Alicia Morgans: Hi, this is Alicia Morgans, Medical Oncologist at Northwestern University. I am talking today with Dr. Phuoc Tran, who is an Associate Professor Of Radiation Oncology at Johns Hopkins University. Thank you so much for speaking with me today.

Phuoc Tran: Oh, it's my pleasure, Alicia. Thank you for having me.

Alicia Morgans: Of course. So we've worked together on other projects and I'm always so impressed with your ability to really get some studies for radiation oncology together that really I think will change the course of disease for men with prostate cancer. And you're working on a few right now that I think are really right along this vein and I'd love to talk to you about them. Let's start though with the first one, which is SALV-ENZA. And I'd love to hear you just explain what's the purpose of this trial in the salvage setting for men who have had a prostatectomy before. And really, what's the scheme of the study? What could men expect from this trial?

Phuoc Tran: Absolutely. Thank you for allowing us to share this information. So just to set the backdrop, about 30,000 men in the United States die every year of metastatic, what's known as castration-resistant prostate cancer, where the prostate cancer no longer responds to hormonal therapy. If we look at those men, their whole history, only a small number or minority, about 10,000 of those men actually are diagnosed with metastatic disease upfront. The majority, 20,000 or so actually at one point in their disease process had localized and potentially curable disease and they underwent surgery, primary therapy with surgery and radiation.

Unfortunately, as we know, those therapies are not always successful and in the case following surgery, those men with positive margins or what's known as an extracapsular extension or seminal vesicle invasion, have a higher propensity to undergo disease relapse in the form of a rising PSA. And that happens, depending on those factors, as little as 20% of the time or as many as 80% of the time.

But if we take it as a whole, about half of guys in that situation will have a biochemical failure. And those patients, if not treated appropriately, will then progress on to having metastatic disease, which we will talk about a little bit later. And then eventually after treatment with hormonal-directed therapies will develop castration resistance and then ultimately succumb to their disease.

So it was our hope, the whole genesis behind these studies, these salvage treatment studies was, "Well, can we try to intervene in an earlier stage where the patients are still potentially curable?". And there is a known set of therapies, salvage therapies, in particular, salvage radiation where radiation is directed towards the areas in the pelvis where we believe that a residual prostate cancer still resides that are known to be potentially curative therapies in this biochemically recurrent setting. Bottom line though, those salvage therapies only work in about half of patients.

So we would like to improve upon that data. And so that is where SALV-ENZA was born. So SALV-ENZA is a Phase II randomized placebo-controlled trial of salvage radiation, which is standard of care, then randomizing either to placebo or the oral next-generation antiandrogen drug known as enzalutamide. It's a 122 patient trial, one-to-one randomization where patients are given either placebo or enzalutamide for six months. And the salvage radiation is integrated within that six month period. And then the patients are followed for a period of up to two years with the primary endpoint being something known as progression-free survival or failure from PSA failure.

And we are about two thirds of the way through the trial. So about 82 patients have been enrolled through a number of sites. The lead site is here at Hopkins and then we have some satellite sites out in DC and our suburban areas. But we also have a number of other academic institutions that are involved with SALV-ENZA, namely University of Michigan, Wayne State Karmanos, University of Chicago, the University of Texas Southwestern down in Dallas and then Oregon Health and Sciences University out west in Portland as well as the University Of Indiana in the midwest.

Alicia Morgans: That's great. And if a patient has this rising PSA after prostatectomy and is potentially eligible, is there a PSA limit that the patient would have to meet or is this all-comers? And the reason I ask this question is there was some interesting data from the RTOG Study 9601, the Shipley's study, that showed that if patients who have a rising PSA post-prostatectomy get salvage radiation, they can be helped by about two years of bicalutamide. And I think we're all interested in ensuring the best outcomes for our patients, but two years of bicalutamide could be over treatment for some, it could be under treatment for others. And it also has its own side-effects and risks associated with it. So it's not perfect. And I love that this trial is trying to better define a duration maybe that is meaningful to patients. Maybe with a drug that's a little better tolerated than high-dose bicalutamide. And so really thinking about who are those patients to get back to that question, is there a PSA cutoff? Is that people with low PSA, high PSA, who are these patients?

Phuoc Tran: That is an excellent question. And so I'll touch on a few points. but the eligibility criteria for SALV-ENZA, you have to have had obviously a radical prostatectomy, either margin positivity or a Gleason of eight. Any one of those. So Gleason grouping now would be four and any one of those will make you eligible for the trial with a rising PSA of at least 0.05 and then confirmed on a subsequent test a month later.

