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 at Memorial Sloan Kettering Cancer Center in New York.
Dr. Wulff:
And I'm Libby Wulff. I am a genitourinary medical oncologist and palliative care physician at the University of Kansas in Kansas City.
Dr. Choudhury:
And for our second case, we'll discuss the management of PTEN-deficient metastatic prostate cancer. So this case is R.G., who's a 61-year-old man found to have an elevated screening PSA of 36.8, which had increased from 3.9 the prior year. No prior medical history and no medications. He had a CT of the chest, abdomen, and pelvis that showed an enlarged prostate gland extending into the base of the urinary bladder as well as several bony lesions concerning for early metastases. Unfortunately, a bone scan showed diffuse bony metastatic disease. He has an MRI of the prostate, which shows a 66-mL gland with a large PI-RADS 5 mid through apex posterior transition zone lesion with capsular invasion with irregular capsular margin and extensive osseous metastases.
So he undergoes prostate biopsies, which reveal up to Gleason 4 + 5 = 9 prostate adenocarcinoma and intraductal carcinoma. He enrolled in a research study for PSMA PET imaging and mHSPC at our institution, which confirms high-volume metastatic disease involving lymph nodes in the bone, and you can see what the baseline PET scan looks like in the figure here. And his PSA continues to increase over just a few weeks up to 84.75 ng/mL. And so case 2, question one, would you recommend docetaxel for this patient and would results of germline or somatic testing help guide your decision? Libby, do you recommend docetaxel for patients like these?
Dr. Wulff:
Yeah. I would say this is a little tough since this patient has extremely high-volume disease and I do think it's urgent for it to be debulked. I would. I think if I had the luxury of knowing if they had somatic testing available when we were planning treatment or certainly if they had germline, then that could impact it. But I guess my perspective is this patient likely needs to be debulked pretty quickly, so I would tend toward that.
Dr. Choudhury:
So Karen, let's say this patient had less aggressive features and slightly less disease on a PET scan and you're trying to make a decision around docetaxel. Have you ever used biomarkers to help guide that decision?
Dr. Autio:
I mean, I certainly get germline and somatic testing on all of my patients with de novo metastatic disease. At this juncture, it hasn't necessarily impacted my treatment decisions as far as the use of docetaxel, although that's very much an evolving process. And now that we have PARP inhibitors for our patients in hormone-sensitive disease, I anticipate that will start to change my thought processes on docetaxel in high-volume metastatic disease. In terms of other sort of biomarker testing like PTEN loss or Decipher testing, it's not something that I commonly do to inform the first treatment decisions.
Dr. Choudhury:
Yeah, there was very interesting data around the Decipher test from STAMPEDE and from ENZAMET about predicting benefit from docetaxel. So if you have a patient who doesn't have a biomarker that might suggest benefit from a PARP inhibitor and they don't have a tumor suppressor gene alteration based on somatic testing and you're really on a borderline, maybe these Decipher signatures could play a role. But oftentimes patients present in these sort of extreme fashions one way or the other with either this very extreme high-volume disease or with just oligometastatic disease where you're not really making a decision based on biomarkers.
So this patient, similarly to the previous one, was started on degarelix and then transitioned to leuprolide. And he was also started on abiraterone prednisone and we did perform somatic genomic profiling and it revealed two copy deletions of PTEN. And there was also RB and TP53 mutations that were accompanied by single copy loss of both genes. So he is functionally absent from all three of the important tumor suppressor genes in prostate cancer.
And so Libby, this gets back to some questions that we asked before. So this is a patient that you're definitely planning to start docetaxel. When do you actually start the docetaxel in relation to the ADT plus ARPI?
Dr. Wulff:
So I start it about a month in typically, and I would love to say that's highly informed by some data, but that's kind of how I was trained and when I also think we have at least a little bit of a handle on making sure we know what direction either their disease is going or their symptoms are going. So that's usually what we do.
Dr. Choudhury:
And how about you, Karen?
Dr. Autio:
I'm similar. Usually roughly in the 1- to 2-month range is when I initiate the docetaxel. Less commonly, but for a very symptomatic younger patient, I might do it within the first month, but typically more around month 1.
