Scott Tagawa, MD, MS, FACP, a professor of medicine and urology, and medical director of the Genitourinary Oncology Research Program at Weill Cornell Medical College, and an attending physician at New York Presbyterian Hospital, discuss the integration of targeted agents in prostate cancer.

Prostate-specific membrane antigen (PSMA)–targeted agents continue to be an area of interest following the first imaging agent approved for patients, Tagawa says. When looking at the retrospective and prospective non-randomized and randomized data, PSMA-directed therapy seems to be safe across patients, although some adverse events of interest have been observed, Tagawa explains.

However, the next phase 3 trial examining the use of these imaging agents is expected to be positive, and should lead to more FDA approvals, Tagawa continues. Additional research is needed to improve upon available options, as well as to further refine patient selection, Tagawa concludes. 

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Scott Tagawa, MD, MS, FACP, discuss the integration of targeted agents in prostate cancer. 


Dr. Tagawa on the Integration of PSMA-Targeted Agents in Prostate Cancer

Let’s talk a little about the data that led to the 18-fluoride DCFPyL PSMA [prostate-specific membrane antigen] PET [positron emission tomography] agent. This was tested in several trials, both with bird-type names. Birds must have very good eyesight, perhaps that’s why. Scott, I’d love to hear you talk through this with us a little bit. The OSPREY trial was started a few years ago and was presented about a year ago in patients with high-risk prostate cancer, some maybe with locally recurrent metastatic disease. Can you tell us a little about the OSPREY trial and the 2 cohorts that were enrolled?

Yes. Let me speak a little more broadly. Both of the FDA-approved tracers were tested in similar ways in terms of grouping patients, in terms of the label, suspected metastatic disease, or basically higher-risk disease prior to primary treatments. For both of the trials, their major readout in that situation was compared to histology and pathology. Then in post-primary treatment, biochemical relapse disease, there were additional data sets.

There are 3 different uses for PSMA PET that are essentially in prime time today. One is deciding on initial treatments, especially it’s helpful to know if there’s something we see outside the prostate or not. Whether that changes things, we don’t know, but it’s still useful information. With biochemical relapse, the major question is, where’s my PSA [prostate-specific antigen] coming from? When there’s surgery and then radiation, the PSA goes up. Localization can be quite helpful. And then, not that we have an approved agent yet, but it can be helpful in treatment selection, or at least optimization for metastatic disease with PSMA-targeted radionuclide therapy.

The 2 data sets, in terms of the preoperative settings, were almost identical. I agree with Phil that there are clear differences in radiochemistry. But for an end user, I don’t think they really matter. It’s probably not addressing the question today comparing both head to head—and there are several more coming—vs figuring out the best use for them and getting long-term data. That’s more important. But it showed basically the same thing, that when compared with the microscope, each one was only about 40%. But when we look at the larger results, in terms of true positivity, then we’re looking at 95% to 98%.

With OSPREY being published relatively recently in the 

, and the Gallium-68 PSMA-11 from UCSF [University of California, San Francisco] and UCLA [University of California, Los Angeles] in press in the 

, we have to put things into perspective, in that the sensitivity of imaging is not going to be down to the single-cell level, like a microscope, especially with a microscope plus immunohistochemistry. But on a practical basis, it especially would expand this and go to something like proPSMA compared with CT and bone scan, then there’s really no comparison. CT, bone scan, and MRI led to some major advances, but not near the sensitivity of PSMA PET. It doesn’t approach the sensitivity of the microscope, but these are some major advances in prime time now.

I completely agree. Certainly, we’re not here to suggest that the Gallium agent is better or worse than the fluoride agent. From my perspective, any PSMA PET imaging that you can undergo is great, and there’s no evidence that either is better than the other. But it’s important to recognize and tell our patients that this will only identify PSMA-positive disease. That can be a challenge sometimes for patients who think, “Any of my disease should be identified.” But that’s not always the case, and we saw that in the TheraP trial. We’ll probably talk about that later. Some disease can sometimes be FDG [fluorodeoxyglucose]-avid, but not PSMA-avid, so it’s important to recognize this is only going to pick up the PSMA-positive disease. Phil, do you have any comments on that?

 That’s a great point. Something that we should re-emphasize is PSMA PET-CT is not perfect. As Scott mentioned, it doesn’t replace a microscope. For some reason, a lot of times I see PSMA PET equated to identifying micrometastatic disease, and that’s not true. It cannot identify micrometastatic disease. By definition, these are things that we’re detecting with microscope, pathology, and tissue. That’s important because it sheds light on the limitations of the imaging modality. Clearly, we’ve seen a lot of the trials that use PSMA PET to identify patients who will be treated and how they’ll be treated, like those oligometastases types of trials. What we see is those patients still recur. That’s because even though we might see 1, 2, or 3 lesions on a PSMA PET, in reality, there are maybe additional nodes that have micrometastatic disease that we’re not seeing with PSMA PET. It’s because we need a certain threshold of cells that are expressing the PSMA receptor in order to detect it on the PET-CT technology, on the hardware.

