Treatment Approaches for Aggressive Variants of Metastatic Castration-Resistant Prostate Cancer

Ana Aparicio, MD, MD Anderson Cancer Center, Houston, Texas, reviewed her presentation on aggressive variants of metastatic castration-resistant prostate cancer from the 2022 Great Debates and Updates in Genitourinary Oncology virtual meeting.

Dr Aparicio explains that there is a lack of specific treatment options for these “androgen-indifferent” prostate cancers and outlines data surrounding appropriate treatment approaches for this subset of patients.

Transcript:

Hello. My name is Ana Aparicio. I'm a professor in the Department of Genitourinary Medical Oncology at MD Anderson Cancer Center, and I specialize in the treatment of prostate cancer.

My talk at the Great Debates and Updates in Genitourinary Oncology was discussing the aggressive variants of metastatic castration-resistant prostate cancer. What we discussed was the fact that prostate cancer is a heterogeneous disease, and while the vast majority will have prolonged responses to androgen signaling inhibitors, there's about 20% or so that don't respond as well and are considered androgen-indifferent disease. The androgen-indifferent prostate cancers have very few treatment options, and that's in part due to the fact that we really have never had good markers to identify them, and so they get put in with the rest of the prostate cancers and never had their own treatments or treatments that would be specific to them developed.

I talked a little bit about how we and other investigators, to try to address this issue, initially started by looking at what are called a small cell or poorly differentiated neuroendocrine carcinomas of the prostate, which are most often negative for the androgen receptor signaling, and they're known to be resistant to androgen signaling inhibitors. And as in small cell cancers of other organs, they often respond to platinum-based chemotherapy. Many people have seen that they're, indeed, biologically different to the typical prostate adenocarcinoma that are driven by the androgen receptor, and we also found that there were a number of prostate cancers that, even if they didn't have the small-cell cancer morphology — the small cell-cancer is a diagnosis that the pathologist makes when they look at the tumor under the microscope —

a number of times, we would do biopsies thinking that that particular person would have small-cell cancer based on their clinical presentation, and we were surprised to see that there was no small cell cancer reported by the pathologist, and yet that patient would still have an aggressive course and a virulent disease. That's how we came up with this concept of the aggressive variant prostate cancers, which basically encompass a group of prostate tumors that behave like small-cell cancer, even if they don't have the small cell cancer morphology.

We went on to do a series of clinical trials and showed that, indeed, if you just have the clinical features, these virulent and atypical clinical features of the small cell prostate cancers, you are highly likely to benefit from platinum based chemotherapy as if you had the small-cell cancer morphology under the microscope. We also showed that these aggressive variant prostate cancers are characterized by combined defects in at least 2 of 3 tumor suppressors. You had to have alterations in P53, RB1 and P10. They had to be combined — each of them alone didn't actually characterize these tumors. There had to be 2 out of 3.

Early on, we looked at how to look at those tumor suppressors using immunohistochemistry, or the next generation sequencing, this was all in research settings, and so we've done some work to try to see what the performance of these molecular markers might be in CLIA certified assays and how they related to the transcriptional deficits. I talked a little bit about that, and then we discussed that other people are looking at other potential markers for this subset. Himisha Beltran, MD, out of Dana-Farber Cancer Institute has done a lot of work in looking at DNA methylation markers that could potentially be looked at in circulating DNA.

And then we also discussed the fact that even within the aggressive prostate cancers, there's still heterogeneity, and this is not too different from chronic leukemias and acute leukemias —  the acute leukemias, they're different from the chronic leukemias, but still within the acute leukemias, you have quite a bit of heterogeneity. A lot of people are digging into these variants to try to understand if that heterogeneity has therapeutic relevance, and it's been gratifying to see. And I listed some of these trials, that a number of people are now using these criteria, or at least thinking about these tumors a little bit differently and selecting for them, or at least controlling or thinking of them in their clinical trials.

I think that we'll see that we are set to make a number of advances to treat this subset of disease that desperately needs new treatments and treatments that are specific to them, and I think that's about all we talked about.

Source:

Aparicio A. Aggressive Variants in mCRPC. Presented at the Great Debates and Updates in Genitourinary Oncology; September 28-30, 2022. Virtual.