A 67-Year-Old Man With Metastatic Castrate-Sensitive Prostate Cancer - Episode 6
Charles Ryan, MD: CSPC [castration-sensitive prostate cancer] is maybe a slightly different biological entity from CRPC [castration-resistant prostate cancer]. The way I think about it is that CRPC is really an evolved cancer. The term I’ve used my whole career is treatment-mediated selection pressure. That’s basically just a fancy term to say that the more that we apply treatment to this disease that we’re not curing, the more the disease is able to evolve biologically. It just goes to show why CRPC is going to be a potentially more aggressive entity.
What’s really going on there? I think there are a number of factors that come into play. First, this patient had metastatic disease at the time of diagnosis. This is not a person who had a screening PSA [prostate-specific antigen] test and had his prostate removed whose PSA level rose a year later. This is somebody who began to have pain in his back and was found to have metastatic prostate cancer.
Right there you know that this disease is probably more aggressive. In fact, we’ve shown that people who present with metastatic CSPC, for example, tend to have more of the basal subtype of prostate cancer than the luminal subtype, which is more of your typical adenocarcinoma that we see in the localized setting. When people develop from CSPC to CRPC, and in particular when people develop abiraterone-resistant disease, we see a lot of really interesting and challenging genomic alterations: loss of the TP53, which is probably the most important tumor suppressor gene in all of oncology; loss of retinal blastoma 1, or RB1, is very common in that transition. And RB1 is a suppressor of the cell cycle. If that is lost, you get the entity of uncontrolled cell cycling, which leads to tumor growth. It might be 1 of the reasons why chemotherapy is effective in that setting, because that’s essentially what we’re targeting with chemotherapy.
There are other aberrations as well, such as loss of PTEN, which has been known about for a long time. It’s not very common in localized disease, but it’s quite common—in about two-thirds of patients—in metastatic CRPC.
A lot of us spend a lot of time thinking about the biology of this disease and trying to figure out whether we can develop or invent a more targeted approach that hits these mechanisms. As the science continues to advance and continues to work, the need for that science is continuing as we see patients surviving longer, because patients are getting more treatment up front, and then those who develop recurrent disease are going to have more resistant disease. It’s almost an irony. They’re going to live longer, but their disease may be more resistant when it does develop or progress.
The PARP inhibitors and DNA-repair alterations are, of course, an important observation that I touched on previously. Also, I should say that the other reason we should be sequencing tumors is for those rare instances where a patient had microsatellite instable [MSI] prostate cancer, or MSI-high disease.
In a study like this, I would want to know when he’s developing CRPC. I would want to know if he’s developing MSI-high disease. Because if he is, there’s a high likelihood of benefit from immunotherapy. And we’re seeing even complete responses to patients receiving immunotherapy who have MSI-high disease.
This is complicated. It’s actually a really fascinating science and biology, and it’s a real clinical and translational science for us to figure out how we can integrate new therapy into this complicated genomic environment of the transition from CSPC toward CRPC.
In summary, CRPC has gotten to be quite complicated. We have a number of therapies available with a number of mechanisms of action: taxane chemotherapy, AR-targeted drugs, radioisotope immunotherapy, and now the PARP inhibitors. How to use these therapies and how to sequence them are not fully worked out, but there are some highlights that I’ve pointed out here that demonstrate when one might wish to use a therapy at 1 point in the disease course versus another point in the disease course.
As an investigator into new therapies in prostate cancer, I’m actually excited about these findings and look forward to working over the next years in trying to figure out the best algorithm for patients while integrating new therapies and possibly even combinations of the drugs that we’ve discussed today.
Transcript edited for clarity.
Case: A 67-Year-Old Male with Metastatic Castrate-Sensitive Prostate Cancer
Treatment and Follow-Up