David Albala, MD

 Let’s talk about how PSMA [prostate-specific membrane antigen]–targeted therapies such as lutetium might improve outcomes in patients with prostate cancer. Gary, why don’t you take that? Then we can throw it out to the whole panel.

Thank you, David. I like to refer to this field as molecular imaging and therapy. We image what we treat, and we treat what we image. The purpose of having these agents is not only to see the tumors but also to target them with enough radiation that we can affect a cell kill. The only FDA-approved PSMA-targeted therapy is lutetium-177–PSMA-617, which was published in the 

 in the VISION trial. That trial demonstrated an increasing survival for patients who’ve had both hormonal and taxane chemotherapies. This is just the beginning. There’s going to be much more to say on PSMA-targeted therapies, different constructs of the molecule that binds to PSMA, altering the radiation emitter from lutetium-177 and other beta emitters to alpha emitters like actinium-225, a combination of PSMA-targeted therapies with other forms of therapies, and timing of the therapy in the course of patients’ disease. These will all be areas under hot investigation in many current and upcoming clinical trials.

Gerry, what patient populations is lutetium used in? Do you think it might be used in the future earlier in therapy?

 Gary mentioned the VISION trial, which used patients who had already failed the conventional therapies, including chemotherapy, and androgen manipulation. There’s no doubt in my mind that we’re going to be moving this therapy earlier and earlier in treatment-naïve patients who have metastatic disease. The exact treatment modality, whether it’s exclusively a beta emitter or a combination of a beta and an alpha emitter, might depend on the distribution of metastases that the patients have. The dosing, the timing, and the sequencing of this therapy with other therapies is totally unknown at this point. That will be the subject of a lot of ongoing clinical research in the very near term.

Ashley, what are your thoughts on lutetium?

They’re extremely promising agents. When they started therapeutically, like in the VISION trial and the somewhat smaller trials, it was at the end of the disease state. As we mentioned, PSMA is an antigen-regulated gene. There are times in the disease course when expression is thought to be more. As Gary pointed out very strongly, it’s not going to be just 1 drug. It’s almost like when we were talking about tracers: you’re not going to think I’m just going to use my lutetium–PSMA. There are going to be differences in the compound itself—how does it bind the PSMA, is it a small molecule, is it a “minibody,” is it an antibody? There are going to be differences in the tracer; that would be the therapeutic payload. Is it a beta emitter? Is it an alpha emitter?

We also have to think about the biology of when to deliver it. Is it when the disease volume is greater? Should we debulk the disease and then deliver it? How many cycles are we giving of the drug? There are all the combination therapies that Gary is talking about. If we think back to radium-223, which was a bone-targeting agent, there are some data, but a lot of the combination trials are yet to be reported, and they’re going to blow the field wide open. We’re at the tip of the iceberg with the survival benefits we saw in VISION.

As we go into the hormone-sensitive setting and the early castration-resistant setting, the value of doing the imaging is going to become even higher. If anything, we’re going to do even more PET [positron emission tomography] imaging with FDG [fluorodeoxyglucose]-PET and PET PSMA in later states to see who’s going to be a better treatment responder. As we talked about earlier, maybe we’ll get more standardization of how they read the studies because that’s going to become even more critical for therapeutic selection early on. That’s where the field is wide open. As you said, in terms of staging and imaging, everybody should jump on the bandwagon and do that. In terms of how we do it for treatment, there’s so much to do. My gut tells me that we’re going to see really good results.

This has been great. For the audience, if you’re able to get the 

® from September 2022, there are 2 superb articles, 1 on PSMA and MRI for early detection of prostate cancer and a second on PET imaging for advanced prostate cancer. Many of the points discussed today are illustrated in those articles, so they’re great references. As we look to the future, this is the imaging modality of the future for prostate cancer, in my mind. It’s time to jump on the bandwagon, incorporate it into your practices, ad use it appropriately. It will give you great information and may change how you treat these patients. That‘s the real takeaway message.

We’ve covered a lot of ground tonight; I want to thank Gerry, Ashley, and Gary for spending the time with me. For our viewing audience, I hope that the viewpoints and information we’ve discussed were informative. I recommend looking at 

® from September 2022. Thank you very much.

Videos

Panelists review the recent FDA approval of the PSMA-targeted therapy Lutetium Lu 177 vipivotide tetraxetan for patients with metastatic castration-resistant prostate cancer and discuss additional settings in which it, and other PSMA-targeted treatments, might be used in the future. 

A Look Into The Future of PSMA-Targeted Therapies in Prostate Cancer

 We’ve seen in the pathology, and it’s evolving in all different subspecialties. Gerry, we’re running out of time. Can you summarize for me what you think are the unmet needs and clinical challenges surrounding imaging for prostate cancer patients? Are there any emerging data that you’re particularly excited about? You might talk about PSMA [prostate-specific membrane antigen] targeted therapies in the future. What is getting you excited about this topic and this imaging going forward?

