Advantages of Using Novel Imaging in nmCRPC APCCC 2022 Presentation - Michael Morris

August 11, 2022

At the 2022 Advanced Prostate Cancer Consensus Conference (APCCC) Hybrid Meeting, Michael Morris presents on advantages of using novel imaging in nmCRPC.

Biographies:

Michael Morris, MD, Medical Oncologist Clinical Director, Genitourinary Medical Oncology Service & Prostate Cancer Section Head, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.


Read the Full Video Transcript

Maha Hussain: So we'll move into the next speaker, but I really wanted to take a moment and definitely thank Silke and Aurelius for a fantastic conference and their team for their organization. They've really done in a wonderful job. So maybe we can give them applause. Thank you. Great, thanks. So our next speaker is Dr. Mike Morris and his area of discussion is going to be advantages of using novel imaging in non-metastatic castration resistant prostate cancer. Mike?

Michael Morris: Thank you Maha again, may I echo to Silke and Aurelius, our great thanks and gratitude for organizing this conference and inviting me and everybody else to speak today. I think I have a somewhat easier job than Alberto does here in talking about the advantages of molecular imaging for a non-metastatic CRPC. So thank you for that as well.

It almost seems self-evident, the state of non-metastatic CRPC has been defined specifically because standard imaging techniques cannot image disease here. So it does seem almost self-evident that you should use imaging modalities that can actually visualize disease in this clinical state. And as the lady just showed courtesy of Dr. Fendler and his colleagues in this really quite important paper, almost all of these patients who meet spartan criteria have imageable disease, I believe it's 98%. Half of which have M1 disease, so if we're ever going to really understand disease volume and distribution in these patients, it has to be with molecular imaging. It will improve and optimize our prognostic models. It would allow us to stratify these patients for new treatment paradigms for those who have visualized disease, versus those who do not. And it will allow us to have new eligibility criteria and endpoints by actually being able to visualize disease in these patients.So it does seem self evident almost that you need to use the tools appropriate for the disease state, which by definition are not standard imaging in our molecular imaging.

I think it's important to recognize the importance of imaging, not just in qualifying the definitions of this state, but the goals of care of this state as well. Because these patients are completely asymptomatic from disease, and indeed the only toxicity as Elena was just discussing is from treatment, the only thing to follow is either PSA, which you can look at as a response, but the next seminal event is the prevention of metastasis free survival. Again, hitting on the importance of imaging here.

And we accept MFS now as a proxy for clinical endpoints, such as overall survival. And of course, MFS will need to be redefined and recalibrated and reassessed using new molecular imaging tools. Chris who I see is sitting right over there. Thank you, Dr. Sweeney, for generating these tens of thousands of patients through the icecap project. The relationship between MFS using standard imaging and overall survival, which was really well correlated. I mean the correlation coefficient was 0.9, looking both at Kendall's and in R square. In associating MFS with OS using standard imaging and FDA recognized that this is from their 2021 guidance for industry.

And I think it bears really understanding the regulatory recognition of MFS as a clinically significant endpoint worthy of drug approval. As they said, the transition from non-metastatic CRPC to radiographically detectable metastatic disease is a clinically relevant event that can be associated with morbidity and the need for additional medical intervention. And a large treatment effect on MFS with an acceptable safety profile, which I think Eleni did demonstrate, could demonstrate clinical benefit and support product approval. You can't get a more black and white binary reflection of the importance of a radiographically defined event for drug approval than that really.

So we will of course, need to respect the fact that the regulatory agencies recognize that, approve three drugs on the basis of it, and with these new tools, we are going to have to redefine what MFS is. Of course, we keep saying molecular imaging as if that doesn't encompass standard imaging. And it does, it's a PET CT. You can actually see if you can see a correlating lesion or not. These aren't mutually exclusive. If you get a PSMA PET CT, you can see whether you have achieved an actual MFS event by standard imaging, as well as see whether you see something by the molecular tracer as well, these aren't mutually exclusive.

So molecular imaging, pardon the abbreviation of MI, I don't want to cause anxiety here, will redefine MFS offering new opportunities for intermediate endpoints, which will going to have to clinically qualify. And don't forget that molecular imaging does contain information on anatomic imaging.

The other aspect of this is that these imaging endpoints not only reflect clinical events by proxy, but also biologic events that to date are not understood. This is taken from Wasema Bita's, basically encyclopedia state by state, of the genomic evolution of prostate cancer from diagnosis all the way through metastatic CRPC. But there's a huge gap between local regional disease and metastatic disease, which to date we have not really properly been able to understand because we can't see anything in order to acquire tissue or acquire a bloodborne assay like CT DNA, by which to assess the tumor.

And molecular imaging allows us the opportunity to understand all of those interim points that are now defined that comprise the interstices of this model in which we have this big absent zone in which some magic happens, and the tumor transforms from a relatively straightforward tumor to a much more genomically complex, biologically heterogeneous, and much more resistant cancer between what otherwise was local regional disease and disease defined as metastatic by standard imaging.

Since Movember is here, I just want to reflect our thanks and as well for PCF, for this really valuable collaboration that they're funding between MSK, the VUMC and the Netherlands in Austin Health in Australia, which has allowed us to triple scan these patients through the course of imageable disease, whether that's imageable by molecular means or standard means, with FDG, PSMA, and FDHT. And secure the tissue and the assays to do single cell sequencing, the organoids, and the PDX models so that we can fill in those gaps in our biologic understandings, through the spectrum of the disease using molecular imaging to fill in the empty flesh so to speak on the skeleton so that we can actually understand the biologic changes through multiple tracers, and reflect AR expression, metabolic activity and PSMA expression.

Now what about in terms of acting on clinically, what we see in the molecular imaging? Are there opportunities to intervene? And of course, here it's a little bit more dicey. And I'm sure that Alberto will bring these issues up in his talks. But as we can see from retrospective assessment of this disease state, and there will be a summary slide later that Alberto will show looking at all of these, but this is the largest of these. I can't really say necessarily that an intervention oligo metastatic disease is defined by molecular imaging results in a clinical benefit. But it does seem that if you do SBRT using molecular imaging, that there are selected patients who represent lower risk disease for whom you might delay, either a change to a more toxic systemic therapy or the next disease progression event by applying SBRT. Of course, prospective studies like OREO and Empire 1, while very valuable for metastatic castration sensitive prostate cancer, we don't know that same benefit translates to the non-metastatic castration resistant context.

And so we will need to do those prospective studies, as difficult as they may be from a design perspective, in order to establish that there is value in doing metastasis directed therapy in this context using molecular imaging guidance. But I think all of us who treat patients, see these kinds of patients all the time. This patient is elderly, 88 years old. And I recognize that Alicia has said that, that doesn't matter. But this patient does actually have lots of comorbidities, has had a difficult time. He now has a rising PSA after 17 years of exposure to... I got it. ...of exposure to ADT and he has one site of disease that's identifiable by PSMA PET. I think rather than going on to more toxic therapy, this patient would benefit from metastasis directed therapy. And that's why for these patients, SNMMI has endorsed molecular imaging for non-metastatic CRPC, to be able to do those types of interventions.

So to conclude this is the only imaging modality that you can use to actually see what's going on in these patients. It may present new opportunities to delay and prevent key milestones, such as MSF by standard imaging, and the use of more toxic therapy. And these applications, even with the limited data that we have, have regulatory guidance, they meet the limited data that we have, and of course are just clinical common sense. Thanks very much.