Dr. Matthew Rettig Discusses Precision Medicine in Advanced Prostate Cancer

GU Oncology Now sat down with Matthew B. Rettig, MD, to discuss the impact of precision medicine on prostate cancer, the use of phenotypic biomarkers in prostate cancer, and what treatment modalities may shape the future of prostate cancer care.

Dr. Rettig is a medical oncologist who works at UCLA and the affiliated VA in West Los Angeles. He focuses in genitourinary malignancies, including kidney cancer, testicular cancer, and bladder cancer, with a heavy focus on prostate cancer. He conducts basic science research and clinical research with a emphasis on advanced prostate cancer.

How big an impact has precision medicine had on prostate cancer?

Precision medicine essentially is identifying specific features of an individual’s cancer and using that information to improve management. That could be diagnostics, prognostics, or therapeutics. Often we think about precision medicine as using the right drug for the right patient, and that’s the therapeutics aspect to it. That’s often what I focus on in clinical trial development, as well as in basic science. So identifying genetic lesions, mutations, that a given tumor may have and pairing it with a specific drug. When we are able to do that, those drugs tend to have quite a significant impact, often in patients who don’t have a lot of other therapeutic options.

It certainly varies case by case, but I think overall, precision medicine has had a major impact on the management of advanced prostate cancer, and I only see that increasing over time as we learn more about tumors, as we develop better drugs, that can be applied to the clinical space in an ever-increasing number of situations and for an ever-increasing number of mutations.

What are the advantages (and challenges) of using phenotypic biomarkers in prostate cancer?

Sometimes the challenges can include access to the testing. Not all patients will have access to them and not all physicians are aware of them and their potential. I can tell you that I see that quite often, that genetic sequencing that has become more and more the standard of care for advanced prostate cancer, is not always done, but I also see that it is being done more and more frequently in the community. That’s very encouraging.

Other factors that remain a challenge is just how to interpret the data. How do you interpret results when sequencing comes back? There are a lot of features to interpreting a sequencing result, and it’s not that straightforward, so it needs some expertise and experience. That is not always readily available. That’s another major challenge.

What are the advantages of using PSMA-directed modalities in prostate cancer?

Yeah. PSMA is prostate-specific membrane antigen. It’s a protein on the surface of tumor cells, prostate cancer cells, and that protein can be leveraged for imaging for diagnostics. It’s actually another way of performing precision medicine, not just looking at genetics, but also imaging. It’s called an imaging biomarker. There are some major advantages with imaging that is premised on PSMA expression on the tumor cell. There’s a scan that’s developed called the PSMA PET scan, which outperforms all other imaging modalities. Certainly the conventional imaging modalities, such as a CAT scan or MRI or bone scan, and even other advanced PET imaging modalities such as a choline PET or something called a fluciclovine PET.

PSMA imaging outperforms, all of these other types of imaging tests that are available. It’s more sensitive, so it’s more readily able to detect sites of disease than other imaging techniques. It’s also more specific. When it does detect something, it’s much less likely to be a false positive. When we have PSMA imaging at the outset upon initial staging, we know that it outperforms other imaging modalities and it will upstage patients in about 30% of the cases.

Often we have a patient who has localized prostate cancer, and we do a PSMA scan and we find out that the patient actually has metastatic disease. The reverse is also potentially true. Where conventional imaging may show metastatic disease, yet the clinical scenario is inconsistent with metastatic disease, and when we do a PSMA scan, we often find that the patient does not indeed have metastatic disease. So it can both upstage and downstage patients and improve our staging accuracy, and also detect sites of disease that may be undetectable with conventional imaging.

What are some innovations that may potentially shape the future of prostate cancer care?

Yeah, I think we’re seeing those coming to fruition. I think we have diagnostics, as well as therapeutics. In the diagnostic world, we’re seeing PSMA-based imaging, but other imaging approaches are in the pipeline. There’s imaging that can be used to detect the immune cells and specific immune cell types that can be informative and help direct therapy.

In terms of therapeutics, I think of them broadly in three categories for prostate cancer. One would be immune-based therapies. As we learn more and more about how prostate cancers evade the immune system, we’re able to overcome those resistance mechanisms and design immune therapies that may have a greater potential to have efficacy. A second category relates to hormone therapy. Of course, hormone therapy remains the backbone of treatment of advanced prostate cancer. When I talk about hormone therapy, we’re talking about therapies that inhibit the production or action of male hormones or androgens. Even when patients become resistant, or the tumors become resistant, to hormone therapy, interestingly, the tumor is still dependent upon the hormonal milieu, but has adapted mechanisms that bypass traditional drugs.

I think the second category of drugs that will be coming, hopefully in the near future, are drugs that more effectively target the hormonal milieu, and specifically inhibit the male hormone receptor more effectively.

A third category of drugs are what I call targeted therapies, so where we have a specific mutation, let’s say a hyperactivated oncoprotein, something that’s driving the growth of the tumor cell, then we have drugs that can be developed that inhibit that specific protein. So that’s the third category of targeted therapeutics.