Introduction to PET PSMA Gallium-68 PSMA-11 for Diagnostic Imaging of Prostate Cancer - Tom Hope
November 21, 2020
Tom Hope, MD, Associate Professor, Director of Molecular Therapy, Radiology and Biomedical Imaging, University of California, San Francisco
Rob Flavell, MD, Ph.D., Assistant Professor, Section Chief, Molecular Imaging and Therapeutics, Radiology and Biomedical Imaging, University of California, San Francisco.
Robert Flavell: So it's my pleasure today to welcome you all to join us today for this Prostate Cancer Outreach Webinar. This webinar has been organized in collaboration with the Society of Nuclear Medicine and Molecular Imaging Prostate Cancer Outreach Working Group, together with faculty from the University of California in San Francisco. And the topic of the webinar today is on "Changing the Standard of Care in Prostate Cancer with Advances in Nuclear Medicine, PET, and Theranostics".
So I'll briefly introduce myself to start. So I'm Rob Flavell. I'm an Assistant Professor in the Department of Radiology and Biomedical Imaging at UCSF. Also, the Section Chief for Molecular Imaging and Therapeutics. Today, we have a great selection of speakers, including both nuclear medicine physicians as well as clinicians of various different types involved in prostate cancer care. So really, clinicians and the imagers spanning the spectrum of clinical care in prostate cancer.
So with that, I'll go ahead and start by introducing our first panelist, Dr. Tom Hope. So, Dr. Tom Hope is an Associate Professor in the Department of Radiology and Biomedical Imaging at UCSF. He's also the Director of Molecular Therapy for the Molecular Imaging and Therapeutics Clinical Section. Dr. Hope's main research focus is on the development of novel imaging agents and therapies. He is the PI of our gallium-68 PSMA-11 IND at UCSF, having led the efforts here and published numerous papers on this topic. Also, has an additional interest in the development of peptide receptor radiotherapy, and PET MRI. So thanks very much, Tom, for speaking at today's event and look forward to your presentation.
Thomas Hope: Great. Thank you, Rob, for the introduction. I'm just going to provide a very brief introduction to PSMA PET, just to sort of set the stage for the speakers that follow me. We'll focus on PSMA PET, which will hopefully bring some light to patients with prostate cancer moving forward.
So I would like to start by just sort of talking and introducing the idea of prostate-specific membrane antigen. I think everyone's pretty familiar with this process, and back in the day, it was an antibody that unfortunately targeted the intracellular component of this protein. The PSMA, the transmembrane protein that's overexpressed in the majority of prostate cancers that are out there. It's also expressed actually in non-prostate malignancies as well. So it's not really prostate-specific per se. Things like renal cell carcinoma will express it. It can also be seen on vasculature and other types of diseases as well, and benign bone lesions. But in general, it's very overexpressed in prostate cancer and is very good as a target for prostate cancer for treatment and imaging.
Now, most of the work we've done at UCSF and what the subsequent speakers will talk about a lot is gallium-68 PSMA-11. We use this at our institution because it's not patented, and so we could sort of move forward with it without the limitations that many companies might provide for various compounds. Now, the compound has half of the molecule here. This is a chelator, this is an HBED-CC chelator, and this is what binds to the gallium or any radio metal, actually not any radio metal. You can't bind lutetium to it, so you couldn't do therapy. The other side of the molecule is this targeting motif. It sort of looks like a urea molecule, and this is what gives the molecule its specificity for binding to PSMA. So this is what actually takes the molecule and carries it into prostate cancer cells. So we label that HBED-CC chelator with gallium, and then we can inject it into humans.
Now, this is data back in the day now, but it's really what made me most interested in this target or this compound for imaging of prostate cancer patients. But the comparison between fluorocholine, which used to be the standard imaging modality for patients with prostate cancer, to gallium PSMA-11. You can see particularly on the right side of this slide in patients who have a low mean PSA. So in the study 2 they're out of St. Vincent's in Sydney. The mean PSA was 1.7. The detection rate increased from 32% with choline to 66% with PSMA PET. So you really get a huge increase, particularly in patients with low PSA when using PSMA PET for the detection of metastatic disease in patients with biochemical recurrence. And if you'll hear moving forward, that will have a huge impact on patient care hopefully, although we do need to sort of prove that in prospective clinical trials.
