Technological Advances Specify Optimal Therapies in Prostate Cancer

Emerging technologies such as PSMA-PET and magnetic resonance imaging (MRI), as well as increasingly refined molecular tests, are strengthening the prostate cancer treatment landscape, according to Ashley Ross, MD, PhD. In an interview during the 2022 LUGPA Annual Meeting, Ross, an associate professor of Urology at Northwestern University Feinberg School of Medicine in Chicago, Illinois, discussed the evolution of the treatment paradigm, ongoing prostate cancer research, and the unmet needs that remain in this disease.

Could you describe some of the biggest unmet needs in prostate cancer, in your opinion?

Dr. Ross: There have been a lot of advances in prostate cancer, particularly over the past decade or so. Most of the unmet needs, at least in the near term, are going to be about implementing new technologies. If you think about screening, we've had a lot of new tools that have come to bear for prostate cancer screening, in diagnosis of clinically significant disease, different biomarkers that can tell people their risk, use of imaging—MRI should be standard before biopsies—even the techniques we use for biopsy—perhaps transperineal approaches that reduce infection or the need for antibiotics. If we look at use of those across the country, they're not anywhere near 100%. Certainly, there are some health inequities as well that do stratify by socioeconomics, by race, and by location of the individual and the practitioner.

Even more so, if we look at advanced disease—the cancers that have been detected and we know are aggressive—there's been a lot of evidence that multimodal therapy for those men, even in the hormone-sensitive setting, that show that combining 2 or sometimes even 3 agents can increase their overall survival. But implementation of that has also been lagging. So, that's a life-saving therapy that hasn't been used. If we ask, "What is the path toward the next level of discoveries, pretending that we're implementing everything perfectly?", I think the frontier is going to be twofold. In the advanced setting, we have good tools that we can use upfront in the first and second line of therapy. But we still need to deal with transformed, more androgen-insensitive cancers, particularly ones that are moving towards the neuroendocrine or small-cell type. In the localized setting, it's all about reducing morbidity. There have been some advances there on the radiation side, there are some early signals that focal therapy may work. We're constantly improving surgical approaches as well.

You talked a little bit about some of the emerging technologies and advances in prostate cancer treatment. Could you talk specifically about the emergence of PSMA-PET imaging and how it is transforming the field?

That's a great question. For a long time, in prostate cancer, we were imaging it based on things like size of lymph nodes or bone turnover, looking at technetium and MDP in MDP bone scans. PSMA-PET has been in development for a little over a decade, I believe. It's recently been approved in this country for staging, and staging across the board; really, anytime you suspect that there could be metastatic disease, whether that be upfront, or at time of recurrence, or at time of disease progression. It's been shown in randomized trials to be more accurate in all settings, and also more sensitive for detection of small amounts of disease. It's simply better. There's some early evidence that it may improve decision-making and outcomes for patients. What we know for sure is it's just simply better imaging in terms of accuracy.

Right now, because of its superiority, PSMA-PET imaging should be the first thing that you move toward when you're trying to determine whether someone has metastatic disease. As I alluded to, there are still data that need to bear out to see whether use of PSMA-PET imaging to guide your treatment decisions is going to lead to better overall outcomes for patients or not. That still is yet to be determined. There are some controversies there, but at a basic level, understanding where the cancer is in a person's body and how much cancer is in the person's body is going to lead to better management.

What do you think have been some of the top advances in prostate cancer discovery over the past several years?

Over the past several years, I would say, as we mentioned, better imaging, particularly the utilization of PSMA tracers for PET imaging, has been a big advance. The second big advance in the localized disease setting and now somewhat in the more advanced disease setting is the use of genomics and genetics, specifically molecular tests like Decipher that give you better prognostic risk and having that guide you to treatment decisions. In the advanced setting, the biggest things have been understanding that combinatorial therapies upfront using androgen deprivation therapy, but also another androgen signaling inhibitor—perhaps even with chemotherapy in some cases—can improve overall survival. And then in the castrate-resistant setting, there is also the use of genetics to guide therapies like PARP inhibitors. Finally, there is the use of the PSMA as a radioligand to deliver therapeutics like lutetium PSMA. That's been mostly showing efficacy so far in later-stage disease in trials, but it's being trialed now in earlier-stage disease where I think the impact will be even greater; what I mean is earlier treatment lines.

Please discuss your own particular research.

I cover the spectrum of what we were just talking about. My research focuses a lot on using existing tools and implementation of those tools and then doing clinical trials. There was a point, maybe 5 to 10 years ago, where we were really very engrained in discovery of basic things. I had a wet lab where we were doing mouse experiments and genomics. Now, actually, we have a lot of tools available. My passion has been, how do we use them correctly? And then when we're utilizing them, how do we then disseminate that knowledge? Obviously, the standard of how we utilize these things correctly in humans are through trials, and so the more we can put people on trials and do clinical trials, the better it is. For example, we've done different PET imaging trials to look at PET for staging and for identification of local disease. We're using PET/MR in those studies.

In terms of risk stratification, I've done a lot of work with genomics, looking at gene expression and how that can guide treatment decisions, how it can stratify cancers into different subtypes. Now, there's been a new understanding that maybe we can use artificial intelligence on pathology to recognize some of these characteristics in a higher throughput manner. We've done a lot on taking our screening tools together and putting them into different nomograms that can be easily used to identify risk of having prostate cancer and whether you need a biopsy. And then in the more advanced staging, partnering with industry, we're doing many trials at the hormone-sensitive status to see, can we extend overall survival, perhaps with even de-implementing some therapeutics, going to bimodal vs trimodal therapy?