Evolution of Phenotypic Medicine in Advanced Prostate Cancer

DANIEL J GEORGE, MD is an oncologist at Duke Cancer Center, and Professor of Medicine, and a Professor in Surgery at Duke University School of Medicine, Durham, NC. He is the Director of the Center for Prostate & Urologic Cancers in the Duke Cancer Institute. His background is in drug development and in biomarkers for genitourinary cancers, but more recently he has focused on real-world applications for advances in genitourinary cancers, in particular prostate and kidney cancers.

Novel therapies, new treatment paradigms

Prostate cancer management has changed completely over the past 10 years, Dr. George notes. Of the therapies currently in use, 90% of the treatments for advanced prostate cancer received regulatory approval during the past decade, he recalls. He predicts that “in the next five years, we’re going to see another handful of therapies come into this field, and as it gets more crowded, and as we turn over into more effective therapies, what will come from that is more precision, more understanding of the disease biology and specifically how to target it.”

This is already happening with this next generation of therapies that have become available in the past few years, he says. Some of these therapies are predicated on genetic alterations in the tumor or in the host, like olaparib and rucaparib for molecularly selected patients with mutations in DNA repair genes. Others are focused on a certain clinical phenotype identified either by patterns of spread or by biologic features of the metastases, like radium-223 for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have symptomatic bone metastases and no known visceral metastatic disease.

Imaging phenotypes in precision medicine

“Phenotypic precision medicine” is a relatively new term to the field, Dr. George notes. “When we talk about a phenotype, most people think about something like eye color or hair color. It doesn’t change the function of the eye or the hair, but it does change its outward appearance. However, phenotypes in prostate cancer are more complex, because some of them have prognostic and biologic implications for the disease.”

“When we think about an imaging phenotype, such as when patients that have a certain fluorodeoxyglucose (FDG) or prostate-specific membrane antigen (PSMA) uptake on a positron emission tomography (PET) scan, we can visualize the tumor directly and we can see tumors that have high, medium, or low avidity for that marker. Then we can see an intratumoral variation between patients, between sites of disease according to high, medium, or no uptake. So phenotypes are really giving us a whole body look. It’s an outward appearance, something that is expressed on typically the surface of cells or within cells, but not necessarily at the genetic molecular level. It really gives us an opportunity, especially with imaging, to look at the sum of all of those features in the patient. That’s particularly important with advanced prostate cancer, where we see greater and greater heterogeneity, not just within the population, but within each individual patient.”

Combining phenotypic and genotypic precision medicine

Prostate cancer is no longer regarded as one disease, Dr. George stresses. “A few years ago, we would call it hormone-refractory or castration-resistant, metastatic or non-metastatic. That was the only terminology that we used,” he recalls. “The fact is, that it is not a monolithic disease,” he stresses. “There’s a spectrum of biology across the population and even within individual patients, particularly as that tumor burden increases. So now I think we’re going to start thinking about PSMA-avid tumors and FDG-avid tumors. Maybe we’ll start looking at neuroendocrine imaging or features. We are already thinking about BRCA2– positive tumors and we may start thinking about PTEN loss or other genetic alterations.”

Some of the genotypic subtypes will be overlaid with phenotypic subtypes, which will lead to enrichment of current therapeutic approaches, Dr. George predicts. “Those therapeutic approaches will get moved into patients earlier and earlier as we begin to look at how to combine those with other settings like androgen deprivation therapy (ADT), then maybe also with the next generation androgen receptor pathway (ARP) inhibitors, or layering with chemotherapy or even other investigational or newly emerging therapies like PARP [poly(ADP-ribose) polymerase] inhibitors or immunotherapy.”

Time of change for clinical practice

“This is a time of change in prostate cancer, not just in the way we treat this disease, but the way that we work up and evaluate this disease longitudinally,” Dr. George says. “As we’ve begun to become systematic in

our approach to genetic profiling, I think we’re going to have to become systematic in our approach to imaging in this disease,” he stresses, acknowledging that this change will be challenging because it will create a different workflow, involving communication with payers and more explanation to patients. “It isn’t simply a time of another therapy now, it is a time of another paradigm

or approach to how we really characterize this disease going forward – to me this is super exciting,” he enthuses, “but it’s also more work.” Oncologists have to embrace changes in the way they practice, and this evolution in precision medicine will be more effective and deliver greater benefits to patients, he believes. “Change is going to become the norm,” he predicts.

Bibliography

Dillard, R. Daniel J. George, MD on Phenotypic Precision Medicine in Advanced Prostate Cancer. August 9, 2021.  Docwire News.