Dr. Atish 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, and 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 third and final case, we'll discuss the management of BRCA gene-mutated metastatic prostate cancer. So case 3, K.I. is a 62-year-old man with no prior PSA screening history who presents with severe chest wall and back pain. His past medical history was asthma, hypercholesterolemia, and chronic kidney disease, and he presented with a PSA over 3,000. He had a PET/CT that revealed no PE, but does show metastatic rib lesions greatest in the posterior right ninth and posterior lateral left fifth ribs, numerous bilateral pulmonary nodules, and enlarged prevascular lymph node.
He had an MRI of the cervical, thoracic, and lumbar spine, which shows extensive involvement of the vertebral column, chest wall, and iliac bones. No cord compression, but there was abnormal epidural soft tissue at multiple levels, noticeably at T4, T7 and L1. He has known germline pathogenic BRCA1 mutation. He knows this because he has a family history, he has sisters with breast cancer, and his PSA continues to increase to 6,447 at the time that I meet him. So we urgently gave him degarelix 240 mg and sent him for palliative radiation to the sites with epidural extension at T5 to T8 and a painful site at the left rib. So would you consider a PARP inhibitor an upfront management for this patient? Karen, why don't you start?
Dr. Autio:
We're in a somewhat fortunate place with this case in that we actually know his germline and somatic testing at presentation, in which case with the presence of a BRCA mutation, I certainly would be thinking about a PARP inhibitor in his upfront management, whether to sequence that with docetaxel first and then a PARP inhibitor or just upfront PARP inhibitor I think would be certainly a point of discussion with the patient.
Dr. Choudhury:
So this patient comes to see you, he has had radiation. When are you starting the ARPI and which ARPI are you choosing? And does that ARPI decision then make the decision for you on which PARP inhibitor to use if that's what you're considering?
Dr. Autio:
So usually with the ARPI, I usually start that after the first month, but about 4 to 6 weeks later roughly after starting on ADT. I don't think that your initial choice of the ARPI necessarily has to dictate that it can't be changed. So if for some reason the patient was started on darolutamide and then I found out they had a BRCA mutation and I wanted to use niraparib and abiraterone combination, I don't think that there's any reason why that couldn't be changed. But at the same time, if I was thinking from day 1 they have a BRCA mutation and I'm going to go for abiraterone and niraparib or enzalutamide and talazoparib. If that ends up becoming approved, I probably would just go ahead and start with that ARPI from the onset.
Dr. Choudhury:
So do you have any thoughts between the two regimens?
Dr. Autio:
Well, at this exact moment, I think the only one approved is nirapaparib and abiraterone. So that would be the one that I could offer.
Dr. Choudhury:
Okay, fair enough. You're squirreling your way out of that question. So Libby, what are your thoughts on this patient?
Dr. Wulff:
Yeah, I mean, I do think the data are really compelling for improvement of progression-free survival with the addition of an upfront PARP inhibitor for patients. I think a lot of times these patients with BRCA mutation, I find it harder to salvage and control their cancer after initial progression. And so I do personally find the PFS really motivating to me because I really want them to have disease control for as long as possible for their quality of life and wellbeing, of course. And also to give some important innovation time to percolate and have even better treatments for them on salvage. Yeah, I definitely would think about abiraterone/niraparib for this patient. I would have a very low threshold to do that. I mean, I think again, the question about docetaxel is again, this patient, their cancer needs to be debulked. It's something that could be considered upfront before adding their PARP inhibitor.
Dr. Choudhury:
Yeah. So for a couple points of clarification, this patient did not have somatic testing, so this was just known germline based on family history. Niraparib's label is actually only for BRCA2. So in the hormone-sensitive setting, its approval in CRPC is for BRCA1 and BRCA2. So that is one subtle difference. And very interestingly, if you look at the gene by gene benefit from talazoparib, enzalutamide, BRCA1 is pretty overlapping with one. Granted it's a pretty small number of patients, whereas interestingly, ATM and CDK12 do fall pretty far to the left of that one. So one thing that is also interesting to know with BRCA1 is that there's not always loss of the second copy. In fact, I think that's been reported that happens a minority of the time in prostate cancer. So I do think that in a case like this, somatic testing and knowing if there was loss of the wild-type allele could be helpful if there was a way to detect that.
Now in a patient like this who presents with a PSA of 6,000, I think that it's just hard to know from my perspective whether docetaxel is not going to be beneficial in a patient like this. So I might start with a strategy with an intention of quadruplet treatment where you give the docetaxel upfront and then consolidate with one of the other agents just because of the very significant volume of disease that this patient presented with upfront. So Libby, if you started this patient or any other patient and you're not giving docetaxel, what would you say would be your timing when you would go in with a PARP inhibitor? Because you said you don't start the ARPI until a month has passed in the first place.
