Robert Flavell: 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's 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.

I'll briefly introduce myself to start. 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 imagers spanning the spectrum of clinical care in prostate cancer.

Our next speaker is Hao Nguyen. He is a urologist and Associate Professor in the Department of Urologic Oncology. He's also the Goldberg-Benioff Endowed Professorship in Cancer Biology. Dr. Nguyen is a physician scientist whose clinical interests include early detection, diagnosis, and management of prostate cancer, kidney cancer, bladder cancer, and other genital urinary malignancies. He performs a variety of surgeries for those indications. And he also runs an active laboratory with major focus on elucidating adaptive response pathways that prostate cancer cells use to avoid cell death upon acquiring oxygenic lesions or stresses. So thanks very much Hao for agreeing to speak today, and look forward to your lecture.

Hao Nguyen: Great, thank you Rob for that introduction. I want to discuss cause the role of PSMA PET scan. I think it has a revolutionary kind of effect on a few as a surgeon. You know, we always look in a better way how to integrate this into the operating room. So I'll discuss briefly of how that is changing the way we practice and some upcoming trials that we very excited about integrating PSMA base for us and molecular imaging during robotic prostatectomy.

So, when I was in residency, we used to operate on low-risk cancer, and that has minimal benefit to mild benefits to the patient and a lot of overtreatment and side effects. But now that radical prostatectomy has evolved into more of a multi-modal approach in treating high-risk prostate cancer patients, and we integrate better biomarker and more advanced imaging into the caring of those patients.

So here's a paper recently published in JAMA looking at the treatment trends of prostate cancer over the last two decades. And in 2009, you can see a huge uptick in surgery offering for patients with high-risk prostate cancer, CAPRA 6-10. At UCSF you can see the trend as well. We see over the years, we've offered surgery more to patients presented with high-risk prostate cancer. Because we have better imaging, we now know with advanced imaging, we have more than finding risks. And what is driving this trend is mainly, for some patients it is a preferred treatment for some and an important one as well. And also the molecular catheterization advanced imaging is also guideline-driven, is driving this trend.

So some radical prostatectomy has its limitations. The main thing is surgical margin. Still a big problem for patients with high-grade and high-stage disease. Positive surgical margin is associated with the highest stage regardless. The extended lymph node dissection, there's morbidity in doing lymph node dissection for this patient. So, what are some of the dissections that we need to do to get all the cancer without cutting into normal tissue? And then there's also problem with recognizing, or not being able to recognize distant metastasis early on. And so surgery often fails in those patients because we fail to recognize the distant or original risk.

Here's data from UCSF showing a patient who has recurrent cancer. This is all gray, but with T3A, patient with positive surgical margin, they tend to have less of a percentage of degrees of recurrent-free survival. Although this does not correlate to overall survival, but a biochemical recurrent at least to or needing more treatment or anxiety for this patient.

So PSMA as Tom had mentioned, it had changed the way we manage high-risk disease. Mainly it helps us with more accurate staging information initially. So, here's an example of how we use its technologies. This is one on my patients who presented in 2018 with a Gleason 8 cancer, PSA 24. And initially I was hesitant to offer surgery, but then when we got the PSMA PET scan, we found only one other sign of diseases in this left lymph node. So, we offered him surgery or radiation and he picked surgery. So I took him to surgery. The final pathology is consistent with stage 3 N1 disease, 1 out of 15 lymph node positive, and his PSAs remained undetectable two years after. So this is one of the few patients who had no positive and undetectable PSA two years out.

Now, this is another patient, a 51-year-old man with a PSA actually of 24, Gleason 9. His clinical staging on MRI bone scan was T3aN0M0, at the time PSMA was not available. So I took him to surgery, and the pathology showed he has a positive lymph node on the left side and a 2 millimeter focal positive surgical margin. His PSA after surgery was .8, so we got the PSMA scan. You can see here, the PET scan shows a 8 millimeter PSMA node right below this lymph node dissection. So I did standard node dissection. I didn't go deep enough. I didn't see this at the time. If we had obtained this prior to surgery, I may kind of look, spend a little bit more time and find it, but this is out of the surgical template. We didn't see this one. So you can see how that impacts the treatment out. So he's currently on Zytiga® and Lupron®. He also was going to get adjuvant radiation. PSA is currently undetectable.