Dr. Choudhury:
Yeah, there is interesting data around the pharmacokinetics of docetaxel where castration actually leads to decrease in docetaxel levels. So there is a higher risk of febrile neutropenia if docetaxel is started too early after starting ADT. So I usually wait for about 6 to 8 weeks before I start. The CHAARTED trial did allow docetaxel up to 120 days, so somewhere within that timeframe is reasonable, but I think that our audience should know that it's not critical to start docetaxel immediately after starting ADT. And in fact, there might be some harms associated with doing so. So this is a patient who has molecularly aggressive variant disease. Karen, do you ever give carboplatin upfront in a patient like this?
Dr. Autio:
Yeah, I think that's a wonderful question. If they're adenocarcinoma despite those multiple tumor suppressor genes, I typically do not use carboplatin. If there are adenocarcinoma with some neuroendocrine features, I would be more tempted to.
Dr. Choudhury:
How about you, Libby? Have you ever done it?
Dr. Wulff:
I have done, it and the patients who have received that from me are the patients who have neuroendocrine features. They don't have small cell carcinoma and they have a really, really, really ugly looking prostate adenocarcinoma with those neuroendocrine features. I've done it a few times, but it certainly isn't a common occurrence for me, at least not yet.
Dr. Choudhury:
And definitely agree. I do it based on the histology and not solely by genomics, but it is something to think about in these bad cases. So imagine now you have this patient and he has this very bulky disease and you have now options with lutetium potentially coming on board and capivasertib was just recently approved and you can think about different scenarios where he has all three tumor suppressor gene loss or just the PTEN loss. How are you going to think through these three agents and strategies in this sort of biomarker selected population, Libby?
Dr. Wulff:
Gosh, that's a really tough... I mean, based on my clinical experience and my understanding of the data, I don't have as much faith in lutetium-177-PSMA-617 for patients whose cancers have these tumor suppressor gene loss. Their response rates seem to be lower to me.
Now I will admit I've never prescribed capivasertib. I didn't have access to those trials, so I've not administered that to patients. And please, I would love to hear from one or both of you regarding comparisons with that agent and docetaxel if it's available and I'm unaware because that certainly could be the case. But I would personally favor the capivasertib over the lutetium if that's the choice. But certainly I know we have access to docetaxel too, so I think that's particularly hard.
Dr. Choudhury:
So how do you think about the difference between capivasertib and docetaxel? I've not prescribed capivasertib either, so we're all flying blind, but we're going to be facing this decision.
Dr. Wulff:
Again, so for PTEN loss, if I have a patient who I don't think that they can tolerate chemotherapy, patients who won't receive chemotherapy, I would very much consider capivasertib for that patient if their cancer has PTEN loss. And it looks to me like responses are at least comparable depending on some of the patterns of PTEN loss. So it would be on offer, but I have more comfort with docetaxel and understanding what we can expect from that in terms of response.
Dr. Choudhury:
So if a patient is a chemotherapy candidate, your inclination is still towards docetaxel?
Dr. Wulff:
I think at this moment, yes, I do.
Dr. Choudhury:
I agree, and I'll talk about my thoughts too. Karen, what are your thoughts?
Dr. Autio:
Yeah. So first off, I think for patients with PTEN loss, we have probably two good options, at least two good options on the table because PTEN is predictive of response to docetaxel, but also to capivasertib. So it's not that we're in a lamp where we don't have options for these patients.
I think in the CAPItello-281 trial, I don't believe they allowed anybody with prior docetaxel on, though unfortunately we can't say, well, we'll use our docetaxel in combination with ADT and abiraterone, and then when they've completed their docetaxel, then we'll do capi as an adjunct. I think that would be wonderful to be able to feel confident in offering that, but I won't offer that because we don't have that data to suggest. I think ultimately it'll be sort of an individualized decision and there may be certain factors. An insulin-requiring diabetic is probably not a great candidate for capivasertib, but may still be a very good candidate for docetaxel. A patient who doesn't want docetaxel, I would offer capivasertib.
