Unveiling the Clinical Potential of ctDNA: Implications for Prostate Cancer Management - Neeraj Agarwal

January 31, 2023

Neeraj Agarwal delves into two ground-breaking studies, discussing the importance of ctDNA testing and the clinical implications of SPOP mutations in patients with metastatic prostate cancer. The first study, led by Dr. Kim Chi, demonstrates that ctDNA testing is a viable alternative to invasive tissue testing, particularly in detecting BRCA and ATM mutations. CtDNA tests showed impressive sensitivity and specificity (81% and 92%, respectively) in detecting these mutations, which are pertinent to homologous recombination repair. This finding has significant implications for the increasing number of targeted therapies being approved for patients. The second study sheds light on SPOP mutations in the context of metastatic hormone-sensitive prostate cancer, a field bereft of useful biomarkers. By analyzing the Foundation Medicine and Flatiron databases, the team discovers that patients with SPOP mutations have a substantially better response and survival rates when treated with ADT plus novel hormonal therapies, as opposed to ADT plus docetaxel chemotherapy. 


Neeraj Agarwal, MD, Clinical Research Innovation, University of Utah Health - Huntsman Cancer Institute, Salt Lake City, UT

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Neeraj Agarwal who is joining us to talk about two recent publications that I think are so incredibly important and clinically useful just right off the bat, right out of publication. And you are involved in both of these really groundbreaking studies. So thank you for talking with me.

Neeraj Agarwal: Thank you. Always a pleasure to be here.

Alicia Morgans: Alright, let's start with the first one.

Neeraj Agarwal: Yes. So the first one is basically showing the utility of ctDNA testing to detect mutations or somatic mutations in our patients with metastatic prostate cancer. So this was a publication which was led by Dr. Kim Chi and published in Clinical Cancer Research a few months ago. And in this paper, the focus was to look for the utility of ctDNA and how good the ctDNA or plasma DNA, plasma cfDNA was as far as detecting BRCA and ATM mutations of concern, and how that correlated with the tissue testing.

So the first paper was focusing on looking at utility of ctDNA testing, of plasma cfDNA testing as far as detection of BRCA mutation and ATM mutation is concerned, in the context of a phase three trial, a PROfound trial. Before I discuss that trial, I would like to highlight the challenges of tissue testing in our patients with metastatic prostate cancer. These are elderly patients. Many of them are frail, many of them do not want invasive testing, especially something like bone biopsies. And even when they have testing, bone biopsies done, many times tissue is not available with sufficient quantity. Many times bone biopsies are done, but they have to be decalcified and that can lead to degradation of the DNA. So there are multiple challenges associated with even obtaining the tissue. But then when you have the tissue available, 31% of patients in the PROfound trial who had tissue available did not qualify for further screening because the tissue was either not of sufficient quantity or quality.

So with this backdrop, this research that was conducted, looking at how good ctDNA is as far as detection of these mutations are concerned. BRCA1, BRCA2, and ATM mutation. Interestingly, and here are some figures, if ctDNA was positive for those mutations, tissue was positive in 81% patients. If ctDNA was negative for these mutations, tissue was negative in 92% of patients. That translates into 80% or 81% sensitivity and 92% specificity of the ctDNA as far as detection of these homologous recombination repair mutations are concerned.

And based on these results, I feel very comfortable in saying, which was also the conclusion of the paper, that ctDNA is very complementary to tissue testing. And in many of our patients, and I suspect in the real world, more than 50% of patients may not be eligible for targeted therapies of any kind because of lack of availability of tissue if you do not rely on ctDNA testing.

So this is just one of those studies which show how important ctDNA testing is going to be moving forward as we have more targeted therapies getting approved for our patients in the clinic, and how important ctDNA testing will be in implementing the results of our phase three trials in the clinic.

Alicia Morgans: Well, I agree with you completely that from a clinical perspective. When we're talking about taking care of patients, this is such important and useful information to really again, characterize that sensitivity and specificity of an alternate approach to our gold standard, which of course has been this tissue based assay, and really ensuring that we have access for patients to the testing that may open the door to these targeted therapies that are incredibly personalized because they're based on the genetic permutations that the patient himself has. This is critical.

