And he did have a CT chest, abdomen, pelvis and bone scan that confirmed high-volume bony disease by CHAARTED criteria. There was no visceral disease. He had no germline genetic variance, and his PSA, by the time he saw me, had decreased from 32 to 0.3 after 2 months of ADT.
This gets to the idea that both of you were discussing is that the decisions for doublet therapy and triplet therapy are not made at the first visit. So, we do have time to see how things are going before we make decisions about the next steps.
Looking at this very favorable early PSA response and knowing data that if your PSA gets to less than 0.2 by 6 months, and he was well on his way there, and when we discussed the risks and benefits of docetaxel, the patient elected not to receive docetaxel. And I thought that that was a very reasonable decision, given the trend of his PSA. And in fact, his PSA went to completely undetectable after 6 months of ADT. So, we discussed the role of prostate radiation.
So, for patients with high-volume metastatic disease, there was no overall survival benefit in either the STAMPEDE trial with ADT alone or the PEACE-1 trial with ADT and abiraterone. However, there was a failure-free survival advantage in STAMPEDE, and there was prolongation of time to serious GU event and time to CRPC in PEACE-1. So, he did elect to have prostate radiation, but he was having side effects, so severe fatigue, concern for cognitive changes. And he elected to discontinue leuprolide at the time, knowing that the CYP17,20-lyase activity of abiraterone does keep testosterone castrate without the leuprolide.
We engaged our colleagues in social work, psychosocial oncology, and neurology, and he had a PET scan after a year of abiraterone that showed resolution of uptake at the sites of disease. And then we also had him switch the abiraterone to 250 mg with low-fat meal due to nausea with the 750 mg fasting. And just very briefly, Libby and Karen, have you ever prescribed 250 mg?
Dr. Wulff:
Yeah, I've only done it for patients who needed to save the money, essentially. That's when it's come up. And that's actually a relatively high proportion of the patients I serve, so it's happened a few times.
Dr. Choudhury:
Absolutely. I've done it for that reason, as well. And Karen?
Dr. Autio:
I have not done it, but if I were to, it would be that scenario.
Dr. Choudhury:
Yes. So, just for background there, so generally from pharmacies like Cost Plus Drugs, the cost of 250 mg daily with a low-fat meal is somewhere between $30 and $40, so one-fourth of what you would be paying for the 1,000-mg dose. However, it is dependent on the patients actually eating consistent low-fat meal, so it does lead to much more unpredictable actual pharmacokinetic properties. So, it's really only favored in situations where the patient either can't afford or can't tolerate the 1,000 mg.
So, after 2 years of abiraterone, the PSA PET showed no uptake. His PSA is undetectable. His testosterone is undetectable. Would you consider a treatment break in this setting? And how would you advise the patient? So, Karen, have you ever had patients take a treatment break if they've presented with high-volume disease?
Dr. Autio:
I have, but I wouldn't say commonly when they present with high-volume disease. But I think we're learning more and more about who can appropriately take a break and be monitored carefully with resumption of treatment as needed. So, I would say that I've done it very commonly in my low-volume metastatic disease patients, less commonly in the high-volume metastatic disease. But I think with a very reassuring PSMA PET scan and that PSA and just how quickly that this particular patient responded, it's very reasonable to consider a treatment holiday, especially given the toxicities that they've been experiencing.
Dr. Choudhury:
And for clarification, PSMA PET has not been validated for disease response assessment in hormone-sensitive prostate cancer, but it does provide reassurance to the patient, sometimes, that there's no active disease. So, Libby, what do you think about taking a break in a patient like this?
Dr. Wulff:
I've been pretty conservative, in general. I tend to be a trial purist, but I think we're seeing data that's reassuring about that with our imaging being more sensitive, even though the use is considered investigational in Prostate Cancer Working Group 4 to use as disease response assessment. I do think I, as a clinician, have increasing confidence in the sensitivity of it.
And as well as data from your trial, A-DREAM, I think it's a really great proof of principle and really important and valiant effort. It's really hard to do de-intensification or de-implementation trials, and so I think that data has... I've had several patients who've been waiting on the line to hear about it, and I sent them a MyChart message from ASCO saying, "Okay, we can talk about it now." So, it's something that is helping, I think, make that possible for patients.
Dr. Choudhury:
So, one thing we did observe in A-DREAM is that the patients who presented with high-volume disease were more likely to have to resume. So, if a patient like this does want to take a break because of toxicity, I do advise them that it's highly likely that they'll have to go back on treatment and that we can use imaging to find sites of disease very early during the off-treatment interval, potentially use radiation as an option in conjunction with resumption of hormonal treatment.
Sometimes patients might recur with a single site of disease. And if they had terrible side effects with androgen deprivation, you might be able to get away with just focal treatment. So, there are many different scenarios here, but you do have to advise the patient around the uncertainties and the lack of Phase 3 data around equivalent outcomes, though that some patients we are observing have a prolonged off-treatment interval.
So this specific patient, due to ongoing side effects, he did elect for a treatment break. He was on abiraterone monotherapy at this point, so the testosterone did normalize relatively quickly after stopping just 3 months later. And I just saw him for a visit 15 months after stopping abiraterone. His PSA remains less than 0.02.
Now, this is not going to be the common outcome for patients with this particular presentation, but we did find in A-DREAM that patients remained off treatment, on average, much longer than we expected. The median time off treatment was more than 2 years, so there are patients who do achieve this much longer off-treatment interval than you might expect. So, again, the close monitoring here is going to be highly critical, and imaging, including conventional imaging, is going to be important in case this patient progresses with PSA non-producing disease.
So, these are my clinical key takeaways. Multiple LHRH agonists and antagonists and androgen receptor pathway inhibitors are available, and they all have different modes of administration, dosing schedules, pharmacologic properties, and side effect profiles. The decision to add docetaxel is based on the disease features, chemotherapy fitness and patient preference. Molecular tests, like the tumor suppressor gene loss, as Libby had mentioned, or a high-risk gene expression profile, might guide patient selection.
Radiation to the prostate has been associated with survival benefit with ADT and a radiographic progression-free survival benefit with abiraterone in patients with low-volume mHSPC, but there was also an improvement in time to serious GU event and time to CRPC with abiraterone in patients with high-volume mHSPC. So, side effect can be challenging despite dose modifications, and so treatment breaks, I would argue, can be considered in exceptional responders.
I don't know if, Karen and Libby, you have additional takeaways you wanted to add to this particular case.
Dr. Wulff:
I think that's a great summary, and I think this continues on the theme of... A lot of the theme from, I would say, 2010 to 2020 was about treatment intensification. And now, I think a lot of what we're seeing is treatment personalization and a lot of what you raised really falls into that framework.
Dr. Autio:
Well said.
Dr. Choudhury:
Okay. So, that brings us to the end of the case. Please see the other segments for further discussion about the latest research in prostate cancer or visit ascopost.com.