Dr. Choudhury:
I mean, diabetics are also hard for docetaxel because of the neuropathy risks, and especially the need for the steroids with the docetaxel can also exacerbate blood sugar. So it's very challenging situations. I think one thing that does provide discomfort with docetaxel is that it stops after six cycles. So you do the 18 weeks and then you're done and you can always dose reduce or stop. And with capivasertib, it is an ongoing drug. So I think for patients with strong contraindications to chemotherapy, it's great to have this option. But for patients who are really good candidates for both, I think it's really hard to know for an individual patient what's going to be the most favored strategy.
And the other thing is that for patients who do start on an agent like capivasertib or a PARP inhibitor, you don't know how long you're supposed to stay on them, especially if you do have an exceptional response. So there's a lot of questions that remain completely unknown and that we're all going to have to navigate because many in the audience will never have prescribed capivasertib either, and they're going to be facing these same situations.
So this patient, after 6 weeks of abiraterone, his PSA went down to 3.61, and that was the timeframe that we chose to start the docetaxel. And then after six cycles of docetaxel, his PSA did go down to 0.25. And again, he was on a research study at our institution and had a research PSMA PET that showed significant improvement from the pretreatment PSMA PET. However, there's obviously these multiple residual sites of active disease and his PSA got down to 0.19 after 7 months of ADT.
So given a persistently detectable PSA and detectable disease on a PSMA PET, do you consider any change in management? And I've listed some options here. So Karen, are there situations when a patient is still technically mHSPC, but they're just not getting the response that you would have hoped for where you think about changing something about their management before they're actually manifesting true CRPC?
Dr. Autio:
I don't think we have good trial data yet to help inform us as to what to switch to or add to. So I guess of the ones on the list, the switch to an AR antagonist, definitely not. Capivasertib, again, I think that's a gray zone. We don't know if that's going to be an appropriate sort of adjunct medication. Lutetium, sort of the same.
Niraparib might be one where I'd really think about it because at least with Amplitude, there were a percentage of patients that did have prior docetaxel. So if this patient also had a BRCA mutation, I think it would be reasonable to give them abiraterone and niraparib. But generally speaking, I would say I tend to just monitor closely and then intervene upon progression.
Dr. Choudhury:
So let's say his PSA went from 84 to 5 and that was where it got to at the end of docetaxel. Does that change anything or do you still just wait until the PSA goes the other way before thinking about doing anything different?
Dr. Autio:
That would be a scenario where if they were a BRCA patient, I would think about adding on a PARP.
Dr. Choudhury:
Yeah, I definitely agree.
Dr. Autio:
But the other things I wouldn't change.
Dr. Choudhury:
How about you, Libby? What are your thoughts?
Libby Wulff:
I agree. I don't know that I would augment with a PARP if they had had a PSA complete response. And even if they've had PSA 90, we think the data looks pretty good about outcomes for patients who get to that point. But I do think if they didn't have a great response, especially if they didn't have a PSA 90 response, and then I figured out that they would qualify for if they had a BRCA mutation, then I would really think about intensifying the regimen that way.
I always debate within myself, am I treating that number to make myself feel better or to actually help the patient? And that's hard because we always are rooting for them. So that can be a little hard for me to discern myself sometimes.
Dr. Choudhury:
I think that there is good enough data to say that PSA less than 0.2 is a prognostically favorable feature. That we're not just treating a number as the number, but it really is actually a very good biomarker for where patients are. I have not done it, but that scenario where a patient with PTEN loss was treated with docetaxel, but didn't have a great response, I would think about doing capivasertib even though those patients weren't enrolled in those trials, just because that patient has sort of manifested that the ADT ARPI docetaxel triplet has not gotten them to where we want them to go. Whether that's going to make some difference in their long-term outcomes I think is totally unclear and those patients were not included in CAPItello.
But I think that we're all just stuck in these gray zones where, as Libby said, we're just trying to do what's right for the patient and have to use very incomplete data to try to make some of those decisions. But in this case, the patient manifested even before any of those considerations came into play because 3 months later his PSA went from 0.19 to 0.80. The PSMA PET did show overall increased extent of radiotracer avid osseous metastatic disease throughout the axial and proximal appendicular skeleton.
