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 Dr. Felix Feng, he's our radiation oncologist and the leader in the field of translational research. The main goal [inaudible 00:01:12] individualized therapy for patients with aggressive prostate cancer by identifying determinants of treatment resistance and developing strategies to overcome resistance. He's a Professor of Radiation Oncology and a George and Judy Marcus Distinguished Professor. So thank you very much, Felix, for speaking to us today.

Felix Feng: Fantastic, Robert, thanks for inviting me to present. Today I'm going to talk about the management of oligometastatic prostate cancer. And I'm going to discuss imaging for this disease, as well as therapy. And this does play into a discussion of the space of PSA recurrences after surgery as well. So we're going to touch upon all of that.

Here are my disclosures. I have a lot of disclosures, but none are actually directly relevant to today's talk. I want to begin by discussing what is oligometastatic disease? Oligometastatic disease is an intermediate state of cancer spread between localized disease and widespread metastasis. It was initially proposed as a distinct clinical state by Sam Hellman and Ralph Weichselbaum a number of years ago. And to-date, there isn't a great consensus definition of oligometastatic disease, it's typically defined as prostate cancer patients with one to five metastases. Some people define it as three or less. Some people define it as five or less. But I think the field is evolving, and overall it's just a low burden of metastatic disease.

Now, the reason why we're talking about oligometastatic disease today is that this particular clinical space has significantly increased over the past few years. And the reason why is because of the advent of PET imaging. And so here are some graphs showing the increasing use of PSMA PET at the Peter Mac Cancer Centre at Melbourne. This is courtesy of Michael Hofman, and also at our own institution at UCSF. And what happens invariably is that, when centers get PSMA PET imaging, all of a sudden they start seeing a lot of oligometastatic patients. And so when I was at the University of Michigan for over 15 years, we didn't have PSMA PET imaging, I rarely saw an oligometastatic patient. Now I've come to UCSF and Tom Hope is sprinkling PSMA PET like it's water. And all of a sudden about a third of my clinical service is patients with oligometastatic disease.

And it's not just PSMA PET. Axumin® (fluciclovine) PET is now FDA approved for use in the biochemical recurrence setting and reimbursed by Medicare. And that itself also contributes to what we're seeing in terms of increases in the oligometastatic patient space. And what's clear though, is that regardless of what PET imaging modality you use, whether it's fluciclovine or gallium-68 PSMA PET, these imaging modalities can be used to detect extra pelvic disease in patients with PSA recurrences. And so, here on the left, what I want to point out, is the detection of extraprostatic or extra pelvic disease as a function of rising PSA. And not surprisingly, and what you can see is that as PSA levels rise, we start seeing a greater prevalence of prostate cancer, metastatic disease, outside of the pelvis.

And not only can PSMA PET identify these oligometastatic lesions, but it can actually identify them at low PSA levels. And so, this is a graph showing the UCSF experience using PSMA PET at the time of recurrence. This was one of our early reports, and this was in 125 men with biochemical recurrence after prostatectomy with low PSAs, meaning PSA is below 2.0. Over half of them had a lesion detected on PSMA PET, even at low PSA levels, 38% of them had a lesion outside of the pelvis. And as you can see, there's a faint striped area in all these curves, and it turns out that 30% of patients had a lesion outside of what we would have treated with a standard radiation field. And so, what you can see is that, even at low PSAs, PSMA PET can pick up a disease that we didn't see previously.

It's not just PSMA PET that's increasing our detection of oligometastatic disease. Genomic classifiers are becoming more prevalent in use in the context of prostate cancer, particularly in the post-surgical space. And so what we did at UCSF was we looked at 91 patients who had both genomic testing with the clinically available test Decipher®, and also had had PSMA PET at recurrence. And what we found was a high Decipher® score was associated with PSMA PET-avid nodal disease. So here, what you could see on the left of panel B, is patients who have a high-risk Decipher® score, or genomic classifier (GC) score, you can see a lot more nodal disease, and also distant nodal disease, compared to patients who had a low Decipher® score. And what this means is that, since this Decipher® test is already reimbursed by Medicare, it's probably going to trigger increased use of PSMA PET, which will trigger increased detection of oligometastatic disease.

So, I think the first conclusion we can make is that the increasing use of advanced PET imaging has led to the increased detection of oligometastatic disease. And so having discovered this oligometastatic disease, or having been able to identify this, the next question should be, what is the best treatment approach for oligometastatic disease?

