How Genomic Biomarkers Aid in Risk Stratification of Prostate Cancer

In part three of this roundtable series, Drs. Irbaz B. Riaz, Chad Cherington, Roopesh Kantala, and James Ewing share insights on the role of genomic biomarkers and the evolving use of doublet and triplet therapies in managing metastatic hormone-sensitive prostate cancer. The panel examines genomic testing, high-risk mutation markers, and practical considerations for treatment stratification. They also explore how patient factors like disease volume, risk profile, and tolerance for side effects influence choices between agents like abiraterone, apalutamide, and darolutamide. This conversation provides a comprehensive overview of balancing efficacy, side effects, and quality of life in tailoring prostate cancer treatment strategies.

Watch part four of this roundtable: Identifying Castration Resistance in Prostate Cancer

_

Dr. Riaz:
What are your thoughts about genomic biomarkers or genomics in risk stratification of these patients? Are you using that in practice? Are you still thinking of this as, you know, very researchy and not really applying to practice? How are you thinking about genomic stratification in in CSPC patients?

Dr. Cherington:
I think for every patient that’s metastatic, we always want to check germline somatic testing. There are markers that might help predict for responsiveness to treatments, but no, I haven’t used those in my practice yet.

Dr. Kantala:
I agree with him pretty much. I mean, definitely in the sense hormone sensitive space, not really much of a use at this time.

Dr. Ewing:
Just the BRCA2 subset, so we are looking at that. But we’re doing genetic testing on new patients coming in, and I think it’s gonna change things in the future.

Dr. Riaz:
Yeah, I think that the field is rapidly evolving and there’s no consistent guiding recommendation to use genomic guided risk stratification in castration sensitive disease. What I’ve been thinking about more recently is the data that has evolved in tumor suppressor genes as a marker to identify high risk patients and SPOP mutations as a marker for patients who are more sensitive to NHT alone. Sometimes, at least in my thought processes, if there’s a patient who has high risk tumor suppressor genes, you know, P53s, PTENS, RBs, I tend to favor triplet therapy in those like adding docetaxel on top of NHTs.

If there’s a SPOP mutation, I tend to think about using ADT plus NHT alone in that setting. But you’re correct that it is evolving. Actually, we have a trial ongoing, which is testing for genomics, and then if there’s an HRR mutation, BRCA and other related genes, those patients could get a PARP inhibitor as well in the CSPC setting. So, no, this is fantastic. I think we are moving into very exciting times and even in CSPC.

So now thinking about data from ARASENS and ARANOTE, you know, I think one of the challenges is again, you know, ARASENS showed that triplet therapy in all comers is better than doublet therapy with docetaxel doublet. And ARANOTE suggests that, you know, that darolutamide doublet is better than single ADT. So I just want to get your final thoughts on how you reconcile this data on a way to use triplets and a way to use doublets.

Dr. Cherington:
I personally wish a trial would combine the two, because one of the questions is, how important is the docetaxel for some of the lower risk individuals? And can you compare that group to those who don’t get double? So triplet therapy versus double therapy with darolutamide in lower risk individuals. I think to me the question is, is there a benefit to docetaxel? I don’t think that’s really been answered by any study yet.

Dr. Kantala:
In my practice, docetaxel is for the high volume, high risk diseases and never with single agent ADT. If that patient is fit enough to handle docetaxel, in my practice, that patient is fit enough to handle doublet therapy, so it’s going always be triplet. I haven’t tried ADT with the docetaxel personally, because if they can’t handle it, they can’t handle even docetaxel.

Dr. Ewing:
Much the same, the triplet regimen, certainly for high volume, high risk disease and good performance status patients, I think that’s considered the standard. Other than that, it’s shared decision making for the other group there on whether they’re doing triplet or doublet.  I really don’t use ADT alone or recommend it that often for patients.

Dr. Riaz:
Yeah, I think all of us kind of agree that, you know, doublet is at least the standard of care; ADT plus NHT and think about adding docetaxel for high risk patients where we see fit. When you are using a doublet treatment option, how do you pick between darolutamide now that ARANTOE data is here, or enzalutamide, abiraterone or apalutamide?

Dr. Cherington:
Yeah, it’s tough. I have my personal biases for darolutamide or apalutamide, particularly for the lower side effect profile, the lower CNS penetrants, but of course, we’ll have to wait for the data to be able to use that in the first line. But otherwise, I’m usually going to apalutamide; a lot of it has to do with financial toxicity or just looking at either side effects or comorbidities. So for someone with cardiovascular disease or hypertension, I might shy away from abiraterone unless that’s the only one that we can afford.

Dr. Kantala:
In general, abiraterone is much more covered and also for slightly higher volume disease or more aggressive disease. I still use abiraterone where I need to, especially higher risk disease, low volume, low risk. I think either of the other two options Dr. Cherington mentioned is very reasonable and well tolerated, actually.

Dr. Ewing:
My preference is for darolutamide or apalutamide when we’re looking at things; the abiraterone, the prednisone can be challenging, but sometimes it’s a cost concern because it’s generic now. So we use a bit of each in different situations depending on the patient, what other medications they’re on, what the comorbidities are.

Dr. Riaz:
So I guess you all agree that there is little to choose in terms of efficacy between these drugs. So really the patient profile access to treatment, which helps us determine which of these agents to pick, I think darolutamide is unique. And with the ARANOTE data, the side effects profile was actually pretty exceptional. It really doesn’t add any toxicity.

Our takeaway message here is that the era of single agent ADT is pretty much gone based on conventional scans. The risk stratification helps us to think about whether we use doublets or triplets. Most patients should be receiving NHT doublets, especially in synchronous high volume patients. For anybody who wants to be treated aggressively and can tolerate chemotherapy, triplet therapy is the best treatment option.

I think moving forward, genomics is likely going to play a role. Right now, there is no guideline based evidence to use genomics to do this risk stratification, but just thinking through these high risk mutations, the tumor suppressive gene expressions and SPOP mutations definitely seem to be where the future is moving. And also I think HRR trials are also coming.

Dr. Kantala:
What I’ve seen in my practice is 50% right under treatment or single agent treatments. Sem of an elderly subgroup still fits. They follow the urologist, the treatments are at the urologist. So I don’t cross lines and say, “let me add this.” So we have to educate them and kind of give our recommendations, but we let the urologist keep treating those patients.

Dr. Ewing:
And under utilization of the bone modifying agents. In castration resistant disease where they’ve been on a DT for a long time and they have extensive bone metastases. It’s something that should not be forgotten.

Dr. Riaz:
I agree that all of us have those patients, where, for whatever the reason may be, we are still using single agents.

Dr. Ewing:
I wouldn’t necessarily change it if it’s working at this point. These are patients we inherit and if they have a very good PSA response, you know, why add?