So here's an example of a patient. This is a 69-year-old man who had a radical prostatectomy, and his PSA was 0.7. The standard therapy in this patient would be to give salvage radiotherapy to the prostate bed in the pelvic lymph nodes. But in this case, you can see clearly an osseous metastasis here in the right humerus and also left internal iliac lymph node that is also positive PSMA PET. And I think this case really nicely highlights how PSMA PET can be both used for soft tissue staging as well as osseous staging. And we're getting very close to a point where we can sort of move forward and have a single imaging study to stage patients with prostate cancer rather than having a CT or a bone scan.
The other thing I want to highlight is there are lots of compounds out there that target PSMA. And this is an old slide now, but it's sort of still true. The majority of these compounds contain that same urea motif. So in the bottom right here, you have PSMA-617, and that has a DOTA chelator and is what was used in the VISION trial for therapy. The middle bottoms, PSMA-11 with the HBED chelator, DCFPyL is the bottom left there, which has a flooring attached to it, all share the same targeting motif. And so to a certain extent, they all bind to PSMA in a very similar way. And I think about the difference in these compounds really in terms of the variation and biodistribution. So for example, a PSMA 1007, the second one there, has very high renal uptake or not renal liver uptake.
And you can see a very avid liver in the selling point with that drug might be that you have very decreased urinary excretion, which is why this case you can see maybe this local disease adjacent to the bladder, possibly better. For example, this other compound over here, CTT, seems to have a little more blood pool because of the difference in the chelator in the backbone of the molecule. But all of them do bind to prostate cells in the same way, bind a PSMA, and have a reasonably good detection sensitivity. So I think of them as a class with some variations in biodistribution, keep moving forward.
I do want to specifically highlight 18F-DCFPyL. We don't use that in our sort of standard of care, compassionate use trials at UCSF we've involved in many of the Phase II and III trials that have been performed. And this is going to be, hopefully, the first company-sponsored drug to get approved by the FDA. And it's actually really important because gallium-68 PSMA-11, although currently under review by the FDA, isn't going to be easily widely available because of the short half-life of gallium. But F-18 has a longer half-life of 109 minutes and can be produced on a cyclotron, and so distributed more easily using the existing radiopharmaceutical network. So wide availability of PSMA PET radiotracers will likely rely on the availability of this compound. So we, as a field are really looking forward to the approval of this agent, which works similarly to PSMA-11, for the detection of metastatic disease.
Now, I do want to say sort of the opposite about fluciclovine. So I have a little couple of slides on a comparison to fluciclovine. So here's a patient who's in this, both with fluciclovine and PSMA-11 PET at our institution within a week of each other. And you can see how this local recurrence here on the right pelvic sidewall can be seen both on PSMA and fluciclovine, but the tumor to background ratio is much, much higher with PSMA compared to fluciclovine. So for example, the tumor to background ratio here is in the 50 range with PSMA compared to about three with fluciclovine, both because you have higher tumor uptake and better wash out of background activity, which increases your ability to detect and interpret confidently with imaging. It also plays a role in disease that is more subtle. So for example, in this case, you have this disease in the right seminal vesicle. Now on the PSMA PET, this has a lower tumor to background ratio, more around eight or nine, but with fluciclovine it's in the range of maybe less than two.
So it's much harder to feel confident in detecting and characterizing that recurrent disease compared to what you would see with PSMA PET. And I would note here that although you do have activity in the bladder, which is one of the knocks on many PSMA radiotracers, you usually, particularly when you're using a timing slice scanner can easily detect the adjacent local recurrence and distinguish it from bladder activity. Now the best paper in comparing fluciclovine to PSMA PET is this paper by Jeremie Calais out of UCLA where they in essence did fluciclovine PETs compared to PSMA PETs one week apart. And these were all done in patients with a PSA less than two after radical prostatectomy. So a patient population that's fairly hard to detect recurrent disease. And these were all read by three blinded readers, three separate readers who are experts in fluciclovine, and three readers with PSMA PET.
And you can see overall the PSMA PET detected over two-fold, an increase in disease and patients compared to fluciclovine. And the fluciclovine primarily detected tumor in the prostate bed and really didn't see any metastatic disease or nodal disease, which is really the important site of disease in patients after radical prostatectomy. So, overall PSMA appears to strongly outperform fluciclovine. And I think the real take-home point of this is interpretability. So the kappa value of the inter-reader variability of PSMA was 0.67 overall in this trial compared to 0.2 with fluciclovine really suggesting that a higher tumor to background ratio makes it easier to characterize local recurrence.