And so, I want to actually touch upon this paper that was published in Nature by Steve Bova's group from Hopkins. And what he did was, he took a number of patients who had passed away, unfortunately from prostate cancer, and undergone autopsy and basically obtained samples of all the different metastases and sites of prostate cancer in those patients, and did deep genomic sequencing to try to study which tumors had given rise to which other tumors. So he had looked at lineage tracing, evolutionary trajectories based on genomics.

And his main findings were that, number one, both the primary cancer, meaning the one in the prostate, and existing metastases can seed new metastases. But it turns out that the principal mode of spread was from one metastasis seeding another metastasis. And therefore, based on this, one could argue that to cure oligometastatic disease, one might need to ablate both the primary tumor as well as every metastasis that you can see, assuming that there's a limited number.

And so when I think about the management of oligometastatic disease, I think about three main components. Number one is prostate-directed therapy, meaning treatment aimed at the prostate itself. That could be surgery or radiation. The second is metastasis-directed therapy, which typically means radiation to the sites of the limited metastases. And the third is systemic consolidated therapy, meaning hormone therapy and potentially more hormone therapy. And today I'm going to largely touch upon the first two, and just briefly touch upon the last one.

Prostate-directed therapy, it turns out that there was recently a large Phase III study reported, STAMPEDE Arm H, and it was a randomized trial of radiation versus no radiation to the primary tumor in men with newly diagnosed metastatic prostate cancer. It was a large study of over 2,000 patients. And in this cohort, about 40% of them had low metastatic burden, which would be more consistent with the oligometastatic state. And here are the main findings from this particular trial. Number one, what it showed was that radiation of the primary tumor improves outcomes for prostate cancer patients with low metastatic burden. So here, what you can see is overall Kaplan-Meier curves for overall survival in the top row, and for failure-free survival in the bottom row, broken down by patients with low metastatic burden in the first column, and high metastatic burden in the second column.

So you could see that radiation to the primary tumor had no benefit in either of these endpoints with patients with high metastatic burden, but it improved overall survival with a hazard ratio of 0.68, and a strong p-value for patients with low metastatic burden and also had significant improvements in failure-free survival. So based on this, I think the standard of care for patients with oligometastatic disease now includes some kind of treatment to the primary, most often radiation.

There is an ongoing study being conducted in the United States by the SWOG cooperative group. And this is a randomized Phase III trial of standard systemic therapy plus/minus definitive treatment to the primary tumor in patients with metastatic prostate cancer, being led by Brian Chapin. This is actually very similar to the study I just showed you, but instead of mandating radiation to the primary, most of the patients in this particular study are undergoing surgery. They're also allowed to have radiation as well. But this will potentially define whether surgery can have the same effects on the primary tumor in patients with oligometastatic disease in terms of improving survival, as radiation has been shown in the STAMPEDE study.

At this point in time, I'd like to touch upon the second aspect of treatment for oligometastatic disease, and that is what we term metastasis-directed therapy. And this usually means radiation aimed at the few spots of metastasis. There are two randomized Phase II studies in this area. The first is the STOMP trial, and the second is the ORIOLE study, and I'm going to discuss both of them.

The STOMP trial was a randomized study, this was run out of Belgium by Piet Ost and his group. And everybody in this study underwent choline PET. Those patients who were detected to have oligometastasis were randomized to either arm A, where they got radiation or surgery to all the different sites of metastasis. Or arm B, where they actually just underwent surveillance. The primary endpoint for this was ADT, or androgen deprivation therapy-free survival. And there were specified reasons to start the ADT, and they also looked at PSA recurrences.

Here were the results. The main finding was that metastasis-directed therapy improves biochemical recurrence-free survival. And so here you can see a waterfall plot on the left. Those patients who got surveillance are shown in red, those patients who got metastasis-directed therapy are shown in blue. And the Y-axis represents the best PSA response in each patient. Each column represents a different patient. And what you can see here is that there's a lot more blue on the right than on the left. A lot more red on the left than on the right, suggesting that metastasis-directed therapy causes better PSA responses. When you look at Kaplan-Meier curves for biochemical recurrence-free survival on the right, you can see that there was an improvement for metastasis-directed therapy in this particular endpoint, even though this was a small study.