Dr. Wulff:
So if I knew I weren't going to be giving docetaxel to the patient, then again, usually my current practice is to, at their first visit, work on getting them on their ADT, talking to them about conceptually that we're going to be augmenting and intensifying their treatment and then getting... That's when I personally, I usually get their somatic testing going at that point in the hope that at their next follow-up we'll have all of that data and can start both at either one or in this case potentially more than one treatment intensification to their regimen. That's typically my practice now, and that usually is between 4 and 6 weeks after their ADT.
Dr. Choudhury:
So you would basically make the decision on the PARP inhibitor plus ARPI combination at that second visit. So you would choose the regimen that you're going through. Do you think that there are patients that you would start with an ARPI first and then do the PARP inhibitor?
Dr. Wulff:
Sure. I mean, I think certainly I certainly have done that as well. That's not what I try to do when we have control over a lot of things, but I've had patients who weren't comfortable with any form of genetic testing, patients who we knew we could use a grant to get them the medicine, but we weren't sure if we could use a grant as quickly to get them testing. And certainly I would want to get their cancer debulked and wouldn't want to wait indefinitely. We're always trying to get patients started within the timeframes that the trial's used. So I don't think there's anything medically or ethically wrong with choosing a combination. I personally don't have a great deal of angst about choosing a combination based on the patient you have in front of you and their needs at the time and then switching to update based on additional data gained. I think that's fine, especially if it's relatively early on. I don't think anything is lost.
Dr. Choudhury:
Yeah. The tricky thing about these trials is that there wasn't 100% crossover at the time of castration resistance. So it is hard to know in whom that you're losing something vs not losing something by just starting with the ARPI and seeing what their response is and that the first indication that things aren't going well, either their PSA isn't getting the appropriate nadir or it starts to tick up. We really don't know because those two strategies weren't compared directly. So when we have our individual patients in front of us, we really have to understand their preferences, their disease burden. Are they really going to tolerate a regimen like talazoparib and enzalutamide, which does lead to a lot of fatigue? And both PARP inhibitors do have a fair likelihood of requiring blood transfusions. So it is definitely meaningfully different in terms of patient experience to be on a triplet that includes the PARP inhibitor than being on an ARPI alone.
And then we just have to help patients make decisions that are correct for themselves about whether that decrease in quality of life is really worth that upfront delaying the progression as Libby had mentioned. It's very challenging in more borderline cases, but obviously this patient had very high-volume disease to start. So I’m going to cheat a little bit and say actually this patient was treated many uears ago the pre-triplet era, and he received CHAARTED docetaxel and his PSA went down to 23.66 on cycle 2, day 1, but then increased to 27.84 on cycle 3, day 1 and then 31 on cycle 4, day 1. And so before triplets were actually approved, we made the decision to just add abiraterone prednisone to the docetaxel and the PSA went down to 1.92.
Unfortunately, he suffered a cardiac arrest that was attributed to ventricular arrhythmia, and that is a concern around many of these agents, particularly abiraterone can increase risk of arrhythmias. And so we held the abiraterone and switched to darolutamide after recovery. And then we discussed prostate radiation based on the PEACE-1 results and the PSA continued to downtrend. It went down to 0.08 again from 6,000 something to start with. So 22 months later, the PSA goes up to 0.70 and PSMA PET demonstrates a solitary site of progression at T9. And so are there situations where you would consider focal treatment to sites of progression or would you just switch this patient to a PARP inhibitor, Libby?
Dr. Wulff:
I will offer patients oligoprogression treatment at times. Some of my radiation oncology partners have done some work in this arena. We've actually had some trials in this arena. And so I do think that it can be appropriate to do so to extend the duration of benefit. I've done that for patients and had patients get years back out of their original regimen by doing so. And of course it depends on the site and the volume of disease that would need to be radiated. If someone popped up with one disease site but many mediastinal nodes and I know they're at risk of esophagitis, I wouldn't offer it to that patient. But if it's a solitary or a couple bone metastases or even a solitary lung metastasis, I'm finding so many more of those now than I ever thought I would in my training just because we're using more PSMA directed imaging. Yeah, I think it's fair game now.
Dr. Choudhury:
Absolutely. And so Karen, so you have a patient, their PSA is rising and it's going from 0.08 to 0.15 to 0.7. And maybe you do some imaging and the PET is kind of indeterminate. The teaching that we've all had in our training is that you should not stop treatment until radiographic progression. And generally that's by prostate cancer working group three criteria. But we're clearly seeing that patients are having rapidly rising PSA even in the absence of that kind of progression. And now that we have more treatment options than just chemotherapy, how are you trying to make that decision for an individual patient for when a new treatment is actually indicated?
