Dr. Alicia Morgans:
Hi, 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. Why don't you please both introduce yourselves? We'll start with you, Dr. Ryan.
Dr. Chuck Ryan:
Hi, I am Chuck Ryan. I'm a GU medical oncologist and I'm at Memorial Sloan Kettering Cancer Center in New York.
Dr. Alicia Morgans:
Wonderful, thank you. Dr. VanderWeele?
Dr. David VanderWeele:
Hey, I'm David VanderWeele, also a GU medical oncologist, and I'm at Northwestern University.
Dr. Alicia Morgans:
Great. It's wonderful to have both of you here. Today, we'll be discussing the treatment and management of metastatic hormone-sensitive prostate cancer with three patient case studies. Our first installment is going to focus on de novo high-volume metastatic hormone-sensitive prostate cancer in a patient who has PTEN deficiency. So, let's get started.
Mr. SR is a 68-year-old man who presented to his primary care doctor for evaluation of worsening back pain after really not coming to his physician visits for the last few years due to concerns around COVID. He has a history of hypertension and arthritis in his lower back, and he's also a current smoker.
He does use omeprazole and ibuprofen as needed, and he's married and has three adult children and five grandchildren, all of whom live nearby and do provide good support. He's a retired construction manager. As he's being worked up for that back pain, his workup shows that he has some L-1 areas that are concerning for metastatic disease and he starts off with x-rays. His PCP after finding that does do some additional lab assessments, which include a PSA, and that's elevated at 23. He goes on for further bone scan and CTs to try to look into this further. As he's completing that workup, the imaging shows that he has multifocal bone metastases consistent with de novo high-volume metastatic hormone-sensitive prostate cancer.
So, now we have this situation. Patient is coming to see you in clinic. Guys, what else are you thinking about when you're considering the workup of this patient? We know there are a lot of things that we could do, including PSMA PET scans, of course, FDG PET scans, there's potentially additional blood work or other testing. Dr. VanderWeele, David, I'll start with you. What else would you think about doing for this patient?
Dr. David VanderWeele:
Yeah, good question. I think probably I'm less reliant on PET imaging at this point. We already know it's high volume. For early on in the diagnosis, I think the value of PET imaging is, especially when patients are oligometastatic disease, and I'm thinking about if there's any role for metastasis-directed radiotherapy. We already know this guy has high-volume disease and so I'm probably thinking more about triplet therapy and focusing on systemic therapy, but I would also be interested in getting genetic testing done. I talk to patients about testing both your genetics and your cancer's genetics.
So, getting germline and somatic testing done, that would probably be a big priority. It helps me figure out how I'm going to think about the cancer and potentially change some approaches to management, if not now, then further down the road.
Dr. Alicia Morgans:
Yeah, I think that's so important and the guidelines for a few years have really recommended germline testing in any patient with metastatic disease, and I think increasingly, we're ensuring that we have NGS somatic testing early on too. You mentioned some of the treatment options. I think it's important for us to explore all of those. So, Chuck, I'll turn to you and ask you what you're thinking about in terms of treatment, but let's imagine that this patient had somatic testing that demonstrated a PTEN deficiency.
What would you think about in terms of treatment generally and then now that we anticipate that we might be able to think about PTEN deficiency as a subset of tumors that might be potentially sensitive to a new group of agents coming around for prostate cancer? I'd love if you could include a little bit of a discussion there as well.
Dr. Chuck Ryan:
Sure. Well, thank you. So, before we get to that, I would like to point out that in this particular case, we have a patient with a high PSA and a positive bone scan consistent with prostate cancer, but we have not yet acquired tissue. So, one of the questions is where do you get the tissue from? Do you do a prostate biopsy? Do you do a metastatic biopsy? Either are reasonable. I tend to defer to a prostate biopsy in most situations like this because you can get a Gleason score that you can't get from metastatic lesions. Sometimes with the metastatic lesions that come from bone, it's hard to decalcify and get a good read on the NGS, et cetera. So, he needs a biopsy. We're going to do next-generation sequencing and then we're thinking about therapy.
First of all, when I talk to patients, I talk about therapies in terms of layers. Layer one of therapy is androgen-deprivation therapy, something to suppress testosterone. Layer two is going to be something to target the androgen receptor more directly. That could be abiraterone. It could be an ARPI such as enzalutamide, darolutamide, et cetera, apalutamide, all of which are indicated and approved in this setting. Then the third layer is a little bit more nuanced because chemotherapy is out there. It has been done. It is not an unreasonable choice for a patient like this. There are other therapies that are coming. So, for example, we just heard at ASCO about the addition of a PARP inhibitor in patients who have a DNA repair alteration.
We don't know if he has that yet because we don't have our NGS back. We talked about PTEN deficiency and that may lead to therapeutic choices. Then finally, there's new data to demonstrate that potentially even a radio ligand therapy in this space could be useful. So, as far as layer three, I need a little bit more data.
