What Should We Do with the Exceptional Responders?

I have been thinking a lot about the outliers, the exceptional responders, those rare patients for whom we have cracked the code and end up with a PSA of zero after we treat them with abiraterone, immunotherapy or other treatments - and what to do about them.

Let me give you three brief case vignettes:
  1. A 65-year-old man develops mCRPC and enrolls on a clinical trial of ketoconazole ( this was about 1999). PSA goes from somewhere in the ’80s to zero. He comes monthly to receive his study drug allocation -for TEN YEARs. Then asks if we could stop it. I say yes. Two years later he shows up. PSA still zero. He ‘confesses” to me at that point that he has stopped BOTH the ketoconazole and LHRH agonist….and PSA remains zero. No ongoing therapy, no evidence of disease. Is he cured?
  2. A 68-year-old man develops mCRPC and experiences disease progression despite multiple therapies. His primary tumor is sequenced and he is found to have a mutation of MSH2 indicating MSI high disease. On Pembrolizumab his PSA declines from 160 to zero and he discontinues therapy after 6 doses. Is he cured?
  3. A 58-year-old man presents with low volume metastatic castration sensitive prostate cancer and a PSA of 45. You put him on ADT plus abiraterone. His PSA goes to zero. 12 months later his PSA remains zero and he comes to you complaining of the cost of abiraterone, skin fragility from the prednisone and asks to go off therapy. Is he cured?
All of these scenarios have perplexed me in the clinic as I am beginning to worry that we have entered into an era where some patients are being overtreated, even for metastatic disease. I think we may have some windows of opportunity that are able to open up that allow us to scale back the treatment for some patients.

In the early days of the management of testicular cancer, right after it was determined that curative therapy was possible, a movement to scale back treatment was begun. There was a time when patients received BEPx6, then BEPx4 was shown to be equivalent, and finally BEPx3, for example. This took a few years and of course could only be done because MOST patients were being cured – a totally different situation from what we see now in the world of prostate cancer, where only a minority of patients experiencing these outlier responses to the point where we can even begin to use the “C” Word.

And yet, parallels do exist as we begin to think of various strategies to ‘manage our success’. I have, on certain circumstances like those above, discontinued therapy, but only have done so when I can be assured that I will be able to watch the patient closely and recapture control of the disease if signs of recurrence. I don’t recommend it overall, but rather I recommend that we study it, and only do it off study in very special circumstances.

Here are some points in favor of stopping therapy
  1. PSA is such a sensitive marker of recurrence that it will preceed, by a long shot, any clinical event.
  2. In the case of abiraterone or enzalutamide, it is likely that the bulk of the tumor will remain sensitive to the interventions. Thus, if the patients PSA rises we could always restart.
  3. In the case of immunotherapy, it is unknown whether restarting the treatment will be advantageous, or potentially even harmful
Here are some points that may argue against it
  1. It is a data-free zone. We haven’t done any definitive trials on treatment discontinuation and it is hard to do it in an era of ‘evidence-based medicine’.
  2. We don’t have a way to prove the absence of cancer. All we can do is prove its existence, and while our imaging gets better and better. We may make some progress with circulating tumor cells or cell-free DNA, but the fact remains that the only way to prove cancer is gone is for it not to recur over time.
  3. PSA may not always be the best marker of the resurgence of cancer. We could miss the emergence of a PSA non secreting tumor, that may or may not arise in the form of treatment-emergent small cell type tumors ( more to come on this topic).
  4. It may increase patient anxiety. In the case of a few exceptional responders, or even patients with low volume rising PSA disease who have long term responses to ADT when I recommend that we pare back to therapy, they get skittish and opt to continue. Typically they do so while at the same time minimizing the side effects. I understand this fully and support them.
Recently, a few clinical trials have been proposed that look at this question and I look at this as a good sign. We still have a long way to go to cure this disease of course but the fact that we are already beginning in to look at the way we can cut down the treatment intensity in response to exceptional response is, to say the least, encouraging.
  • Post Script. I started writing this yesterday. I wrote a few paragraphs and formulated some thoughts then stopped and went on to something else. As fate would have it, shortly after this I received a phone call from a patient from my old practice in California. He had been an exceptional responder, with a PSA that went to zero after going on abiraterone and ADT for a paraspinal mass, that we also irradiated. The mass had disappeared and his PSA was zero for several years. So, last year I stopped treatment. He called because his PSA had risen and he was back on the abiraterone and the ADT. Doing fine, no symptoms and not upset. He was actually grateful for the year off therapy. We need trials to find out who could benefit from this approach. With this call, I learned a lesson, even as I was literally writing this out as a lesson!

Written by: Charles J. Ryan, MD
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