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Improvements in Detecting and Treating Metastatic CRPC

Panelists: Raoul S. Concepcion, MD, FACS, Comprehensive Prostate Center; Daniel George, MD, Duke Cancer Institute; Alec Koo, MD, Skyline Urology; Phillip Koo, MD, MD Anderson Cancer Center; Neal D. Shore, MD, FACS, Carolina Urologic Research Center
Published: Monday, May 07, 2018



Transcript: 

Raoul S. Concepcion, MD, FACS: I think we’ve all talked about this. We’ve seen this discussed in multiple publications. There have been multiple discussion points about these patients who progress to true metastatic castration-resistant prostate cancer. Phil, is there any role for some of these newer biomolecular imaging tools?

Phillip Koo, MD: Currently, I would not recommend any of these next-generation imaging tools in the M1 CRPC space for patients undergoing therapy. For those patients, it makes sense to stick with the tried-and-true bone scans and CTs, and these need to be tailored based on the type of therapy they’re receiving and how they’re presenting. Again, you guys are the experts on the triggers to image. That being said, I think there are some specific scenarios where we need to be cognizant of the image and interpret it carefully. Clearly, we know that a flare can occur. Radium-223 is a good example of patients who undergo 6 cycles of therapy. I don’t think the St. Gallen recommendations suggest bone scans after your third dose, which a lot of people do. A lot of times that could be misinterpreted as progression when it is a flare. We need to be careful, but we should stick to the tried-and-true CTs and bone scans.

Raoul S. Concepcion, MD, FACS: We know that the current landscape of therapy includes immunotherapy, traditional taxanes, androgen receptor–signaling inhibitors, androgen synthesis inhibitors, and alpha-emitting agents. We know that one of the big unmet needs is having the ability to monitor patients’ progression relative to biomolecular markers, liquid biopsy, and those types of things. Dan, there is a lot of talk on PARP [poly ADP ribose polymerase] inhibitors. What other agents do you foresee, over the next couple of years, coming to the forefront?

Daniel George, MD: I think this is a great opportunity for us to introduce the idea of genetic profiling in this population. The PARP inhibitors give us a really good initial reason to do that. And so, the strategy goes like this: In the metastatic setting of patients—so, this is not for primary prostate cancers, but for cancers that are really stage IV and have gone into the lethal phenotype—we see that about 20%, 25% of tumors will have somatic changes in DNA damage repair pathways. BRCA2 and BRCA1 are sort of the most well recognized, but there’s ATM, CHEK2, and Fanconi anemia.

A number of these genes play a key role in DNA damage repair, that are going to make the tumor susceptible to PARP inhibitors, which are really sort of inhibiting the single-strand repair. So, you have the homologous double-stranded repair pathways knocked out. You’re dependent on that single-strand repair mechanism. When you block that with PARP, they’re particularly sensitive to this. So, that strategy is working, even as single agents. What’s nice is that there is an opportunity to potentially combine those with other strategies in the future, and we’re starting to see that with immunotherapy and other things.

So, for us to be able to treat patients like that, we have to know about this. The best way to know is if we can biopsy that metastatic disease and then profile it. Sometimes, that’s not amenable. The biopsies are hard to get. The bone is hard to biopsy. So, we’ll do things like circulating tumor DNA, which can also be a hint to this. Some of the PARP inhibitors are being developed with companion diagnostics specifically for that purpose. Then, there’s one other approach, and that’s to look at the germline mutation. Historically, we think that we should look for germline changes in the really young patients with prostate cancer. But we also do this in older patients. It’s important to recognize that these changes that we’re looking for are associated with lethal disease, not necessarily the incidence of disease. So, the genes that are associated with prostate cancer incidence are different than the genes that are associated with prostate cancer progression and lethality.

That’s why we think about germline testing in the metastatic setting and not necessarily in the up-front patients with family histories of prostate cancer but no lethal disease. It’s that kind of context, and it doesn’t have to be a prostate cancer family history. It could be ovarian cancer. It could be any sets of multiple cancers. Sometimes, we’ll find things like Lynch syndrome and other things that predispose to other therapies, like immunotherapy. So, not all of this is simply for PARP. PARP is the most common one, and it gives us the opportunity frame, to the patient, how this profiling can be actionable. And just like Phil said about doing the imaging if you’re going to act on it, we want to do this if this is a patient in whom we would actually treat, if they have that genetic predisposition. Germline is not as frequent, but it’s still almost 8% to 10%. So, if you send enough, you’re going to find it.

