How is Precision Medicine Utilized in Advanced Prostate Cancer?

An interview with Andrew J. Armstrong, MD ScM FACP, Professor of Medicine, Surgery, Pharmacology and Cancer Biology, Director of Research, the Duke Cancer Institute Center for Prostate and Urologic Cancers Divisions of Medical Oncology and Urology, Duke University.

Interviewed by Daniel Tennenbaum, MD, chief resident at the Maimonides Medical Center urology residency program in Brooklyn, New York.

This is the first part of a three-part conversation with Dr. Armstrong. Watch part two here.

Dr. Daniel Tennenbaum: Hello everyone; from GU Oncology Now, I’m Daniel Tennenbaum, a urology chief resident at Maimonides Medical Center in Brooklyn, New York. Today we are speaking with Dr. Andrew Armstrong. He’s a professor of Medicine, Urology and Pharmacology, specializing in the treatment of GU malignancies. Having completed his medical school training at the University of Virginia School of Medicine, he proceeded to train in internal medicine at the Hospital of the University of Pennsylvania, followed by a fellowship in medical oncology at Johns Hopkins. Dr. Armstrong has authored numerous peer reviewed journal articles and maintains a robust clinical practice with a focus on improving care in prostate cancer. Today, Dr. Armstrong will help us gain a better understanding of phenotypic precision medicine and what phenotypic predictors may impact clinical efficacy in advanced prostate cancer. Dr. Armstrong, thank you so much for joining us today.

Dr. Andrew Armstrong: Daniel, thanks for the invitation. It’s a pleasure to be here.

Dr. Tennenbaum: So to begin, Dr. Armstrong, can you please help clarify what exactly is precision medicine and how is it utilized in the care of advanced prostate cancer?

Dr. Armstrong: Sure. So when I think of precision medicine, what I’m thinking of is using a biomarker to guide therapy in a patient who otherwise wouldn’t receive such a therapy. A classic example of this in oncology would be HER2 in breast cancer, where a biomarker, like a protein assay or a genomic alteration in that oncogene leads to a treatment that can block that cancer pathway and results in the better survival of women with HER2 driven breast cancer. An example of this recently in prostate cancer, really the first time for a phenotypic precision medicine target is the PSMA PET scan. I’m sure many of the readers are very familiar with the advances in PSMA PET technology to detect a tracer, but here it’s an example of using a phenotype instead of a genotype to guide therapy. And here it’s probably important to unpack what we mean by the word phenotype.

So everybody’s familiar with genotype or genetic, so that’s something that’s encoded in your DNA and very important. For example, in prostate cancer, you have the BRCA2 gene or BRCA1 and DNA repair alterations, mismatch repair, that’s genotype. Phenotype refers to something that encompasses the form or the function of a tumor, its behavior. And so think of some really classic phenotypes in prostate cancer that we all kind of use clinically when we see our patients. Pain, for example, the pattern of spread of a cancer on imaging, whether a cancer makes a lot of PSA or not, whether it’s AR dependent. Neuroendocrine histology, that’s a transformed phenotype, for example.

And so molecular imaging now can capture phenotype. The PSMA expression as detectable by one of several validated PSMA PET scans can tell you whether your patient has very bright or dim PSMA expression in their tumor. And now it’s tied directly to an FDA-approved therapy that can extend the lives of patients that have PSMA PET positive metastatic castrate resistant prostate cancer. And that’s now called PLUVICTO, which is also PSMA Lutetium-177. So that’s a great example of marrying a precision biomarker, which in this case is a PSMA PET as a tool with something that can improve the survival of our patients and not just survival, but quality of life and delay progression, which is really critical. So that is the only drug right now approved in 2022. And so that’s why we’re covering this today.

Dr. Tennenbaum: Very well, Dr. Armstrong. Thank you for the initial explanation. That’s a lot to unpack.

Dr. Armstrong: Yes.

Dr. Tennenbaum: Let me just delve into some of your responses please. You had mentioned about phenotypic precision medicine utilizing phenotypic biomarkers. So does this involve the use of basket trials to treat patients with perhaps different cancers but similar phenotypic biomarkers?

Dr. Armstrong: It could. I mean, we actually use phenotypes right now in MCRPC treatment. So for example, the FDA approval of sipuleucel-T or PROVENGE is tied to the presence or absence of symptoms. So asymptomatic men with MCRPC and the lack of visceral metastases per NCCN guidelines. And so two phenotypes are represented in the guidance of using that drug in early disease where there’s a lymph node or bone predominant pattern of spread. Likewise, radium or Xofigo is tied to the opposite symptoms and a bone predominant pattern of spread. So there, if you read our NCCN guidelines or the FDA labels, those encompass some phenotypes that we maybe don’t think of as phenotypes, but they are. And those guide our treatment algorithm.

Certainly, when you’re designing a precision medicine trials, a basket trial is sometimes employed to decide between various drugs that may have differential activity depending on patient context. And you’ve probably heard of those with molecular basket studies. Like in prostate cancer, basket studies have been done with homologous repair deficiencies and mismatch repair deficiencies, and that’s also done in lung cancer and breast cancer to try to find new drugs that may have better activity.

You could design a phenotypic precision medicine study along those same lines. As long as the biomarker is reproducible, has analytical and clinical validation, it’s associated with differential outcomes and is targetable by your precision medicine approach, you can design such studies. The VISION Study was not a basket study, it was a randomized trial. All patients had to have the biomarker to get in because it was generally believed and there was good data that if you lack the biomarker PSMA expression, you would not respond to this treatment. The treatment would not be a smart bomb. It would go right past the cancer and the cancer would not be targeted. And so the trial was designed just for patients with positive PSMA PET imaging.

And even in those patients you did see differential activity as we’ve reported it, the GU Symposium and at ASCO just this past year, there’s definitely heterogeneity in the patients who benefit. You have some patients that have very bright PSMA expression throughout their body in their tumors, they have a phenomenal response. There’s patients that have disconnects, some negative and some positive tumors or very dim disease and they don’t have as much of a benefit. So even degrees of precision medicine within a patient with a positive biomarker could be helpful. And certainly as you’re moving towards combination trials or other precision medicine approaches using a validated biomarker that’s a precision biomarker could be helpful.

And different phenotypes exist out there. I mean, it could be the symptom of a patient, the pattern of spread, a PET tracer for whatever tracer you want to measure, a RNA or a protein biomarker. That’s also encompassed within this broad term phenotype because that may not be predictable by the genotype. So PSMA expression, for example, we’re studying right now in circulating tumor cells, and we had a presentation at ESMO in Paris just a few weeks ago where we developed a liquid biopsy for PSMA expression, and that’s a phenotype but it’s using a liquid biopsy, not a whole body PET scan.