Dr. Autio:
Yeah, so I mean it certainly is still very much individualized and for me at least it's not purely confirming radiographic progression of two plus two criteria on a bone scan. And some of it depends on what's the next treatment, what's the next systemic therapy going to be? And a PSA that's rising with not much change on unconventional imaging or not much change on a PSMA PET is not necessarily somebody that needs to jump towards starting on chemotherapy or something that's going to significantly impact their quality of life. On the other hand, if there's a really compelling clinical trial option that's allowing patients to go on with the rising PSA and stable scans, that's certainly a discussion I would have with a patient.
Dr. Choudhury:
Yeah, I definitely consider trials. I definitely still use sipuleucel-T in my practice for situations where you don't need immediate cytoreduction. I often incorporate radium in that kind of setting as well because these are not really debulking agents. So sometimes when patients have relatively low volume of disease, it is a great opportunity for clinical trials and things that are less cytoreductive. But you wouldn't want to do that just for a very slowly rising PSA. So there is a little bit of an art of medicine around when to actually pull the trigger on a treatment switch.
So this patient underwent SBRT to the oligoprogressive lesion at T9 and his PSA went down to 0.51 from the 0.70. And then his PSA goes up to 3.03 months later, and now he has two new lesions. And so I advised this patient, "Well, this is a pretty short interval from the prior SBRT to now have a PSA up to three and two new lesions." So I advised that a switch in systemic therapy is likely to be indicated whether now or pretty soon after next round of SBRT if he chose to do that. But he was planning on some global travel and so he really wanted to hold off on any systemic therapy switch and he got two rounds of SBRT to these two lesions. And then his PSA got to a nadir of 0.05 7 months after the SBRT. And so his PSA at last checked 17 months after this SBRT was 0.15, and it's been 8 years since his initial diagnosis.
So I have some points that I'd like to make on this particular case, which is that one, ADT and docetaxel doublet is no longer recommended given the OS benefit from triplet regimens. Metastatic prostate cancer with BRCA1 and two gene mutations is generally associated with aggressive clinical course and both niraparib plus abiraterone and talozaparib plus enzalutamide have demonstrated an RPFS benefit compared to ARPI alone in mHSPC, but any interpretation of the OS signal by using these agents in HSPC is limited by the incomplete crossover in both trials.
So we talked about the clinical features as well as the patient comorbidities and preferences to guide the decision for upfront PARP and choice of regimen because maybe there are reasons to pick abiraterone vs enzalutamide for a particular patient and that might help guide which PARP inhibitor you might choose. But the last point that I did want to make is that even though many of these patients do have an aggressive clinical course with all the novel treatment options that we have available using PSMA PETs and SBRT for oligoprogression with many clinical trial options, that even these patients can have a pretty prolonged survival after MHSPC diagnosis. And so late-term toxicities are pretty relevant.
So if you have a patient who's starting niraparib plus abiraterone or talazoparib plus enzalutamide and they achieve an exceptional response, trials required you to stay on the PARP inhibitor forever, but we know that prolonged treatment with PARP inhibitors can increase the risk of MDS and AML. So I don't know, Libby, if you have any thoughts around how you were going to counsel patients around these potential risks of catastrophic outcomes, especially if they're doing well from their hormone-sensitive prostate cancer.
Dr. Wulff:
Yeah, that's really hard and scary because I do think the practice of oncology is always a chess match. Whether the patient's aware of that, we're looking for our next move and the one after just as they take their very first step on the first path. So I would want to talk to patients about the question of paring back after, I don't know, I would say an amount of time that is similar to some other treatment holiday studies, 18 to 24 months. And certainly we'd have to see what risks they're willing to take and which ones they aren't. But I do think it's our responsibility to be looking at our future moves so that we can protect them from negative outcomes.
Dr. Choudhury:
And Karen, what are your thoughts on that question and anything else that came up with this case?
Dr. Autio:
Yeah, I think those are great points and it's really important that we're counseling our patients early on. I think just as we got comfortable with the idea of deescalation with ADT and ARPI, we're going to get there with PARP inhibitors and AKT inhibitors as well. I think the other just important take-home message for this particular case for me was despite all of those extremely aggressive features that we saw at diagnosis with high-volume disease, this is still a patient who has done extraordinarily well and oftentimes with some upfront aggressive treatment with systemic therapies, but also incorporating metastasis directed treatment. So I just think it's nice to see sometimes what you see at the onset, you might be thinking about how this patient's going to have a poor prognosis, but in this case, and we all have many like this, our patients continue to do well with hormone-sensitive disease.
Dr. Choudhury:
And this patient has all the options available for everything standard of care and investigational other than ADT or PI at this point. So we hope that he continues to do well. So thank you both so much for your thoughts on all three of these cases. It's been incredibly helpful and I think does reveal a lot of the uncertainties that we're dealing with in this new era of mHSPC management incorporating biomarkers. So I really do appreciate both of your contributions. 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.
