The Year in mCRPC – an Unobjective Look at Some of 2018’s Best Papers

I love the year-end lists and the person of the year articles that always come out at this time. whether it is TIME magazine or Sports Illustrated or even People magazine (…not that I follow the worlds sexiest man and woman contest that closely), they help us give a perspective of the shifts in our world that occur within a year.

Well, 2018 was quite a year in our world too, both for me personally (A new job, a big move, publishing a book), as well as in the world I write about in this blog ( mCRPC treatment). As we look at CRPC treatment we can be pleased to reflect on a number of developments, both scientifically and clinically, that shape our understanding of the disease and its treatment as well as what we are likely to be doing in the 5, 10 and maybe even 15 years.

At the PCF Annual retreat this year ( It takes place in October – we did a lot of interviews that you can watch on urotoday.com) the top 25 papers of the year were listed.  I have gone through that list and distilled the papers that are most relevant to clinical CRPC care around the world.

These are listed in no particular order, and probably reflect some of my own biases. The truth is there was a lot of great work published in 2018 and I can’t wait to see what the coming year brings too!


1.  HSD3B1(1245A>C) Variant Regulates Dueling Abiraterone Metabolite Effects in Prostate Cancer.1

I wrote a blog entry on this paper and I think it is part of an important story for two reasons. First, the discovery of this variant identifies a subset of the population with a gain of function alteration in the HSD3B1 gene – potentially raising their levels of androgens and resulting in a potentially accelerated progression of prostate cancer.  That’s the bad news, the good news is that this might predict greater efficacy of therapies that lower androgen levels such as abiraterone. Finally, the topic of this particular paper was the effect of this variant enzyme on abiraterone metabolism and the production of abiraterone metabolite that may have antagonistic effects on the androgen receptor. These data give us a window in how the genetics of the host ( the patient) can drive tumor behavior and even responses to various drugs. More to learn on this point I’m sure.

2. Abiraterone Alone or in Combination with Enzalutamide in Metastatic Castration-Resistant Prostate Cancer with Rising Prostate-Specific Antigen During Enzalutamide Treatment. 2

This paper goes a long way to put the “Sequencing” question of abiraterone and enzalutamide to rest. In the study, patients were treated with enzalutamide until disease progression and then were randomized to a switch to abiraterone or the addition of abiraterone ( combination therapy). The results were quite conclusive – not only is there no benefit to the addition of abiraterone to enzalutamide, but there is also really very little benefit to switching from Enzalutamide to Abiraterone alone. Over time we are getting a closer and closer look at this question and the conclusions to me are quite clear – we really only have one shot on goal with next-generation AR-targeted therapies. We should choose EITHER abiraterone OR Enzalutamide, not both together and not both in sequence. More data are likely to emerge as there are a number of studies looking at this or that combination, including the abiraterone and apalutamide combination, but all of these results keep pointing us in the same direction.  More and more I am convinced that we should be putting our clinical trial resources, and most importantly, our patients time, towards other pursuits such as the addition of novel approaches that target mechanisms of resistance. Easier said than done, but in my previous entry on Rb gene mutations, I offer one potential approach  - targeting CDK4/6.

3. Immunogenomic Analyses Associate Immunological Alterations with Mismatch Repair Defects in Prostate Cancer.3

A tremendous amount of excitement surrounds the identification of defective Mismatch Repair (dMMR) status in mCRPC and its association with responses to immunotherapy, as I have written about in previous blog posts. One of the problems in the link between MMR status and responses to immunotherapy is that not all dMMR cancers respond to immunotherapy and that immunotherapy responses are not seen in only dMMR cancers. In this paper published by the Royal Marsden group teamed up with the Stand up 2 Cancer team, next-generation sequencing data from whole exome sequencing (WES) resulted in the identification of two mutational signatures based on dMMR status, Their findings confirm that typically this status is present at the time of diagnosis ( as opposed to emerging as the result of treatment mediated selection pressure) and they identify those tumors that have both defective mismatch repair WITH hypermutation as the ones that are likely to respond to immunotherapy. Interestingly, such tumors also exhibit high levels of PDL-1 expression. So, the immunotherapy and mismatch repair story is in the process of getting clarified for us.

4.  Radiotherapy to the Primary Tumour for Newly Diagnosed, Metastatic Prostate Cancer (STAMPEDE): A Randomised Controlled Phase 3 Trial Parker C,  *on Behalf of the Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE).4

For years we have theorized that treatment of the primary tumor might be of benefit for patients with metastatic disease. This was the case in kidney cancer until very recently, and there are several studies underway in prostate cancer and other solid tumors that are working to address this. In this arm of the STAMPEDE study patients with metastatic disease (both low and high volume) were randomized to receive radiation therapy to the prostate with standard ADT versus no radiation. Interestingly both a failure-free and overall survival benefit was detected with this approach in the low volume group of patients but not in high volume.

So does this change the standard of care? Should we be treating patients with low volume disease with radiation to the prostate? Although the statistical purists may argue about the power of the study to detect such a difference, there were 829 patients low volume patients randomized, and the dichotomous results between the low vs high volume metastatic patients were striking. The hazard ratio for death in the radiotherapy-treated low volume patients was 0.68 with a p-value of about 0.01 for the interaction.

More evidence indeed that low volume metastatic disease patients are distinct from those with a higher burden. The question remains, is radiating the primary simply ‘debulking’ a low tumor volume overall, or does this treatment confer some other as yet unclarified biological advantage? I think of the primary tumor in these cases as a type of ‘metastases spigot’ that, when turned off, will lead to benefits. At some point in the disease volume spectrum, however, the metastases become a secondary spigot. There is a tipping point, which appears to hover some point around 4 metastases, interestingly.

Written by: Charles J. Ryan, MD

References:
1. Alyamani et al. (2018) HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer. The Journal of Clinical Investigation, 128 (8), 3333-3340.
2. Attard et al. (2018) Abiraterone Alone or in Combination With Enzalutamide in Metastatic Castration-Resistant Prostate Cancer With Rising Prostate-Specific Antigen During Enzalutamide Treatment. Journal of Clinical Oncology, 36 (25), 2639-2646.
3. Nava Rodrigues et al. (2018) Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. The Journal of Clinical Investigation, 128 (10), 4441-4453.
4. Parker et al. (2018) Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet, 392 (10162), 2353-2366.
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