Now the third patient, this is a 52-year-old with a PSA of 7.5, Gleason 9. He had a PSMA PET scan prior to surgery and that showed pT3bN1 disease, with 7 millimeter lymph node on the right pelvic here. So we offer surgery or radiation. He picked surgery, and you can see in surgery, we found three lymph nodes that were positive. So two on this side, but one on the left side. So that was not visible on the PET scan. So post surgery his PSA was 1.48. So he probably has microscopic disease elsewhere in the pelvis that was not visible on the PET scan. so I wonder if we can, if we have a better way to find these, with integrating PET or PSMA imaging into the OR. That would be better.

So that's what we strive to do in the next few years. Though in the last 20 years or so, surgery, robotic prostatectomy, our goal was to manage side effects and only treat patients who may benefit from it. We kind of preserved the nerve, to reserve continence and treat the patient well. The question is, is there anything else that we can do intraoperatively to achieve cancer control and maintain the quality of life? So as you know, about 80% of these men opted for radical prostatectomy use the robotic system, the da Vinci robotic system. Unfortunately, up to 30% of the men will have some residual positive surgical margin or a nearby lymph node that was unrecognized by our inability to visualize the difference between tumor and normal tissue using conventional white light endoscopy.

So, we also know that PSMA PET scan done at UCSF showing up to 40% of the lymph node that was positive in the high-risk patients found outside of the surgical view or the surgical template. So, in response, we've collaborated with surgical intuitive to translate the novel fluorescent in vivo agent that is based on PSMA. And if we can augment the surgeon's vision to visualize this at the molecular level. So currently, to improve cancer visualization during surgery, is an urgent unmet need and potentially, could be solved with this in vivo fluorescent-based imaging. That was our hypothesis coming into this trial that I'm going to show you. The goal is to improve oncologic outcomes and preserve sexual and urinary continence.

So this compound is basically very similar to gallium PSMA, except that is linked to a fluorescent ICG based diet instead of gallium. It's the same concept. Here we have a preclinical model to show that this work in the mouse first before we integrated into the operating room whatsoever. So what I did was we use a pediatric patient, derived xenografts, a tumor that was taken from the patient who we operated on and tested this drug on.

So on the top panel, you see, this is during the surgery, a part of the bottom panel. There's different near-infrared imaging right now, the current Firefly® system, we cannot visualize this. But with the new camera system that we developed over the last year and a half, it's now a hundred more sensitive to detect this. So you can see here, as an example, I remove this patient-derived xenograft tumor here. We left a little bit of margin just to show you this. With two millimeters of tissue that we can see it really brightly. And this is the normal endoscope. This is the new enhanced endoscope. So this is the scope that we going to be using for our Phase I trial.

So you can see here, this is different mouse models, showing different uptake of this PSMA based, fluorescent dye. You can see here in the tumor, the kidneys is expected, there's some and the GI tract. Nothing in the fat and muscle, the spleen. So the signal to background ratio is quite good with this compound. We test it on three different models of patient-derived xenografts, different tumors, all of them had expressed PSMA quite well. You can see some variation in different degrees of brightness in these three different models. So we're very excited we got the IND approved for this agent for the FDA recently. We have a plan to stop this in by October to Phase I, looking at the safety and efficacy of this new IS-002 in patients undergoing robotics prostatectomy.

We planned to robot probably 405 patients over the next six months. The different primary and secondary objectives that we've aimed for, the main thing is to evaluate the safety in the Phase I. Some of our exploratory objectives is to determine the histology correlations with the signal and the cancerous tissue also. So we're very excited about this trial. It's coming up soon.

So in summary, men with high-risk disease may benefit from aggressive, local regional therapy. We think healthy men who have a long life expectancy are the ones that are likely to benefit from it. And novel imaging and molecular characterization will better refine the risk and benefit. And then a randomized trial data from the registry will be of great value in these. In future directions, the main thing is targeted treatment. Hopefully, this technology will delay the onset of systemic therapy and improve survival. That will conclude the part of my talk, and I'll pass over to Dr. Felix Feng next.