Barata on the Latest Updates in Metastatic Prostate Cancer

Pedro Barata, MD, MSc

Patients with microsatellite instability–high, mismatch repair–deficient prostate cancer, and patients who have high tumor mutational burden are likely to benefit from treatment with checkpoint inhibitors.

According to Pedro Barata, MD, MSc, it is expected that 2%-3% of prostate cancers have microsatellite instability or high tumor mutational burden, and these tumors are known to be responsive to immune checkpoint inhibitors. Patients with homologous recombination deficient tumors are also known to respond to PARP inhibitors. However, Barata notes that there are many other biomarkers, including PSMA.

In addition to these therapies and emerging biomarkers in the metastatic prostate cancer space, Barata, director, Clinical Genitourinary Medical Oncology Research Program, UH Seidman Cancer Center, and associate professor of Medicine, Section of Hematology and Medical Oncology at Case Western University, discussed that while immunotherapies have led to an unfortunate response rate of around 10% among patients, targeted therapies have shown potential. Some of these therapies include PARP inhibitors, PSMA-targeted therapy, and BiTE therapy.

Moving forward, many ongoing studies in the space are focusing research efforts to further evaluate PARP inhibition and treatment based on homologous recombination status. Still, there are many unmet needs, including racial disparities and limited access to care, that must be addressed to better outcomes for patients with this disease.

In an interview with Targeted Oncology^TM, Barata discussed in detail the current therapies available, unmet needs, and ongoing studies for patients with metastatic prostate cancer.

Targeted Oncology: Can you talk about the existing and emerging biomarkers for prostate cancer?

Barata: Prostate cancer is a vast topic. Focusing on metastatic castration-resistant disease, we've been seeing an emergence of molecular profiling, genomic testing, referring not only to somatic testing, meaning what the genomic alterations are in the tumor, but also to germline level, meaning genomic alterations you were born with. There is helpful information that we can get from genetic testing, both germline and somatic, that we can use to make treatment decisions, and all based on their predictive value, in addition to also having some of them having prognostic value.

One example is the story on homologous recombination deficient genes and their ability to predict response to target therapies, such PARP inhibitors, for example. That's a hot topic right now. That's 1 example of that we have others, for example, in 2% or 3% of advanced prostate cancer, we expect microsatellite instability or high tumor mutational burden, and we know those are predictive of response to immune checkpoint inhibitors, for example, so a different therapeutic weapon for those patients. Then we have other kinds of biomarkers. I'm thinking of the expression of prostate specific membrane antigen, PSMA, and the use of a PSMA-based therapy. Or, we can even have this kind of specific alteration genes, for example, TP53, RB1, PTEN, where you basically define molecularly, this aggressive variant, prostate cancer, and for instance, there's data suggesting that for those particular patients, a combination of a chemotherapy regimen of carboplatin and cabazitaxel seems to be better than cabazitaxel alone.

With the emergence of molecular profiling, and as it becomes available, I think we are learning a lot more about how we can start number 1, select treatments for our patients, and number 2, when we will have them available and is that a logic around sequencing them? Is that an optimal sequence? This is emerging and a story is in progress, meaning it's not over, and I think we're going to find out a lot more about this.

What are the latest targeted immunotherapies that have entered the prostate cancer space? What kind of efficacy and safety are we seeing with these drugs?

In general, for unselected men with prostate cancer, immunotherapies are very disappointing. We are talking about response rates around 10%. It's not great, and that is monotherapy. There's some data with combination with checkpoint inhibitors, for example, CTLA4 inhibitor and PD-1, and response rates will be higher in the high 20s. But, in general, they are not considered standard of care because we have other therapeutic options that are able to provide the same, if not better, degree of benefit. The secret here is how do we select our patients? We have no doubt prostate cancer is heterogeneous, therefore, we will find a subset of patients who will benefit from it. The question is, how do we select those? The low hanging fruit would be mismatch repair deficient, germline or microsatellite instability in addition to high tumor mutational burden, however, that represents a small fraction of the population of advanced prostate cancer, again 2%-3% or so.

In addition to that, there seems to be an association between patients who have certain homologous recombination deficient genes and a response to immune checkpoint inhibitors. That number can potentially be higher, including CDK12 and others, where immune checkpoint inhibitors seem to play a role. We have not cleared that out completely, but that's kind of what the field is going.