Dr. Alicia Morgans:
Yeah, I think that that's totally fair, and I would say even in the last couple of weeks to have new opportunities open up to us in prostate cancer is only making things more complicated. That's for sure. So, David, if you're trying to make a decision with the patient around all of these options and the HRR mutation testing that you've done, both germline and somatic, is negative and you're left with otherwise a doublet ADT-AR pathway inhibitor combination or a triplet ADT-docetaxel chemotherapy and an ARPI combination or this patient has a PTEN deficiency.
We can also think about that, or a combination that would include an AKT inhibitor. How do you think through that and how do you have a conversation with a patient? Are there any prognostic features or clinical features other than the genetic testing that could point you in one direction or another as you're having that conversation?
Dr. David VanderWeele:
So for patients with de novo high-volume metastatic prostate cancer, I do tend to favor a triplet therapy in that setting and talk about an investment of 4 to 5 months of chemotherapy with a worse quality of life with the hope that that pays off in the end with a longer duration and the hormone-sensitive state and with a better quality of life while on hormone therapy maintenance. So, it's always a discussion with folks, but especially in the de novo high-volume setting, that seems to be where there's the most data indicating benefit. Of course, we don't have any trials that show that triplet therapy is better than doublet hormone therapy. Hopefully, we'll have that data soon.
But I think the data for docetaxel, in addition to ADT to me, is pretty convincing that in patients with aggressive disease and high-volume disease, that makes sense. Adding to that, the PSA is elevated, but it's not all that elevated for someone with high-volume disease. So, that also makes me a little bit more worried actually about not being as responsive to AR-targeted therapy. These are softer calls, but in just getting a sense of their overall disease. I think you mentioned we found PTEN deficiency. So, there's data that these cancers tend to have a worse prognosis in general. They also tend to respond to AR-targeted therapies for a shorter duration, so be less responsive.
There is just data presented at ASCO indicating that from the STAMPEDE trial, patients that had activity in the PTEN PI3 kinase pathway seemed to benefit more from docetaxel and less from the addition of abiraterone. So, for multiple reasons, and I think there's other data from CHAARTED that if you have a tumor-suppressor gene loss... Well, if you don't have a tumor-suppressor gene loss, you actually can do quite well with AR-targeted therapies, but that's not the case if you have loss of a tumor-suppressor gene, of which PTEN would be one of them. So, multiple reasons to encourage consideration of addition of docetaxel in our current treatment paradigm. You mentioned upcoming therapies.
So, capivasertib is an AKT inhibitor being looked at in the metastatic hormone-sensitive setting for patients with PTEN loss. We have a report, a release that that was a positive trial, and so that could be an exciting addition in the future. I'm still interested in seeing what that data looks like before I change all the recommendations, but as you said, there's many new options for hormone-sensitive prostate cancer coming down the pike. So, this is already sometimes a more nuanced conversation and soon we'll get even more so. But in the current setting, I think this is the kind of patient I would encourage them to consider triplet therapy.
Dr. Alicia Morgans:
I think that's totally fair and probably a commonly held thought and conversation with patients among people who think about triplet. There's definitely a split in the field. I'm a triplet believer myself, and like you said, we'll have some data at some point that randomizes around the use of chemotherapy that might help us try to understand that a little bit better. But when it comes to that new data, as you mentioned, CAPItello-281, we've had a press release that suggests that this is going to be a positive trial with the combination of abiraterone and capivasertib in this metastatic hormone-sensitive setting vs abiraterone and ADT in both arms, of course.
Chuck, I know that you're interested in designing clinical trials, certainly, and this is an agent that you're interested in doing further work with. So, I'm sure this was an exciting press release. I wonder though, as we think about this rolling into clinic, how do you think about the side effect profile? What are you thinking about? Because if we're using this in combination with abiraterone and it's well understood and very familiar side-effect profile, what else do we have to think about if we are now going to include capivasertib?
Dr. Chuck Ryan:
Sure. So, I would just first say that the exciting thing about this approach is that PTEN loss is not only a marker for drug sensitivity, it's also a poor prognostic marker. So, you have a situation where, as David nicely said, you know that the patient has a more aggressive form of the disease and now we have a treatment for that. So, it's really gratifying that hopefully we're going to have that. It's an oral agent and there are some GI side effects and others that need to be accommodated for. This is going to be a challenge, again, as we think about polypharmacy and drug-drug interactions and whether there's a situation there.
We really need to see the data from the phase III trial to know if there are substantial marrow and other side effects that would preclude long-term dosing. We need to learn as a field with this new therapy, which is by the way, approved for breast cancer, how to do the dose reductions and the dose treatment breaks and all of those types of things that come with a new agent. That is not going to be as straightforward, I don't think, as an AR-targeted therapy is, which I think we're now as a field fairly comfortable with the nuances between the various agents, but I think it's mostly GI side effects that we're going to be looking at as we move forward with this.
Dr. Alicia Morgans:
Yeah, great. Yeah, certainly diarrhea seems to be something that people have to deal with. The other thing that I just wanted to bring up, and David, I would love to hear your thoughts. I think hyperglycemia and blood sugar control can be a challenge with some of these agents. What are your thoughts there in terms of management? I could be wrong, but as I could tell from reading, it looks like patients who are on insulin, insulin dependent diabetes also were excluded from the trial. So, this is definitely something we have to think about.
