Clinical Cases in Advanced Prostate Cancer - Episode 8

Case 1: Therapy and Long PSA Doubling Time in nmCRPC

Experts in genitourinary oncology discuss how they choose therapy for patients with long PSA doubling times in nonmetastatic castration-resistant prostate cancer (nmCRPC).

Jorge A. Garcia, MD, FACP: After significant discussions between the patient and the providers, darolutamide was initiated in this patient. I think part of that has to do with his prior history of seizure activity. Although, there is a trial called the UPWARD study that Michael Morris, [MD,] and Susan Slovin, [MD, PhD,] from Memorial Sloan Kettering Cancer Center published, aimed at studying enzalutamide in patients who were at risk for seizure activity. I don’t think they saw a significant difference compared to what we have seen in the previous trials with enzalutamide.

But I think that the uniqueness of darolutamide is the chemical structure and the ability to perhaps not have the CNS [central nervous system] and neurocognitive dysfunction that most of you have discussed,by virtue of the lack of penetrance in the CNS.

Mary-Ellen, if this case was identical to what we just reviewed today but his PSA [prostate-specific antigen] doubling time was not less than 10 months, would you have changed your mind as to treatment? If so, what would be your threshold if you were to reconsider therapy for a patient like this?

Mary-Ellen Taplin, MD: That’s a great question. I tend to not prescribe anything to patients with a long PSA doubling time. Usually, you have a sense of who they are from many years of taking care of them before that. They’ve been indolent the whole way through their course, so I wouldn’t prescribe anything.

I generally put them on a monitoring program. We use a lot of 3-month LHRH [luteinizing hormone-releasing hormone] antagonists. The patients generally come in every 3 months, we get a PSA, and then recalculate their doubling time every time we see them. That’s a caveat. Make sure they’re staying favorable. Then I get imaging at least yearly to make sure I know that they’re still nonmetastatic CRPC [castration-resistant prostate cancer]. I generally don’t start them on something else until a metastasis shows up. I don’t use any certain PSA. Again, it’s 10 or 15 [months of doubling time] to start it. They tend to be indolent and they tend to go, time measured in 1, 2, or even 3 years, before they need another treatment. I feel like I’ve served them by not starting a potentially expensive medication that could have a lot of [adverse] effects during that period.

Jorge A. Garcia, MD, FACP: That’s great. I have to imagine that all of us, including the audience, face the same challenges in clinical practice, and that is that once you commit to initiate someone on ADT [androgen deprivation therapy] up front, then they become M0 [nonmetastatic], it’s a very difficult discussion to tell a patient, recognizing the data we have of doubling time, to hold tight when they’re seeing their PSA going up. This is especially true since the beginning of ADT initiation was induced by that rise in PSA to some extent.

Ganesh, since you keep these patients within urology in Dallas, one of the biggest concerns that we have had with this class of agents, which may also be tied to ADT and the lack of testosterone, is bone health. The increased risk for falling, for skeletal-related events, specifically fractures. Do you have a sense in your practices what the true impact of these agents is with regard to bone health in the patients, especially as you see them from the beginning after surgery?

Ganesh V Raj, MD, PhD: Any patient who’s initiated androgen deprivation therapy in our practice immediately sees a bone health specialist. We have people in endocrinology who have taken an academic interest in following bone health. So they all get immediately seen. The moment you start them on ADT, it triggers a referral in the Epic computer system to mineral metabolism and bone health. They get started on vitamin D, calcium, and then they almost always get a DEXA [dual energy x-ray absorptiometry] scan up front within a few weeks of starting ADT. This includes patients going on a year or two of ADT for salvage radiation. Even those patients will get a DEXA scan. And they get follow-up with mineral metabolism. You should really talk to them about the risks of osteoporosis and bone health.

We are very proactive about our approach with bone health. That’s not to say there isn’t a deterioration of bone health. I think all these patients will have some degree of deterioration, but we try to be as proactive as we can, including starting them on denosumab with Prolia or Xgeva, depending on the setting.

Jorge A. Garcia, MD, FACP: I want to remind the audience that toxicity does matter. These agents seem to be super healthy and have great functional capacity. It is great to see PSA reductions. It’s great to see delay in the metastasis-free survival and survival improvement. We cannot deter from those [adverse] effects that many people don’t come complaining of that are critical for us, which are neurocognitive dysfunction, cardiovascular issues, and bone health-related issues. As you think of treatment of these patients, it’s critically important for us to think of the whole patient and not only the prostate cancer.

Just to remind the group, these are the NCCN [National Comprehensive Cancer Network] guidelines for systemic therapy for M0 CRPC.

As the team has alluded to, the main guideline talks about patients with doubling times greater than 10 months, or patients with PSA doubling times less than 10 months. As Mary-Ellen alluded to, usually when you have a patient who is M0 and progressing serologically, who has a doubling time of greater than 10 months, we tend to prefer observation. That’s supported by the NCCN guidelines. If you look at doubling times less than 10 months, apalutamide, darolutamide, and enzalutamide are category 1 agents in this case. As patients progress through that process, there are guidelines that one can follow as to the frequency of imaging and how often you need to get tested with PSA.

Transcript edited for clarity.