Now, we also did a prospective study at UCLA and UCSF, the two institutions and biochemical recurrence using gallium PSMA-11. And in this study, this is what sort of formed the backbone of our new drug application for PSMA-11. And this was the data that was published in JAMA Oncology. And as you would expect that there's a decrease in detection, sensitivity detection rate. This is on a per-patient level as you decrease your PSA. So in patients with a PSA less than 0.5, the detection rate went to below 40%. Now it should be noted that it's very difficult to compare detection rates across literature, and that in this study, it was a little bit unusual compared to most of the literature that's been published. And then we use three blind readers who were not at the institution where these were performed. And so the detection rate was based on a consensus of blinded readers. And obviously, when you have blind readers, you're going to have a lower overall detection rate because you get in essence punished by overhauling because you will have a high inner reader variability.
And so overall this is the positive predictive value for the composite endpoint, and this was looking compared to pathology and conventional imaging was 0.92, which is pretty good and really supports the use of PSMA PET. Also in this trial, you can see that the inter-reader variability, the kappa values range between 0.65 and 0.78. Again, suggesting very good confidence in our inter-reader consistency when interpreting PSMA PET, which is really important when you decide that you're going to target just that individual lesion with external beam radiation, as I'm hoping Felix will talk about later.
The other thing that's interesting is this is looking at the change in management, and this was the change in management paper published based on the data from the JAMA Oncology paper. And what ends up happening is that obviously, your management depends on where you see disease on PSMA PET. So for example, if the PSMA PET is negative, more patients ended towards surveillance rather than getting active treatment. If you have local disease, for example, in the prostate bed or pelvic lymph nodes, then you get local therapy. So radiation therapy, if you have metastatic disease, then you start to get systemic therapy. So the results on the PSMA PET in essence, directly inform the type of therapy these patients are getting. Although there's not a lot of prospective data telling you how you should treat these patients.
As I mentioned with UCLA and collaboration, we have put together an NDA that there are actually two separate NDAs, one from UCSF and UCLA, and it's currently under review by the FDA. And we hope by the end of this year, we will have this drug FDA approved for gallium-68 PSMA-11 moving forward.
Now just to remind ourselves and moving forward about the next three talks that are coming, prostate cancer is a continuum and it changes over time. And so you think initially patients are at time of primary treatment, you're going to get a radical prostatectomy or radiation therapy. That's based on a Gleason score and Hao Nguyen is going to talk about the role of PSMA PET in that circumstance. After descending, this therapy, typically your PSA will fall. And then at some point in time, it will start to rise again. And that's turned to biochemical recurrence and wow, blinking here all of a sudden, huh? Felix Feng is going talk about that, our radiation oncologist, about the role of PSMA PET in the setting of biochemical recurrence and how we use PSMA PET to target external beam radiation therapy. And then at some point in time, patients will be treated with androgen deprivation therapy and their PSA will rise on androgen deprivation therapy, and they'll develop castration-resistant prostate cancer, and who Agarwal, medical oncologist, is going to talk about the role of PSMA PET and hopefully a PSMA targeted radiotherapy in that setting.
And obviously, that's one of the most exciting parts of this, which is theranostics, right? So these same compounds that have these urea targeted motifs can also be used to chelate things such as the lutetium or yttrium-90 or actinium alpha particles to treat patients prostate cancer. And so that obviously, is the next move forward in the patients with prostate cancer.
So just quickly, in summary, PSMA PET is superior obviously to existing radiotracers such as fluciclovine and fluorocholine for the detection of metastatic prostate cancer. The use of PSMA PET has a huge impact on clinical care. And that's going to be particularly evident in radiation therapy planning as you're going to hear about. And currently, our NDA in collaboration with UCLA is currently under review. And then we hope the DCFPyL NDA will be submitted later this year and may be approved by the end of next year although, I'm not clear on when that will actually happen. So UCSF, there's a huge number of people to thank who participated in our trials and help make all this success. I don't want to get into that. And then there are many people who also fund the research that we do here. So thank you very much.