Great. Thank you for clarifying that. Although it’s a great way for us to identify low volumes of disease, it will not be able to replace a microscope.

An interpretation of the OSPREY study of 18F-DCFPyL injection in patients with high-risk prostate cancer and implications of its use.

PSMA-Targeted 18F-DCFPyL PET/CT in High-Risk Prostate Cancer

Sandy made a comment on this previously. Scott, before we move on to some imaging-based biomarkers, I want to hear your thoughts on how you’re testing for somatic mutations in particular. Because as Sandy mentioned, many of our patients have bone metastases. Not as many have accessible lymph node or visceral metastases that we can easily biopsy and sequence. What are your thoughts about bone metastases and tissue biopsies vs using prostatectomy specimens vs using liquid biopsies, which are available but not always concordant with our tissue samples?

Optimally, for any given patient, it’s best to use a plethora of different tools. On a practical basis, I agree that getting a tissue-based biopsy at any given time is often the most invasive and difficult. There’s a fairly large percentage of patients, at least by standard imaging, who have bone-only metastasis. That being said, we can get information. About 5 years ago, we published our bone biopsy series, and I believe 85% of the bone biopsies were diagnostic, with 82% able to do whole-exome sequencing and a little less in terms of RNA-seq [RNA sequencing]. So it’s possible.

The caveat is the patients who we thought we probably couldn’t do, like those with a very small rib metastasis, for instance. But that being said, it’s possible. And at least as of today, we get the most depth of analysis from a tissue biopsy. But as I tell patients—you mentioned heterogeneity—we get a great depth of whatever is in the needle, and that’s it. The same tumor in a different location may be a little different. That’s where I think of the addition of blood-based biomarkers, which are clearly the easiest in my mind, as long as someone doesn’t have a hematological malignancy for germline.

I would clarify circulating tumor DNA a little differently than cell-free DNA. Circulating tumor DNA, where we have a germline-matched sample, is very good. It’s not as sensitive, but we can really trust those results. When we have cell-free DNA without a germline sample, we have to worry about clonal hematopoiesis. Just a thought. But we want to take every test into context and at least give prognostic information, which will help guide treatment choices, but also, particularly in the setting of different therapeutic interventions, it can probably give some predictive information to a subset. That subset is 0 if you don’t test.

I couldn’t agree more. And to emphasize that there can be challenges with those cell-free DNA assays having CHIP, or clonal hematopoiesis of indeterminate potential, particularly on genes like 

, it’s so important to make sure you can match with a germline sample. All patients with advanced prostate cancer, high-risk localized or metastatic hormone-sensitive and beyond, are eligible for germline testing at this point in time. They’re not just eligible, it’s recommended. Thank you for clarifying that.

Dr Scott T. Tagawa comments on the pros and cons of liquid and tissue biopsies used to assess patients with advanced prostate cancer.

Tissue and Liquid Biopsies in Advanced Prostate Cancer

 titled, “Evolving Management Landscape for Advanced Prostate Cancer.” My name is Alicia Morgans, and I’m an associate professor of medicine in the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago, Illinois. Joining me today in this discussion are my colleagues and friends, Dr Phil Koo, the chief of diagnostic imaging at the Banner MD Anderson Cancer Center in Phoenix, Arizona; Dr Scott Tagawa, the medical director of the GU [Genitourinary] Oncology Research Program at Weill Cornell Medicine in New York; and Dr Sandy Srinivas, a professor of medicine in the division of oncology at Stanford Medicine in Palo Alto, California.

As we are just past the midpoint of 2021, it has been another year stocked with practice-changing advances in the field of GU oncology. In prostate cancer, several recent FDA approvals have been granted. Today, we will discuss evolving approaches that are transforming how we think about precision medicine in prostate cancer, as well as how we’re using systemic therapies for advanced prostate cancer. We’ll focus on the latest research in the context of existing standards of care and highlight practical implications for patient care. Let’s get started on our first topic.

In our first segment, we’ll be talking about how we’re moving toward precision medicine in advanced prostate cancer. Let’s start by thinking about that topic in general. What is precision medicine? And what is precision medicine when we think specifically about prostate cancer? Sandy, what do you think when we think about this particular topic?

