Changes in Latitude, Changes in Attitudes…and DABGA

I write today not from the files of the Jimmy Buffet musical collection, nor from a Caribbean Margaritaville-esque cabana, as the reference might suggest (for the unfamiliar, I have been humming his song “Changes in Latitude, Changes in Attitude…for about 2 weeks now)  but rather as a dispatch on the latest development in clinical trials in prostate cancer.  The topic:  Data from the Latitude study that was presented at ASCO by Karim Fizazi and simultaneously published in the New England Journal of Medicine.

We have had a few of these ASCOs and other meetings over the years, where we come back thinking our world has been turned upside down. We think that we need to have a new conversation with all subsequent patients and need to ring up the patients we saw the week before to tell them we have rethought their condition and need to restructure our plan for their care. 

It’s exciting to see progress, even more so when it is unambiguous like this. But like all big headlines, as the data sink in, new questions arise.  I don’t know if there are any psychologists out there who study the process by which clinicians or scientists integrate new data into their thinking, but my own sense is that it occurs in stages. I also suspect that we go through something akin to the stages of grief – even though this clearly isn’t grief. 

The human response to loss, as elucidated by Elisabeth Kubler Ross, is that with loss we go through five discrete stages, remembered by the acronym DABGA:  Denial, Anger, Bargaining, Guilt, Acceptance. And, while grief specialists tell us that this is a complicated, sometimes circular and not always linear process, I’m going to assume linearity.

This is a thought experiment, after all. So, allow me to stream the hypothetical consciousness of a clinician/investigator as it internalizes new clinical trial generically, or in this case is Latitude specifically.

Denial: “Wait, these data can’t be real!” As a researcher, I am trained toward skepticism. This training promotes an assumption that studies will generally be negative. It is a way to temper enthusiasm, manage expectations and is the foundation for all statistical plans – the null hypothesis. Assume the intervention doesn’t work and design your study to refute that assumption – reject the null hypothesis. Thus, good science requires denial.

Anger: (this is hopefully a short-lived, self centered, embarrassing and not altogether productive stage) “Why wasn’t I involved? Why am I not on that paper? I had this idea in 2006  and should have led this study. Boy, I am falling behind, I’m angry for not being at the cutting edge.” Sometimes you will hear this from colleagues ‘they stole my idea for a study’. Yeah, you, me, and about a thousand other people thought this was a good study, but they actually did it and got it done. 

Don’t be angry. It’s a big tent.

Bargaining: “Ok, so maybe these data are a big deal, but I’ll have to give it more thought before I change the way I manage my patients. I’ll need to see the full publication.  I need more data. If you can show me more data I’ll think that this is real. Show it to me now please.” 

Guilt: “Shoot. I should have seen this coming. I mean, its obvious that this innovation was going to be useful. I should have started doing this years ago. I have treated many patients like this, and I should have had the foresight to use this innovative approach.”

Acceptance: “Great, this is the new normal. This is how we do things now. Do we need auth?”

The latitude data in particular is quite impressive. I won’t rehash it here because it is available in the NEJM and the presentations are online. Suffice to say that the simple addition of abiraterone to ADT in patients with metastatic de novo untreated prostate cancer resulted in a substantial improvement not only in progression free survival, but overall survival as well, deflating any argument that early potent hormones leads to some highly resistant tumor that hastens death. 

It is, as Eric Small (disclosure: he’s my boss) brilliantly (disclosure: Even though he is my boss it was still a good discussion) elucidated in his discussion at ASCO, an important milestone in hormonal therapy for men with prostate cancer. What Eric did not point out, but certainly could have, is that this is NOT a milestone in our understanding of disease biology, nor is it a major new category of treatment for prostate cancer. This is really ‘only’ the application of ‘earlier is better’ to prostate cancer, by adding a new layer of hormonal ablation to hormonal ablation. 

The development of abiraterone was an important one in the management of CRPC because it proved that even in ‘hormone refractory’ prostate cancer we can still squeeze a lot of benefit out of hormonal therapy. Now we have shown that more potent hormonal ablation at the outset can improve outcome for the population. At least for most of them. 

We are left with some important questions and challenges for those of us doing clinical research in this space:

  1. What about the 33% who died within 3 years?  Is this a different biological entity that we need to address? My thought is that it is. I am confident that this will be sorted out in the years to come. These early progressors may be those with mixed histologies, small cell, BRCA mutations, etc etc. The good news is we are getting better at acquiring tissue, doing sequencing, asking these questions and doing these trials, so these patients will not be forgotten.
  2. Can we still give Docetaxel? If we do should we start the abiraterone afterwards or during? Yes, we certainly can still give docetaxel. Intuitively it feels like we might be able to address different compartments of disease biology by doing both, or sequencing them. We’ll get a sense of that in the coming years, I’m sure.
  3. Do all patients need to take it for this long? Its not unlike the ADT plus radiation story that has been going on for a long time. If three years of Abiraterone prolongs survival, would 2 years be ok? This may seem like a hum drum question, but consider the differential cost and toxicity of an additional year of abiraterone times many thousands of patients worldwide. Something that needs to be considered for future studies.
There are many other questions. But I’m out of words so will address them later. So there you have it: Jimmy Buffet, Elisabeth Kubler Ross, Eric Small and Karim Fizazi. There’s a crowd.

Written By: Charles J. Ryan, MD