PSMA-based therapeutics are obviously very exciting; they must be, it has to be redefined in very specific populations of patients with a slightly longer follow-up. That comes [from] the use of PET [positron emission tomography] scans for biochemical recurrence. Even for staging, will the patient survive longer? Ashley mentioned the EMPIRE-1 study [

 ], which did show improved biochemical recurrence after FACBC-based radiation therapy. [That] doesn’t necessarily translate into survival, [but] we’re going to find out [if it does] over the years. That’s a very important thing. In regard to staging, and I think Ashley and Gary also referred to this earlier, is this going to be the Will Rogers phenomenon where we just do a better job categorizing the patient? But in the end, the outcomes are overall the same for the entire group even though individual patients may seem to do better. Those studies are ongoing and they’re waiting. The one thing that I think we’re going to be doing more of in prostate cancer is focal therapy and focal ablation. I wonder how we can integrate PSMA PET/MRI [magnetic resonance imaging] vs PSMA PET/CT [computerized tomography] into planning [and] monitoring the success of a focal ablation. Maybe that’s an open-ended question for Gary. I don’t know the data—if one was to look at patients, the ideal patient for focal therapy right now [has] an MRI target, [if] the targeted biopsies show cancer, [or] the systematic biopsies are negative. In a patient like that, if you also got a PSMA PET scan, would it show other satellite lesions or would it show a larger lesion or a smaller lesion than the MRI did? These are the kinds of things [in which] we’re going to need to do a better job with focal therapy. That’s my final comment; I’ll turn it over to Gary.

I think you summarized it by saying the data is not out there yet. I don’t think I have an answer for you. I would be wary about making size measurements on PET. I don’t think PET is ever going to tell us that the lesion is getting bigger or smaller; depending upon how you window the PET scan, the PET signal looks larger or smaller. So size is not as valuable [of a] component [in] a PET scan as [it is] on your CT or your [MRI]. But certainly, finding additional lesions would be a role of the PET scan. I look forward to the continuing and growing literature that is found [on] PSMA PET and how its value is going to contribute to the care of our patients.

I wish everyone had the ability to have access to all of these agents. I hope that it will be that way as soon as possible. I would draw an analogy to what happened with FDG [fluorodeoxyglucose]. When FDG first came out, it was only available in the big cities that we’re discussing. Now, the production is available virtually everywhere; you can get FDG virtually anywhere. I think that will be the case with PSMA agents sooner rather than later. To look just a little bit into the future, there is research on development of PSMA-targeted imaging agents using copper…which now have half-lives in the 3-4 hour range. With agents like that, you would need very few central sites to produce and deliver to the entire continental United States. I [foresee] current PSMA-targeted agents rapidly becoming available to places that currently don’t have [them], and the future generation of agents will make that even more so.

Drs Albala, Andriole, Ross, and Ulaner sum up recent advances and remaining unmet needs in the field of prostate cancer imaging and share hopes for the future.

A Summary of Recent Advances and Remaining Unmet Needs in Targeted Prostate Cancer Imaging

I want to look into the crystal ball and look toward the future. One of the key things that’s starting to [be utilized] is artificial intelligence. How do you think artificial intelligence will be integrated in this type of technology? Do you foresee something in the future soon? Is it way down the road? How do you see it helping us, as clinicians and radiologists, using this artificial intelligence to help us with this imaging? Gary, I’ll start with you, and then I’ll whip around the panel.

I will start by saying I am not an expert in artificial intelligence, but when I started in radiology, several people said to me, “Why bother? By the time you graduate, artificial intelligence will replace all radiologists.” Fortunately for me, that hasn’t happened yet. I don’t think artificial intelligence is going to be replacing radiologists. I’ve heard it said that radiologists who use artificial intelligence will replace radiologists who don’t use artificial intelligence. Currently, we use artificial intelligence systems that screen for things such as pulmonary emboli, rib fractures, other incidents in the brain, which you can overlook when you’re scrolling through 2000 images. I see artificial intelligence performing a greater role in radiology. I don’t foresee artificial intelligence replacing the radiologist anytime soon. Then, for PSMA PET [prostate-specific membrane antigen positron emission tomography] specifically, the role of artificial intelligence has been to pick up lesions that might miss our consciousness. Small pulmonary emboli are easy to miss when you’re scrolling through images. With PSMA PET, the sensitivity doesn’t seem to be the problem. You see the red dot or the black dot, or whatever color scheme you put your PET scan on; it’s then that the problem is the interpretation of the dot. I would say artificial intelligence has proven to be more valuable in other fields of radiology than it has yet been proven to be valuable in PSMA PET.

Gary’s comments were excellent. People like to say “artificial intelligence” for everything. I would say “computer assistance”—none of us think computer assistance is not going to be a big part of PET reading because we had more storage space, more fast computing time, [and the] ability to analyze this large data. You can think that you don’t really need artificial intelligence per se, but you can have the computer go through, recognize the lesions, [and] put their SUVs [standardized uptake values]. If you start doing serial imaging of progression or per-treatment response in the future, knowing which lesions responded to what, [you could] look at the microbiology [to figure out] what are you going to biopsy, [and] when. Or to just make the scans happen faster. That’s the next step. It’s just like our cars. I still drive a manual transmission; I haven’t gotten on board at all with anything automatic. However, I love having the blind spot warning [icon light alert me]if someone’s in my blind spot. I don’t drive fast anymore, but it makes me drive safer. So, we have a lot of that computer assistance, just like Gary was saying. “Artificial intelligence,” I don’t know what that means. But I do like his statement. I think you’re going to see radiologists who [leave the profession] and radiologists who use computer assistance. [That’s] going to be the how the future goes.

