GU Oncology Now recently spoke with Andrew J. Armstrong, MD, a physician at Duke Cancer Institute Center for Prostate and Urologic Cancers. Dr. Armstrong discussed the development of new precision medicine approaches to treat advanced prostate cancer.

GU Oncology Now: Can you provide us with some background on yourself?

Dr. Andrew Armstrong: Sure. I’m a medical oncologist at Duke, I’ve been here for 15 years. I run a laboratory and a large clinical trial operation, where, as a GU medical oncologist, I see patients with advanced GU malignancies, particularly prostate cancer, and my lab is focused on how prostate cancer spreads, develops hormone resistance, and we develop precision medicine approaches, particularly using the liquid biopsy approach, to guide therapies and to develop new therapies in men with advanced prostate cancer.

What are the challenges of genetic-based precision medicine? 

Oh, many challenges. Prostate cancer, even 5 years ago, we very rarely would do germline or somatic tumor profiling, and it’s really the advent of the capabilities, both commercial and through regulatory approvals, that have broadened the applicability of germline and somatic profiling, both solid biopsies, like a foundation medicine approach, or liquid biopsies, such as plasma DNA. On the research side, we have been focused on comparing and contrasting different forms of liquid biopsies, such as circulating tumor cell, molecular profiling we helped developed, for example, the circulating tumor cell AR-V7 assay as a precision medicine tool to identify men who may not respond to hormonal therapies.

We’ve also been working with many companies to develop new liquid biopsy tools, such as the assessment of neuroendocrine phenotypes in men with prostate cancer that we published in Clinical Cancer Research this year, that also identified men that are more likely to have an aggressive disease course and a poor response to hormonal therapies. And we know that this neuroendocrine or small-cell phenotype of prostate cancer is one of the hardest to treat. We recently, just this week, launched a large clinical trial that’ll be multicentered, that will be designed to overcome some of those mechanisms of resistance in small-cell neuroendocrine prostate cancer, through what’s called chemohormonal therapy. So we’re excited to be able to offer that to our patients.

Why is precision medicine less prevalent in advanced prostate cancer?

It’s becoming more prevalent. I sit on the NCCN guidelines, and it’s now recommended over the last few years to do germline testing in all men with metastatic prostate cancer, to consider germline testing in men with high-risk disease, and even to consider it in all-comers based on a strong suggestive family history. Somatic and germline testing is now guiding therapies, such as the FDA approvals of olaparib and rucaparib, which are two PARP inhibitors that have provided clinical benefits to men that harbor a homologous deficiencies like the BRCA2 gene mutation.

Olaparib, for example, in the PROfound trial, improved overall survival in this subgroup of patients. So this has really increased the incentive to do the tumor testing, and also the germline testing, because about half of the men that have these alterations, it is inherited, but the other half, it’s specific to the tumor. So really, just doing germline testing would not be adequate, but rather looking at a more comprehensive tumor profiling, either a liquid biopsy or a tumor biopsy can really help guide therapy.

PARP inhibitors are just one category, but immunotherapies are emerging as another category, where patients with prostate cancer that have microsatellite instability, mismatch repair deficiencies, perhaps CDK12 mutations, and a number of other mutations. We recently identified a mutation in a gene called LRP1B that suggests a very strong response to PD-1 inhibition in advanced prostate cancer, which we’ve now extrapolated to other solid tumors. So it’s an exciting time. We’re learning much more about the genome.

We do appreciate that there are limitations in the DNA that the commercial testing may not capture. For example, mRNA variants are not captured in DNA tests, so having parallel assay’s that may assess for mRNA splice variants of the androgen receptor can compliment existing tests. We are working on a large-scale grant to develop assays that can measure androgen receptor genomic structural rearrangements that may predict for poor therapy to drugs like enzalutamide and abiraterone.

But there’s also phenotypes. Phenotypes are a really important aspect of prostate cancer, where for example, the form and function of a tumor may not be fully captured by the DNA sequence. For example, PSMA expression in prostate cancer, probably one of the hottest topics of 2021, where PSMA PET imaging is now FDA approved, and many men worldwide are undergoing this more sensitive prostate-cancer-specific imaging to detect metastatic disease, to target that metastatic disease, either with radiation or surgery, or PSMA-directed therapies, such as PSMA lutetium or bispecific antibodies or CAR T-cells, and knowledge of that phenotype can help direct therapy. But that phenotype is not necessarily known when you do a plasma test or a foundation test. So emphasizing the importance of imaging, such as a PSMA PET scan, to help guide a therapy that’s now life-prolonging based on the VISION study, which is PSMA lutetium, and we’re very hopeful for our patients that we’ll be able to offer that therapy in early 2022.

Can you talk to us about the PROPHECY study?

The PROPHECY study is a multicenter prospective study where men with metastatic castration-resistant prostate cancer were treated with standard of care hormonal therapies, abiraterone or enzalutamide. And these men underwent a liquid biopsy for comprehensive molecular profiling of their tumor DNA and tumor RNA, as well as androgen receptor splice variants, using either the Epic Sciences assay or the Johns Hopkins mRNA assay. The primary results we published in the Journal of Clinical Oncology, and followup results this past year in JCO Precision Oncology demonstrated that the detection of circulating tumor cell AR-V7 was strongly associated with resistance, lack of response, and very short progression-free and overall survival times with enzalutamide or abiraterone, but not with taxane, such as docetaxel or cabazitaxel, suggesting that knowledge of the result of this assay, even independent of other measures of disease burden clinical prognostic factors, could identify men that would not benefit from a hormonal therapy, but could benefit from alternatives.

The clinical cancer research paper you’re describing kind of looks beyond AR-V7 at a new CTC assay called the small-cell neuroendocrine phenotype, which as I mentioned earlier, is associated with a very poor prognosis and a lack of response to all of our conventional therapies. And now we can measure this with a liquid biopsy instead of an invasive tumor-directed biopsy. So this liquid biopsy assay for neuroendocrine disease can help identify men in the future that might benefit from neuroendocrine-specific targeted therapies that could benefit them.

Are you involved in any future studies?

Sure. Patients that come to Duke for their clinical trials have access to first-in-human studies of some pretty interesting new small molecules that are showing some promise, both in the laboratory and in early phase clinical trials. We are working across the board on a range of trials, and we have dozens of trials open across many different disease states in men with prostate cancer, and these include AR degraders, androgen receptor degraders, bispecific T-cell redirectors, so novel immunotherapies against particular targets relevant to prostate cancer, the VISION trial, which was open here at Duke for PSMA lutetium, and we’re exploring new trials to move that therapy earlier into the disease. We are looking at the use of newer hormonal therapies and immunotherapy combinations into earlier disease settings, even into hormone-sensitive disease settings, to see if we can actually improve cure rates, to improve remission, and improve survival in earlier disease settings before castration-resistance takes effect.

We’re also looking at other small molecule inhibitors that are really outside of the box of traditional therapies, very unique inhibitors of hormonal signaling like CBP/p300 inhibitors. We have a first-in-human study called the Courage study, which we presented at ASCO just about 3 weeks ago. Finally, for neuroendocrine patients, this is really a major unmet need, a number of approaches looking at combinations of chemotherapy with immunotherapy, much like how we treat lung cancer that has a small-cell differentiation pattern, to try to improve their outcomes.

Any closing thoughts?

Sure. I would say our DCI center really is a broad center that takes the basic bench research and tries to bring it into clinic, but also it’s interdisciplinary. We work together with our urologists, our radiation oncologists, with our industry partners to really bring these new therapies into earlier disease settings to make a difference for our patients. So we’re excited to work with all of these different partners.