Transcript Edited for Clarity 

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Transcript: 

Raoul S. Concepcion, MD, FACS: I think we’ve all talked about this. We’ve seen this discussed in multiple publications. There have been multiple discussion points about these patients who progress to true metastatic castration-resistant prostate cancer. Phil, is there any role for some of these newer biomolecular imaging tools?

Phillip Koo, MD: Currently, I would not recommend any of these next-generation imaging tools in the M1 CRPC space for patients undergoing therapy. For those patients, it makes sense to stick with the tried-and-true bone scans and CTs, and these need to be tailored based on the type of therapy they’re receiving and how they’re presenting. Again, you guys are the experts on the triggers to image. That being said, I think there are some specific scenarios where we need to be cognizant of the image and interpret it carefully. Clearly, we know that a flare can occur. Radium-223 is a good example of patients who undergo 6 cycles of therapy. I don’t think the St. Gallen recommendations suggest bone scans after your third dose, which a lot of people do. A lot of times that could be misinterpreted as progression when it is a flare. We need to be careful, but we should stick to the tried-and-true CTs and bone scans.

Raoul S. Concepcion, MD, FACS: We know that the current landscape of therapy includes immunotherapy, traditional taxanes, androgen receptor–signaling inhibitors, androgen synthesis inhibitors, and alpha-emitting agents. We know that one of the big unmet needs is having the ability to monitor patients’ progression relative to biomolecular markers, liquid biopsy, and those types of things. Dan, there is a lot of talk on PARP [poly ADP ribose polymerase] inhibitors. What other agents do you foresee, over the next couple of years, coming to the forefront?

Daniel George, MD: I think this is a great opportunity for us to introduce the idea of genetic profiling in this population. The PARP inhibitors give us a really good initial reason to do that. And so, the strategy goes like this: In the metastatic setting of patients—so, this is not for primary prostate cancers, but for cancers that are really stage IV and have gone into the lethal phenotype—we see that about 20%, 25% of tumors will have somatic changes in DNA damage repair pathways. BRCA2 and BRCA1 are sort of the most well recognized, but there’s ATM, CHEK2, and Fanconi anemia.

A number of these genes play a key role in DNA damage repair, that are going to make the tumor susceptible to PARP inhibitors, which are really sort of inhibiting the single-strand repair. So, you have the homologous double-stranded repair pathways knocked out. You’re dependent on that single-strand repair mechanism. When you block that with PARP, they’re particularly sensitive to this. So, that strategy is working, even as single agents. What’s nice is that there is an opportunity to potentially combine those with other strategies in the future, and we’re starting to see that with immunotherapy and other things.

So, for us to be able to treat patients like that, we have to know about this. The best way to know is if we can biopsy that metastatic disease and then profile it. Sometimes, that’s not amenable. The biopsies are hard to get. The bone is hard to biopsy. So, we’ll do things like circulating tumor DNA, which can also be a hint to this. Some of the PARP inhibitors are being developed with companion diagnostics specifically for that purpose. Then, there’s one other approach, and that’s to look at the germline mutation. Historically, we think that we should look for germline changes in the really young patients with prostate cancer. But we also do this in older patients. It’s important to recognize that these changes that we’re looking for are associated with lethal disease, not necessarily the incidence of disease. So, the genes that are associated with prostate cancer incidence are different than the genes that are associated with prostate cancer progression and lethality.

That’s why we think about germline testing in the metastatic setting and not necessarily in the up-front patients with family histories of prostate cancer but no lethal disease. It’s that kind of context, and it doesn’t have to be a prostate cancer family history. It could be ovarian cancer. It could be any sets of multiple cancers. Sometimes, we’ll find things like Lynch syndrome and other things that predispose to other therapies, like immunotherapy. So, not all of this is simply for PARP. PARP is the most common one, and it gives us the opportunity frame, to the patient, how this profiling can be actionable. And just like Phil said about doing the imaging if you’re going to act on it, we want to do this if this is a patient in whom we would actually treat, if they have that genetic predisposition. Germline is not as frequent, but it’s still almost 8% to 10%. So, if you send enough, you’re going to find it.

Transcript Edited for Clarity 
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