A 66-Year-Old Man With Metastatic Castrate-Sensitive Prostate Cancer - Episode 6
Ralph V. Boccia, MD: We might ask ourselves: Why might multimodality therapy work in a patient with castration-sensitive metastatic prostate cancer? Why would you choose an androgen receptor inhibitor as opposed to something else? We’ve known for many years that prostate cancers in general are driven by the male hormone, androgen testosterone. But what happens at the level of the prostate, especially when resistance develops, is that there is constitutive or constant activation of the androgen receptor in the gland that drives the cancer, no longer requiring testosterone. You’re always going to have testosterone or castration-sensitive cells even later, which is why we continue androgen deprivation therapy even when they become the so-called castration resistance. But that combination of blockade at the prostate level will enhance that activity, which is why we see in TITAN that the results with apalutamide are so much better than with placebo and why the patients might go longer before they develop resistance.
When we follow patients, we have a set pattern for how we follow them. PSA [prostate-specific antigen] has typically been the best measure of how therapies are working in the easiest fashion. You can get a PSA anytime. It isn’t expensive, and typically if patients’ PSAs are elevated and go down, that generally means a response. If they’re lower or whatever level that they go up to, that typically means the patient is progressing.
The progression of PSA does not mean you can measure it any other way. You can’t always measure it radiographically, but it typically means that something is probably happening. Most of us would measure PSAs on some interval basis. It might be measured monthly for a couple of months until you’re sure the patient is responding, and then after that it could be every 3 months. It might be even longer than that, but most of us would probably measure it no less often than every 3 months. If the PSA rises, it’s certainly time to look for radiographic progression, look for the development of new metastases, because that would always indicate that the patient has developed potentially castration resistance.
That said, I want to add 1 caveat to that. Like a lot of tumors, as tumors progress, they often develop multiple mechanisms by which they become resistant. Sometimes the genomics change to the point that, in this case, PSA rise isn’t always measurable. Patients’ tumors may dedifferentiate, and they may no longer produce PSA to the same degree. If a patient develops new symptoms, that’s also a time to be looking for radiographic progression because the PSA isn’t always that perfect indicator.
Anytime you’re faced with progression of cancers in general, typically we always look for a drug that may have a different mechanism of action, presuming that resistance is going to cross over to another drug that happens to have the same mechanism of action. That is why when we had patients in the old days on abiraterone or enzalutamide, although we didn’t have other good options to move to then, chemotherapy was always an option. In a patient who has slowly progressing disease, who you no longer think is responding to the drug you’re using, sometimes we’ll look to use that other drug. We would do that in the old days, but responses are very low, on the order of maybe 10% at best. We really would be looking for a drug with a different mechanism of action.
Today we’re certainly in the targeted drug genomic era. We would be looking at whether we could find another target that we could go after other than the androgen receptor. Earlier on, we would get genomic profiling of the tumor and send off next-generation sequencing, looking for things such as microsatellite instability, DNA repair, and mismatch repair so we could use things like some of the immuno-oncology drugs and some of the PARP inhibitor drugs. But looking for a different mechanism of action should be looked at as soon as you have progression of disease because you may find a unique target where you could find a uniquely specific and effective therapy.
Transcript edited for clarity.
Case: A 66-Year-Old Male with Metastatic Castrate-Sensitive Prostate Cancer
Treatment and Follow-Up