Thought leaders discuss the possibility of using artificial intelligence to help interpret PSMA-PET results. 

The Potential of Using Artificial Intelligence in PSMA-PET Results Interpretation

Ashley, talk to me about the documentation. I’m a practicing urologist; what do I need to have in my notes to suggest that this test will be covered by insurances? In your experience, are there any buzzwords that are critical? You guys have ordered lots of these tests. I’m sure the audience is going to be a wide variety, from none to many. Are there any tips that you can give us to ensure that these studies will be covered by insurance? What do you recommend doing for the documentation?

Quite frankly, it’s become easier in my area. I basically just say that the person has this NCCN [National Comprehensive Cancer Network] risk. I say they’re at risk of having metastatic disease, and we need to appropriately stage them. Where [there is] a biochemical recurrence, I say the PSA [prostate-specific antigen test] is above X. There’s no guideline about where you put it, for that. But I’ll say the PSA is above this. It’s a rising PSA after treatment, and I’m suspicious that there’s metastatic disease present. I want to get a PET PSMA [positron emission tomography-prostate-specific membrane antigen]. When I get a denial, or my office gets a denial, as these new technologies get out there, Gary mentioned that there’s representatives that help us onboard it, get the tracer there, help us with logistics. If you say, “Look, I just want to look at your verbiage. What do you guys do when you talk to them?,” they actually can help you with good summaries of the data. There are papers that, for example, Dr Andriole’s a major author on a lot of these papers with PET scanning. But you don’t want to have to write a huge letter each time, you want to draw from different sources. They often have that consolidated, and you can submit that. Obviously, we’re hoping for the day when all of them just get approved. I think that the reason it’s coming to that is the peers realize. Gerry mentioned earlier, he was alluding to some of the studies, like the EMPIRE-1 study, which used F18 fluciclovine. Then your treatment planning is better. While we don’t know if this going to affect overall survival or not, it certainly can affect the time of your curve of treatment and lessen costs. If you pick the right treatment strategy first, you probably get more quality-of-life years out of your patient and lessen the overall health care cost. I know that Dr Andriole’s had some denials. Gary, I’m not sure about your area, but I’ve seen the resistance going lower and lower and lower, so that I don’t have to write a bunch of, quite frankly, waste-of-time stuff and boiler plate in my note. I can just say, “This is what it is.” The insurance says, “Yup, this is better care.” I guess I’m blessed because in Gerry’s realm, which I used to be on the East Coast, they’re still putting a bunch of resistance to best care. One more soapboxing thing. I always see these things that are judging doctors, that are saying, “Well, this is your doctor metric. This is how your patient reviews were.” I’m still waiting for the day when we’re judging insurance companies. That this insurance company always denies guideline-approved standard of care. If you’re looking at Medicare Advantage plans, I’m sure that Gerry’s patient was not Medicare, but Medicare Advantage. These Medicare Advantage plans frequently refuse guideline-appropriate treatments and better options for your patients. I don’t know why we don’t have that yet, but I think that’s the next thing that I would like to soapbox for this small bit.

You think it’s almost like what we’ve seen with MRIs? Remember, when we first started doing MRI imaging, none of the insurance companies would approve it. Now it’s really the urologist. If you don’t write an MRI fusion biopsy, you’re not going to get one. But you don’t jump the hurdles that we’ve seen. We’ve come a long way with MRI, and I think we’re at the beginning stages of starting to see that progress through with this type of imaging. Gerry, what’s your thought?

I have very little to add to what Ashley said. I think it’s highly dependent on some arcane, local rules. It has varied a bit between St. Louis and the Baltimore-Washington metropolitan area.

If I can go back to buzzwords. What do you want to put on your orders? A summary of what we’ve already said: newly-diagnosed, high-risk, those are good buzzwords for getting your PSMA PET scan approved. Prostate cancer, post-prostatectomy, or radiation therapy, and then use the term, biochemical recurrence, and give the PSA value. Those are good buzzwords. Then “patient is being evaluated for PSMA-targeted therapy.” I think those are buzzwords that, if you do get, then, a rejection, you can turn around and show them the SNMMI [Society of Nuclear Medicine and Molecular Imaging] appropriate use criteria and say, “You asked for these AUCs. Here’s the AUC that says that the PSMA PET scan is appropriate in this patient.”

Panelists discuss how they typically document prostate cancer patient eligibility when ordering PSMA-PET imaging, and share strategies to optimize insurance coverage and reimbursement.

David Albala, MD

Articles

A Look Into The Future of PSMA-Targeted Therapies in Prostate Cancer

A Summary of Recent Advances and Remaining Unmet Needs in Targeted Prostate Cancer Imaging

The Potential of Using Artificial Intelligence in PSMA-PET Results Interpretation

PSMA-PET: Documentation of Patient Eligibility and Reimbursement