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Further Therapeutic Strategies in Metastatic CRPC

Insights From: Evan Yu, MD, University of Washington; Ulka Vaishampayan, MD, Barbara Ann Karmanos Cancer Institute ; Neeraj Agarwal, MD, Huntsman Cancer Institute
Published: Friday, Dec 21, 2018



Transcript: 

Evan Yu, MD:
The idea of combining radium-223 with immunotherapy makes quite a bit of sense. The reason that makes sense is that we’re constantly looking for ways to turn an immune-cold environment, potentially prostate cancer, into an immune-hot environment by getting more inflammatory cells into the tumor.

There are a few studies right now looking at different types of immunotherapies combined with radium-223. The idea is that radium-223 basically releases tumor antigens that serve as more targets for the immune system. There are obviously other ways you could induce that, such as doing external beam radiation. But that being said, there are multiple trials with radium-223. For instance, there’s a trial right now testing sipuleucel-T, which forms an antigen-presenting cell against prostate acid phosphatase, combined with radium-223.

There are also trials with the novel I-O [immuno-oncology] agents, the checkpoint inhibitors that inhibit PD-1 [programmed cell death protein 1] and PD-L1 [programmed death-ligand 1], and that makes a lot of sense too. You release the tumor antigens, hopefully make more antigen-presenting cells, get more tumor inflammation and more cytotoxic T cells into the tumor, and then home in with your PD-1/PD-L1 therapy. There are multiple trials ongoing in that situation as well.

Ulka Vaishampayan, MD: For androgen biosynthesis inhibitors, I would have concerns similar to the abiraterone and radium-223 combination, that there will be an increased risk of fractures. That would need to be evaluated carefully.

Evan Yu, MD: One of the greatest changes that we’re going to see in metastatic prostate cancer is more and more next-generation sequencing. There’s going to be more next-generation sequencing of the tumor itself, but it might move more toward liquid biopsies or circulating tumor DNA. I believe it’s most likely that we will find some of these DNA repair gene alterations will predispose response to PARP [poly ADP ribose polymerase] inhibitors, platinum chemotherapy, and maybe even radium-223.

Additionally, we are looking for microsatellite instability, mismatch repair alterations that lead to hypermutation. This is already in a regulatory approval situation, where you can use pembrolizumab for anybody with microsatellite instability in a solid tumor. This happens anywhere from 3% to 12% of the time in patients with metastatic prostate cancer. Frankly, that’s already a standard of care that we should be considering and using for our patients with metastatic prostate cancer. I just think there will be more and more of it. We’ll have better assays. We’ll understand the predictive value of these biomarkers better in the future.

The second component to that is that there is a difference between somatic and germline. Obviously, germline is inherited, and we might be doing more germline testing as well. The rationale for that is many of these DNA repair alterations are predisposed, not just to prostate cancer but also to breast cancer, ovarian cancer, and GI [gastrointestinal] malignancies. The downstream cascade testing and screening that will occur is going to be very important. Ultimately, we might not just be able to make our prostate cancer patients’ lives better by giving them better therapies, but we might also be able to save a lot of lives through downstream cascade testing and find cancer very early by screening family members who are predisposed to it and curing that before it becomes an issue.


Transcript Edited for Clarity
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Transcript: 

Evan Yu, MD:
The idea of combining radium-223 with immunotherapy makes quite a bit of sense. The reason that makes sense is that we’re constantly looking for ways to turn an immune-cold environment, potentially prostate cancer, into an immune-hot environment by getting more inflammatory cells into the tumor.

There are a few studies right now looking at different types of immunotherapies combined with radium-223. The idea is that radium-223 basically releases tumor antigens that serve as more targets for the immune system. There are obviously other ways you could induce that, such as doing external beam radiation. But that being said, there are multiple trials with radium-223. For instance, there’s a trial right now testing sipuleucel-T, which forms an antigen-presenting cell against prostate acid phosphatase, combined with radium-223.

There are also trials with the novel I-O [immuno-oncology] agents, the checkpoint inhibitors that inhibit PD-1 [programmed cell death protein 1] and PD-L1 [programmed death-ligand 1], and that makes a lot of sense too. You release the tumor antigens, hopefully make more antigen-presenting cells, get more tumor inflammation and more cytotoxic T cells into the tumor, and then home in with your PD-1/PD-L1 therapy. There are multiple trials ongoing in that situation as well.

Ulka Vaishampayan, MD: For androgen biosynthesis inhibitors, I would have concerns similar to the abiraterone and radium-223 combination, that there will be an increased risk of fractures. That would need to be evaluated carefully.

Evan Yu, MD: One of the greatest changes that we’re going to see in metastatic prostate cancer is more and more next-generation sequencing. There’s going to be more next-generation sequencing of the tumor itself, but it might move more toward liquid biopsies or circulating tumor DNA. I believe it’s most likely that we will find some of these DNA repair gene alterations will predispose response to PARP [poly ADP ribose polymerase] inhibitors, platinum chemotherapy, and maybe even radium-223.

Additionally, we are looking for microsatellite instability, mismatch repair alterations that lead to hypermutation. This is already in a regulatory approval situation, where you can use pembrolizumab for anybody with microsatellite instability in a solid tumor. This happens anywhere from 3% to 12% of the time in patients with metastatic prostate cancer. Frankly, that’s already a standard of care that we should be considering and using for our patients with metastatic prostate cancer. I just think there will be more and more of it. We’ll have better assays. We’ll understand the predictive value of these biomarkers better in the future.

The second component to that is that there is a difference between somatic and germline. Obviously, germline is inherited, and we might be doing more germline testing as well. The rationale for that is many of these DNA repair alterations are predisposed, not just to prostate cancer but also to breast cancer, ovarian cancer, and GI [gastrointestinal] malignancies. The downstream cascade testing and screening that will occur is going to be very important. Ultimately, we might not just be able to make our prostate cancer patients’ lives better by giving them better therapies, but we might also be able to save a lot of lives through downstream cascade testing and find cancer very early by screening family members who are predisposed to it and curing that before it becomes an issue.


Transcript Edited for Clarity
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