Overall, I want to point out that 75% of patients who received metastasis-directed therapy had a PSA decline. Now, remember the primary endpoint of this study was median androgen deprivation therapy-free survival. It was 13 months in the surveillance arm, 21 months in the metastasis-directed therapy arm. The p-value was 0.11. So it doesn't mean statistical significance scores, the primary endpoint. But it did show this improvement in PSA recurrence-free survival.

The ORIOLE study was another study that randomized patients with oligometastatic disease to either observation or stereotactic ablative radiation to the sites of metastatic disease. The difference between the ORIOLE study and the STOMP study is that, whereas on the STOMP study everybody underwent choline PET for detection of oligometastatic disease, in the ORIOLE study, the staging was based on CT or bone scan or conventional imaging. And so what you can see here is that the patients who were randomized to the radiation arm, radiation to the sites of detected metastasis, had a better progression-free survival than patients who were put on the observation arm with a hazard ratio of 0.3, quite significant.

What was interesting about the ORIOLE study is, remember people were staged for treatment based on conventional imaging with a bone scan and CT scan. But the majority of the patients who received radiation also underwent a blinded PSMA PET scan, obtained at baseline and also at day 180. And so what this means is that, since patients were treated based on the conventional imaging, there was actually variable coverage of occult PSMA radiotracer-avid lesions among the patients treated with radiation. And so it turns out 19 patients had all their sites of disease that were detected on PSMA PET treated, and 16 had only some of the sites detected on PSMA PET treated with radiation. The other ones didn't show up on the conventional imaging and so were never planned for.

What you can see is that the patients who got total treatment of all the different spots of metastases detected by PSMA PET, these are the ones in blue, they actually did much better in terms of progression-free survival in the patients who had some untreated lesions. And so what this suggests is that you should use PSMA PET, you should treat what you can see in patients with oligometastatic disease.

I want to end with a tale of two patients that I saw recently. Patient 1 was not originally a patient of mine, but he underwent a prostatectomy in 2007. He had a PSA recurrence treated with salvage radiation and four months of androgen deprivation therapy. That was back in 2013. And then in 2017, he presented to me with oligometastatic disease in his left pubic ramus, as you can see here, with a slowly rising PSA at 1.3. He had no other detectable sites of disease. Now, what happened was that I went back and looked at his radiation planning scan from 2013, and lo and behold, I could see his site of oligometastasis, even back then four years ago. And I could see that it was still the only spot I could see on a PSMA PET scan from 2017. So this patient had a single detectable site of metastasis, despite almost no treatment for over four years, had no emergence of additional metastasis during this period. This patient had very stable oligometastatic disease.

Now, I had a second patient roughly, I think, at the same time as the first patient, who was also post-prostatectomy, also treated with salvage radiation and short-term androgen deprivation therapy for PSA recurrence. And he also had a single spot in his left pubic ramus, and I radiated the spot. And then basically a month later, his PSA continued to rise. We imaged him, and now he had four spots. So it turns out that the spot I radiated, you can't tell here, the intensity on the PSMA PET went down, but the problem is he had had three other spots in the same area as well.

And so I think the key point to realize is that not all oligometastatic disease is the same. The first patient I showed you, what we saw was all he had. But in the second patient, what we saw was just the tip of the iceberg, and he had a lot more disease that emerged after we radiated the tip of the iceberg. And so for the first patient, I think we should think about intensification of local therapy for the primary metastases. And for the second patient, we should think about intensification of systemic therapy.

And it turns out that there are a number of ongoing Phase III trials intensifying systemic therapy for patients with high-risk localized disease by conventional imaging. And I bring up this patient population because if you actually were to apply PET imaging to this particular patient population, a fair bit of them would actually have oligometastatic disease. And so we can see that a variety of studies have shown potential benefits to abiraterone or docetaxel in the context of this patient population. And I'm betting that it's the subset of patients who have oligometastatic disease that are most likely to benefit.

So I'd like to end with three conclusions. The first conclusion is that oligometastatic disease is increasingly diagnosed due to advances in molecular imaging. Second, treatment intensification approaches involve local therapy to the primary tumor, metastasis-directed therapy, and also intensification of systemic therapy and randomized clinical trials are needed to determine the importance of each. And lastly, ultimately better predictors of "less aggressive" versus more aggressive oligometastatic disease are needed to help guide treatment approaches.

I'd like to thank our team at UCSF and also collaborators from Hopkins, from Belgium, and from the Peter Mac Cancer Centre. Thank you.