 It is individualizing therapies for patients. Our colleagues in lung cancer have done a remarkable job of biopsying after every single therapy, at progression, and tailoring therapy to what an individual needs. It’s been challenging in prostate cancer, given that our patients have predominantly bone disease. The field hasn’t yet completely gone into having a comfort of analyzing tissue from bone. But for the first time ever, we have therapeutics in prostate cancer based on mutations and altered mutations, so we’re getting there.

But there’s tremendous heterogeneity for patients with prostate cancer. Patients respond so differently to the hormonal therapy ADT [androgen deprivation therapy], which we’ve had for decades. Some patients have a dramatic drop in PSA [prostate-specific antigen] and a long duration of response, and then we have others who have barely a couple of months of response, and they progress. There’s such significant heterogeneity that our ability to pick therapy for a given individual should be based on some selection, and that’s what precision medicine means to me.

That’s a great start. As you said, precision medicine goes back to the time of ADT, because targeting the androgen receptor was one of the very first precise ways of targeting a cancer. It’s really interesting to mention that and to also comment on the heterogeneity of this disease.

Scott, what are your thoughts? In prostate cancer and across cancer, we’re trying to move into precision medicine. Where do you feel that stands in prostate cancer? How do you think we can improve on that and target some of that heterogeneity, including things like racial diversity, that we know may be contributing and is a particular challenge in prostate cancer?

I agree, it can be quite complex. Precision medicine, which I would broadly define as the right treatment for the right patient at the right time, is fortunately in play in all fields of medicine, whether it’s internal medicine with diabetes and who needs insulin, etc. There are many more diabetic drugs than when I trained, so I’m glad that we have that help. In a way, precision medicine has been in prime time within prostate cancer for a number of years. We’re further refining it, and it’s true for all stages of disease. With patients with clinically localized, low-risk disease, I’m considering imaging, blood-based and tissue-based biomarkers to help me give the best advice I can in the context of a patient and their comorbidities and wishes for active surveillance vs interventions.

We have moved to much more sophisticated types of diagnostic tools, which nicely has been matched with advanced disease to many more treatment options. Not just ADT, although that’s the backbone for everything, and not just taxane chemotherapy, but we now have a number of different choices, which makes it much more important. One of the relatively new factors in the longer-term scheme of things is germline alterations. If you think about racial disparities, it’s not just germline genomics, exposures, or access to care, it’s a little of all those and much more. There are some factors that look like they may cut across all the other factors, such as a germline 

, but there are others where we need to take all the other factors into account.

I couldn’t agree more. To comment on germline and somatic mutations, these are things we can target at this point with a couple of FDA-approved therapies, including our PARP inhibitors, and we have things like 

, as you mentioned. Sandy, are you thinking about other alterations at all, like tumor mutational burden or MSI [microsatellite instability]-high status, when you’re seeing patients with very advanced prostate cancer? That would also be a way to enact precision medicine, right?

 Totally. Immunotherapy has been such a welcome change in so many different cancers. In prostate cancer, just monotherapy with checkpoint inhibitors hasn’t been that promising, so we’re fortunate to have FDA approval for pembrolizumab, for instance, which has an approval across all cancers for tumor mutational burden greater than 10 and for MSI-high. I’ve looked very hard, and I can’t tell you the number of times that, especially for patients post-AR [androgen receptor] therapy, where you’re looking for something besides chemotherapy. It’s at that point that I’ve definitely looked at prior tissue and liquid biopsies, but I haven’t yet found that patient who has MSI-high. But certainly, that’s a time to look for these markers, because those patients who have this will have such an amazing therapeutic option where they could have a response that could be more long-lasting.

Absolutely. It’s only 1% to 3% of our patients who are going to have that MSI-high status, and that’s in the mCRPC [metastatic castration-resistant prostate cancer] setting, so these are truly patients who are needles in a haystack. I have 1 patient who I inherited from someone, but haven’t identified any on my own, despite testing as much as I possibly can, just as you mentioned. But despite this being a rare situation for our patients, it’s absolutely imperative that we identify those patients if they’re in our practices, because there can be an option in pembrolizumab.

A panel of physicians who work in the field of genitourinary oncology comment on the evolving role of precision medicine in advanced prostate cancer.

Scott T. Tagawa, MD, MS, FACP, Weill Cornell Medicine

Articles

Dr. Tagawa on the Integration of PSMA-Targeted Agents in Prostate Cancer

PSMA-Targeted 18F-DCFPyL PET/CT in High-Risk Prostate Cancer

Tissue and Liquid Biopsies in Advanced Prostate Cancer

Precision Medicine in Advanced Prostate Cancer