Then, a completely different scenario would be targeted immunotherapies such as bispecific T engagers where you basically find the BRCA-positive cells, most prostate cancer cells do tend to express the PSMA, and then T cells. Basically, this compound can get them both to chat, meaning to attack the cancer cells. That's a nice different form of immunotherapy. There's a number of them and there's others. We've been talking a bit about vaccination, etc. So immune checkpoint inhibitors, that's perhaps where we have most of the data. We need to explore different immunotherapy agents and hopefully, we'll have good news soon on that.

You talked a little bit about some of the lower activity agents, what are some other unmet medical needs for patients with prostate cancer?

Unfortunately, we're not able to cure the vast majority of patients who present with metastatic prostate cancer. The goal of the game then is to control the disease. Once patients become castration-resistant, meaning once they've progressed despite low testosterone levels, the number of treatments we use, unfortunately, are not able to provide us durable remissions for the most part; we do have a few exceptions, but not for most cases. In other words, patients need 1 treatment after the other, and unfortunately, they tend to progress and ultimately succumb to the disease. So, to me, that's an unmet need.

We've made a lot of progress. The median overall survival right now for mCRPC is beyond 2 years or so and we have patients living with stage 4 prostate cancer for almost 7-8 years. Of course, people are not numbers and some people do better or the same as that and some people don't do as well. I'm thinking patients with aggressive disease, a lot of disease, or those with high volume disease, or with newly diagnosed metastatic disease, all of these are some of the poor prognostic factors, in addition to AR-V7 or in addition to BRCA. Those patients tend to do poorly. So, all of these are unmet needs.

The other aspect that is relevant is access to care. It is true that we've been talking a lot more about disparities, and that's a good thing. It's quite interesting that patients of African American descent seem to respond the same, if not better to systemic therapies. But when we see that we kind of match patient and disease characteristics, the thing is access. Often, we see African American patients being diagnosed at later stages, not having access to the same opportunities and same therapies. So, to me there is also an unmet need. How can we provide the same level of care to everybody and that takes into consideration economic factors, socio cultural factors, etc. We need to work together to improve them.

Another is access to genetic testing. Right now, numbers for genetic testing in general is around 40%, and we know if we don't test we don't find. Our conversation has been around what targets you can find in the tumor, but you need to test to find that out. And if you do test, the question is, when do you test? Do you test too late in the game, or do you test when you can do something about it? That is also an unmet need, to raise awareness for the importance of genetic testing and perhaps do work to provide the care teams out there with the ability to have the infrastructure to test. It's not easy because it takes time. We also need to then undergo what the results mean, so there are a lot of barriers. I think genetic testing, or the lack of genetic tests, is another unmet need.

You discussed this topic at the ACCC annual meeting and Cancer Center Business Summit. Do you have any key highlights from that presentation?

The basis for our conversation was molecular profiling. There's a lot to be said for each of these groups. For example, if we think of homologous recombination deficient genes and PARP inhibition, the story's not that simple. It seems like different HR means different things as far as predicting activity of PARP inhibition, for example. One thing we learned is that genetic testing is a good thing. The second thing is maybe they are not all the same. Then, we start to learn a lot more about every one of them.

The other example is the PSMA therapeutics, and the question is, where are we going to go? I think it's a fair statement to say that lutetium PSMA is the first of many, and it's not just beta particles, there are also alpha particles. Again, we're talking about the PSMA-based therapy, but that's a big group. Also, we know for example, CPAP mutations and activity of novel immunotherapies or, as I mentioned, aggressive cancer and the role of chemotherapy with platinum-based chemotherapy, all of these are evolving and over time, we're going to start using molecular profiling to help us decide who gets what.

Are there any ongoing clinical trials in this space that you're excited about?

The number of trials ongoing and exciting and it is insanely high for me to mention. There are important studies that are likely going to change practice once they read out. All the therapies that I mentioned have the potential to change practice, and some already did. In the PARP story, we are now trying to understand if there's a synergistic effect for all comers, irrespective of their HR status. We're starting to learn a lot more about them, the studies have been positive, and we've been discussing what that means to patients. We are starting to learn more about combinations, PARPs, immunotherapy, and is also relevant. Also, do we have a role to combine those therapies with targeted therapies? We are doing studies from that perspective. I know those studies are being designed as we speak, so it would be lovely to see what it comes out of that, because I think there's definitely a potential for patients to benefit from it.

Even with chemotherapy, we're starting to get other signatures, then to help select who gets what, based on those signatures. I think it's an exciting time for prostate cancer, for patients, in a sense that they would expect better novel therapies and to get access to them, and also for investigators and in the care teams, because they will have more tools in their toolbox of options for patients. They are very exciting times.