Dr. Chuck Ryan:
Just to point out, Alicia, that targeting this pathway, there have been other drugs in the pipeline in this pathway that have been basically discontinued because of diabetes related and hyperglycemia related issues.
Dr. Alicia Morgans:
Yes, absolutely. So, we want to make sure that patients are safe. David, what are your thoughts on this on management? Any tips or tricks that you would recommend for people starting treatment with capivasertib?
Dr. David VanderWeele:
Yeah, seconding what Chuck said, new agents and things for us to be familiar with. It's along the lines of mTOR inhibitors for us who also treat renal cell carcinoma, but looking out for hyperglycemia and then also GI side effects. My experience is mostly with other drugs in this category or in this pathway, but the GI side effects can be significant and something to really be looking out. For the hyperglycemia, I don't know, I guess I still need to see the data and see how significant that is. I've heard well also in the GU space, thinking about bladder cancer and enfortumab vedotin and concerns about hyperglycemia. I think there are different thoughts on whether people with insulin-dependent diabetes should be receiving these agents.
On the one hand, they're certainly at higher risk of having worsening hyperglycemia. On the other hand, they're monitoring it regularly and used to that. I think we need to see the data and get a better feel for how to be managing several categories of patients, patients without diabetes, patients maybe at higher risk with pre-diabetes or diabetes that's relatively well-controlled and not checking their blood sugar on a regular basis. Then also patients with more extensive diabetes and requiring more complicated management, but also much more used to regular monitoring and adjusting their medications for that. So, much for us to learn.
Dr. Alicia Morgans:
Agreed. I think we're all excited to try to work out those best practices. So, thank you for talking that through. As we wind down, I would love to hear any comments either of you have or both of you on testing because I think that when it comes to targeted therapies, it's really important to think about the method of testing, both in terms of what was used in registration trials that ultimately can lead to approval of the agents and then what might be used in clinical practice and what our thoughts are on the potential overlap between those. So, Chuck, I'll start with you, and then David, I'll certainly want to hear you chime in and keep in mind that we are winding down. All right, Chuck, go.
Dr. Chuck Ryan:
Sure, I'll be brief. So, we're talking about PTEN testing. PTEN is something that is either present or lost, and that's the issue. It's not necessarily a mutation in all cases. So, there's three ways to do it. NGS, which would be your standard test that you're ordering through one of the commercial vendors where you're looking for your BRCA2, et cetera, et cetera. The other would be that's next generation sequencing. The other would be IHC, which can be done in your pathology lab and you're looking for the presence or absence of PTEN. Then there's the degree of absence which can actually also be quantified. Is it 100% gone? Is it 98% gone?
And we'll see, does that matter in the outcome of the patients? And then the third thing is, and this is what was presented at ASCO, is there is a signature of a PTEN loss, which affects a whole number of other pathways. The recent data was derived from the Decipher test, which is a commercially available test. So, we will see if, A, the Decipher test changes to accommodate that and B, which of those leads to the greatest facility in our ability to use the therapy effectively. So, there'll be a lot more thinking and writing and publishing and presenting on that topic, I think.
Dr. Alicia Morgans:
Great. Thank you. David, final thoughts on that? I do think IHC may have been what was used in CAPItello-281.
Dr. David VanderWeele:
Yeah, I believe you're right that it was IHC. There's another large phase III study with a different AKT inhibitor that was also looking at using IHC to evaluate patients. Actually, in that trial, a select number of patients, they also looked at the DNA level. So, that's the next-generation sequencing, and actually found that the DNA-based assay may have been a bit more effective in identifying patients who benefited from the AKT inhibitor either through loss of PTEN or through activation of other things downstream. So, PIK3CA, the gene for the PI3 kinase gene or AKT1.
So, I don't know what other biomarker testing results we'll get for CAPItello, but my bias is more towards the DNA side or maybe the RNA testing like from Decipher and other tests like that might supersede the protein testing from the immunohistochemistry. This is a case where I'm inclined to not follow what the trial did and what the data tells us because I have a hunch that the DNA may be more useful than the protein level, but hopefully, we'll have more data to help us confirm or refute that.
Dr. Alicia Morgans:
Yes, David, certainly, we all look forward to that and to seeing how it all pans out. So, thank you for that. Let's just review some key clinical takeaways. First, germline and somatic genetic testing are important parts of the workup of patients with metastatic hormone-sensitive prostate cancer. PTEN deficiency is a new biomarker associated with response to treatment with capivasertib plus abiraterone acetate for patients with metastatic hormone-sensitive prostate cancer. When it comes to management of patients who are being treated with capivasertib and abiraterone, this does include monitoring blood sugar levels and there are some specific guidances around how we do that.
There will be on the information from that trial and certainly any package insert should the label be expanded to include prostate cancer and close monitoring and consideration of excluding patients with insulin dependent diabetes are going to be included there, I expect. Diarrhea is a relatively common adverse event during treatment with capivasertib, and so encouraging hydration and management with antidiarrheal agents is recommended. So, thank you. This brings us to the end of this case. Please see the other segments for further discussion about the latest research in metastatic hormone-sensitive prostate cancer or visit ascopost.com.