So if we find ourselves in that position, having this information I think will be helpful in our clinical practices. So thank you for that and congratulations on that work. Now, the next study that I wanted you to speak about is another study that you and the team have done, and I think this in this study, you and the team really characterized SPOP mutations and the clinical implications of that mutation type, which is something we've talked about a little bit in prostate cancer, but I think continued to need to discuss and to really investigate further just as you did with your team. Can you tell us a little bit about that?

Neeraj Agarwal: So in the metastatic hormone-sensitive prostate cancer, we don't have any biomarkers being used in the clinic unlike several other cancers. Common cancers like breast cancer, lung cancer, colon cancer, we use biomarkers, and biomarkers allow us to personalize medicine. As we all know, for newly diagnosed patient with metastatic prostate cancer, the standard of care is either androgen deprivation therapy plus androgen receptor access inhibitor such as abiraterone, enzalutamide, or apalutamide, and now recently darolutamide or ADT plus docetaxel, and in many patients triplet therapy with ADT plus novel hormonal therapy plus docetaxel. There are many patients who may be able to avoid chemotherapy with docetaxel and may not need those therapies. There are many patients who may be able to deescalate treatment if they're having either severe side effects or who are experiencing exceptional responses, but we don't have any biomarkers to identify these patients. So our effort was basically in the direction of sort of validating a biomarker, which has been around for a long time.

And this is SPOP mutation. We know that SPOP mutation is an earlier mutation. It is present in approximately 10% patients with prostate cancer. This mutation stabilizes androgen receptor. So when prostate cancer happens, this prostate cancer is addicted to androgens. So SPOP mutation means a prostate cancer which is addicted to androgens and it's driven by androgens. Interestingly, this mutation is exclusive of TMPRSS ERG mutations, and we don't see the other more aggressive variants to be associated with this cancer. This mutation such as PTEN loss or RB loss or P53 loss are less likely to be associated with SPOP mutation. So our hypothesis was that patients who have SPOP mutations, they will have very good response and outcomes to deeper androgen blockade with androgen receptor access inhibitors or novel hormonal therapies, but they will not have any differential responses to docetaxel chemotherapy.

In the absence of a prospective trial, the next best avenue was to collaborate with Foundation Medicine and to use the Foundation Medicine database and to connect that with Flatiron clinical information. So Flatiron database clinical information is available in that database. And then we connected that clinical information to the tissue on somatic mutation available on SPOP status. Our eligibility criteria were quite strict. Patients had to be diagnosed with metastatic disease within 30 days of the diagnosis of prostate cancer. They could not have started any androgen deprivation therapy prior to the diagnosis... We basically followed the eligibility criteria we use for phase three clinical trials. So if you were to start ADT it should be within three months of the diagnosis and so on. So if you apply all those strict eligibility criteria from thousands of patients, the number dropped down to approximately 440 patients, which is still a good number. We looked at patients who received ADT plus novel hormonal therapy such as enzalutamide, abiraterone, apalutamide, or who received ADT plus docetaxel chemotherapy. And the outcomes were really remarkable. The results were really remarkable.

The time to castration resistance and overall survival were significantly improved in those patients who had SPOP mutations versus who did not. The hazard ratio was 0.2 for those two variables, which translates into 80% reduction in risk of progression and 80% reduction in risk of death in those patients who had ADT plus novel hormonal therapy and who had SPOP mutation versus who did not. On the other side, if patients received ADT plus docetaxel chemotherapy, there were no differences in outcomes from the perspective of SPOP status. These results were presented in ESMO meeting where we got the best poster award for this research. Obviously we think this is one of the first biomarkers for treatment selection, and of course we can always argue that we need a prospective phase three trial to do that. But pending that, I think I feel very comfortable counseling my patients as far as SPOP mutation status is concerned that this means they can avoid docetaxel chemotherapy and they will do fairly well on ADT plus androgen receptor access inhibitors.

Alicia Morgans: And thank you for that. I think at a minimum it suggests they'll do very well with androgen receptor directed approaches, and I think to your point, does raise the question if that's going to be sufficient that they then don't need that additional benefit from docetaxel. So I think that this is extremely important work and SPOP I think will be increasingly important as we do see our patients in clinic and try to make these decisions with them. I just want to congratulate you and your team for the exceptional work that's been done on these two wonderful publications. And thank you so much for your time and your expertise today.

Neeraj Agarwal:
Thank you for having me. Always a pleasure.