Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treatment Yields to Promise and Progress

I am grateful to UroToday for giving me the platform that this Center of Excellence allows. I have dedicated my career to the care of men with metastatic castration-resistant prostate cancer (mCRPC), the development of therapies to treat it, and (hopefully) thoughtful analysis of the biological, clinical, and even societal factors that characterizes it. A forum to generate and share ideas is a gift.  


Recently, however, it dawned on me that calling this Center of Excellence blog "mCRPC Treatment" was not serving me well in the messaging that I was trying to get across to patients who may read it, colleagues, and clinicians around the world. It felt too limiting. I, therefore, requested that the name of this blog be changed to "Progress and Promise in Advanced Prostate Cancer". Doing so allows me to think and write in a little bit more of a broad fashion and to recognize that a focus on mCRPC alone misses the opportunity to evolve as our management of the disease evolves.



Changing the name of the Center of Excellence blog has allowed me the opportunity to consider some thoughts on the language and labels we use in this disease and how, over time, some of them have, and may yet, become obsolete.

For starters, one word that you rarely hear when describing prostate cancer is 'stage IV'. I never tell a patient that he has stage IV prostate cancer and I discourage learners from using the term. I recently co-authored a paper with an epidemiologist where we examined the outcome of patients listed in a large national database as 'stage IV at diagnosis'. This database was created about 30 years ago so I understand the usage, but in terms of documentation, my thought was that this is more aptly termed “de novo metastatic castration-sensitive prostate cancer (mCSPC)”. Stage IV just isn’t descriptive enough because it is not really prognostic – a patient with de novo mCSPC may respond to treatment for many, many years, compared to a patient with mCRPC, and yet they both have 'stage IV' disease.

So why and when did we start calling it mCRPC in the first place? Believe it or not, the term mCRPC really only came into widespread utilization during the time when abiraterone and enzalutamide were going through their regulatory approval processes. Prior to that, we used the term HRPC or hormone-refractory prostate cancer. The first reference in PubMed that I could find that used the term 'castration-resistant prostate cancer' was in about 20061 and that was at a time when it was far more common to see 'hormone-refractory prostate cancer' or 'androgen-independent prostate cancer' both of which are not used with as much frequency now. In fact, 'hormone-refractory prostate cancer' has pretty much disappeared (Figures 1-3 below).

Second, why the “m”? The lower case m is also a product of the regulatory construct and even the early marketing approaches that were developed for the messaging the approval of abiraterone and enzalutamide. Back in the "HRPC" days, after the approval of docetaxel, the extent of disease was a bit of a blind spot for those of us doing clinical trials with novel agents we wished to insert in the 'pre-chemotherapy' space. This was where we used ketoconazole, nilutamide, DES, and other things. This was where I cut my teeth as a clinical researcher and this was where we ultimately did the COU 302 study and other studies that opened the door not only to some new therapies but also to new ways of classifying the disease and outcomes of patients on therapies and clinical trials.

It was the recognition that HRPC could respond to hormonal therapies like the androgen lowering effects of abiraterone or the AR blocking effects of enzalutamide that drove the realization that HRPC was not the best term, hence the development of CRPC to denote a disease and regulatory framework – the disease has metastasized, and it has progressed despite a castrate level (≤50 ng/dL ) of total serum testosterone. The determination of mCRPC created a framework for the communication of clinical-stage, availability of therapies, and clinical trial eligibility. It was and is a very useful shorthand.

So what does this have to do with my blog?

Well, my hope is to address the need for next-level thinking about prostate cancer staging, language, and clinical states. A few opportunities for taking down the limitations of discussing “mCRPC Treatment” include the following:

  • mCRPC treatment is becoming mCSPC treatment: Treatments for CRPC are moving into the CSPC space and we may be able to consider their potential value across the full spectrum of the disease - we may in fact need to get more facile in the use of the terms 'first-line, second-line' etc. One important aspect of this is we need to get the word out, because in the United States currently, although we know there is a significant advantage to the early use of abiraterone, enzalutamide, docetaxel, and apalutamide, there are still many, many patients who are not getting these agents in the CSPC state where they can be maximally leveraged to improve patient outcomes.
  • Non-metastatic is actually metastatic: The "m" in "mCRPC" is increasingly a relative construct defined by antiquated imaging techniques and not recognizing the fact that we are really talking about "systemic disease" that is not always confined to three-dimensional metastases. I was struck by the paper by Fendler and colleagues in 2019 that evaluated 200 patients with “nmCRPC” on conventional imaging and reported that PSMA PET was positive in 98% of them and in 55% of them, distant metastatic disease was present.2
  • It's systemic disease: Even if the advanced imaging is negative, we are better off referring to the disease as "systemic disease" rather than create a false binary definition of non-metastatic or metastatic. Sure, this worked for regulatory approval of apalutamide and darolutamide, but mostly because of the scanning technology available in the everyday clinical settings. This is about to change with the recent Federal Drug Administration (FDA) approval of Ga-68-PSMA PET scanning.

Thus, for now, we have settled on calling it "Progress and Promise in Advanced Prostate Cancer". I appreciate the latitude and the opportunity to discuss the challenges we face together and, most importantly, the progress we are making against them.

Growth of the term Castration Resistant Prostate Cancer

Figure 1. Growth of the term "Castration-Resistant Prostate Cancer" on PubMed.

Decline of the term Hormone Refractory Prostate Cancer on pubmed

Figure 2. The decline of the term "Hormone Refractory Prostate Cancer" on PubMed.

Androgen independent Prostate Cancer use on Pubmed

Figure 3. "Androgen Independent Prostate Cancer" use on PubMed.

Written by: Charles Ryan, MD, B.J. Kennedy Chair in Clinical Medical Oncology, Professor of Medicine and Director of the Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota

References:
1. Attard, G., D. Sarker, A. Reid, R. Molife, C. Parker, and J. S. De Bono. "Improving the outcome of patients with castration-resistant prostate cancer through rational drug development." British journal of cancer 95, no. 7 (2006): 767-774.
2. Fendler, Wolfgang P., Manuel Weber, Amir Iravani, Michael S. Hofman, Jérémie Calais, Johannes Czernin, Harun Ilhan et al. "Prostate-specific membrane antigen ligand positron emission tomography in men with nonmetastatic castration-resistant prostate cancer." Clinical Cancer Research 25, no. 24 (2019): 7448-7454.