So among the many treatment options for mCRPC, we elected for enzalutamide plus radium because he had bone-only disease. He wound up switching from enzalutamide to darolutamide because he was having some fatigue on the enzalutamide. His PSA was going up on the radium. It went from 1.43 to 3.73 on cycle 5 day 1, but his alkaline phosphatase did decrease, and this is what we will commonly see for patients who are receiving radium-223. So it's not by itself alarming.
And in fact, he had restaging imaging and the PSMA PET showed response of most bony sites of disease, but he had two new PSMA non-producing lesions at T4 and L5. And at our institution, we have not only lutetium PSMA, but we have many other PSMA targeted therapies that are under investigation. So the decision was made for radiation to these sites such that he would be a candidate for PSMA-targeted therapy at the completion of radium. So in the therapy trial, what was shown in the comparison of lutetium PSMA vs cabazitaxel is that overall survival was the same no matter which order was picked. However, there were certain biomarkers that did suggest more benefit from one or the other. For example, if there was low SUV at the sites of uptake, those patients did seem to maybe do better with cabazitaxel. So Karen, in a patient like this where you have these two agents or any other patient, how do you make a decision between lutetium vs cabazitaxel as a next line of treatment?
Dr. Autio:
Well, I would say if I had a patient who had new lesions that were not PSMA avid, I typically would get an FDG-PET scan and biopsy as well just because we want to rule out if there was neuroendocrine disease or just poorly differentiated adenocarcinoma. Certainly in the scenario of, let's say it's adenocarcinoma, but there's less PSMA expression or non-PSMA-expressing lesions, that would be a patient I would tend to favor chemotherapy for over lutetium PSMA-617.
Dr. Choudhury:
Absolutely. And Libby, how do you guide patients around this decision?
Dr. Wulff:
Yeah, I agree. I think for this specific patient, I agree that if the patient is completely neutral, they have no preferences, there's nothing related to their decision-making that can contribute, then with this specific patient, I think I would say, "Well, since you had some PSMA non-evident disease, even though we've treated it, that does make me nervous, a little bit less comfortable with lutetium-177, and I would favor cabazitaxel."
But otherwise, we try to be really vigilant about using either one of these therapies. Just like you all, we're getting imaging regularly. We get SPECT scans actually after our doses of lutetium-177, PSMA-617 to look at uptake and are really trying to follow to determine if we need to stop what we're doing and sequence a different treatment in.
Dr. Choudhury:
Absolutely. And another consideration just for everyone's awareness is that we also have a trial called PSMAcTION where the patients are randomized to actinium vs a standard of care. I wanted to leave cabazitaxel as a reasonable standard of care option if he progressed with PSMA-producing disease after lutetium. Obviously, if he progresses with PSMA non-producing disease, then actinium would not be an appropriate strategy at the time of progression. So many things to think about in terms of sequencing.
So these are the key takeaways from this case. Prostate cancer with tumor suppressor gene loss is an aggressive clinical entity for which upfront intensified therapy is clinically indicated. While a PSA declined to less than 0.2 at 6 to 7 months after starting ADT is generally associated with favorable clinical outcomes, reaching this threshold may provide less assurance in molecularly aggressive variant disease. And so the optimal therapeutic approach in the setting is unknown and we still need novel strategies for these challenging patients to manage. So Karen, do you have any last second thoughts?
Dr. Autio:
No, I think I'll just emphasize that we used to think of just sort of doublet vs triplet, but our options within those categories of what we call triplet I think is really evolving beyond just chemotherapy.
Dr. Choudhury:
And Libby, any thoughts on this case?
Dr. Wulff:
Yeah, the only minor thought on the case, which we didn't have time to cover, so I'll just summarize, is just that patients who are getting an ARPI plus radium-223 really just need bone-modifying treatments. I know that's what you did because I know how you practice, but just wanted to remind the audience that that's pretty important for safety for our patients to reduce the risk of fractures.
Dr. Choudhury:
Yes, that patient was already on a bone-modifying agent at the time that he started, but that is an excellent point. So that brings us to the end of this case. Please see the other segments for further discussion about the latest research in prostate cancer or visit ascopost.com.