So early on in our trial, we did have a higher cutoff of PSA failure of 0.1, but there has been a trend over the last few years of using ultra-sensitive PSAs. There's also the data that you mentioned, Alicia, from RTOG 9601, Dr. Shipley's trial, and the subgroup analysis, which obviously is hypothesis-generating at best suggested that patients who have a PSA of 0.7 or less are not the patients that benefit from these two years of high-dose bicalutamide.

Now, that needs to be confirmed further and there'll be data coming out at our ASTRO meeting, our American Society of Radiation Oncology meeting this year that's going to help further substantiate that notion that patients with a PSA 0.7 or less really are not ones that benefit from high-dose bicalutamide for two years. So because of that trial, because of that data I mentioned, we only allow patients who have a PSA of 0.7 or less in our trial.

Alicia Morgans: Great. Thank you so much for clarifying that. And for any patient or any clinician who meets these criteria or thinks that they may, we would encourage them to click on the link that's going to be on the website where we have this podcast. Certainly can reach out to the Hopkins clinical trials group at the cancer center there or even just Google "SALV-ENZA for prostate cancer" and I bet you'll find the information on clinical trials.gov that will give you information about how to potentially connect with the study team and see if going to one of these sites to consider enrollment would be for you.

Before we wrap up though and with you, Phuoc, I'd love to hear some information from other ongoing trials that I think are of high interest to those men with prostate cancer in our community and certainly their clinicians, the ORIOLE and RAVENS trials that are in the works. Can you tell us a little bit about those?

Phuoc Tran: Oh yeah, absolutely. So going again, continuing on the spectrum of disease, going from patients who have been diagnosed originally with what is thought to be localized disease and then either having surgery or primary radiation and then, unfortunately, failing those therapies and then having biochemical failure and either having a salvage therapy such as salvage radiation or cryotherapy or not. We know that after those patients progress from having just biochemical failure to then, in many practices, patients like that or you know they're getting their PSAs very regularly and some people use a cut point of PSA, you know, two, five, ten, start really intensively imaging with conventional imaging such as a CAT scan or a bone scan.

Those patients then, unfortunately, will develop metastases. And what we know from a number of studies, some of them prospective, that examine this is that many of those men actually when they develop their first signs of metastasis, they develop only a few metastases.

So one, three, five and that is the majority, maybe upwards of three quarters or two-thirds develop what's called oligorecurrent disease. So oligo is just a fancy word for few sites of disease and recurrence obviously means recurrence. So when patients progress through that period of being biochemically recurrent to having metastatic hormone-sensitive disease, it's usually through this oligorecurrent paradigm.

There is data that suggests from people out in your neck of the woods, Alicia, that originally coined by Dr. Sam Hellman and Ralph Weichselbaum, who are at the University of Chicago that this theory of metastasis, that it is a spectrum of disease exists and that if you catch patients that are early in this spectrum or present in a spectrum where they have only a few metastases, then perhaps local therapies such as surgery, radiation, directed at those metastases can change the natural history of that patient's disease.

And so we wanted to answer this in a robust fashion. There've been a number of retrospective data looking at this type of oligometastatic patient and local therapies or metastasis-directed therapy. So we opened up a trial here a number of years ago which looked at exactly that patient population, oligorecurrent patients, three or less metastases, reasonable PSA doubling time, which is a known prognostic factor to try to select patients who really needed treatments of 15 months or less.

And we randomized those patients to either an observation period versus metastasis-directed therapy in the form of this intense type of radiation called stereotactic ablative radiation, SABR, or stereotactic body radiation, SBRT. It was a two-to-one randomization to the SABR versus observation and the SABR was directed to all sites of conventionally detected metastases. The patients on the observation, if they progressed by PSA or imaging in six or 12 months could be crossed over to the SABR arm.

It was a 54 patient trial, so 36 patients to SABR, 18 to observation. That accrued about a year ago and the followup is completed. The report is going to hopefully come out this year, but it's consistent with a few other trials that have now come out in the space that this concept of the oligometastatic state is potentially real and the metastasis-directed therapies can be beneficial.

The follow-up trial, which is actually activated and we'll hopefully enroll our next patient this week, is a trial called RAVENS and it's a play on the sports teams we have here in Baltimore. The first trial I spoke about was ORIOLE. The second one, which is RAVENS, which is our football team, plays on the fact that we have a sense that there is a signal here that metastasis-directed therapy or SABR can benefit patients in this oligorecurrent setting. So the next trial is going to look at adding in a radiopharmaceutical known as radium-223 or Xofigo®.

And the way that Xofigo® works is that it's a calcium emetic, meaning it looks like calcium, but also that Xofigo® or radium-223 goes to the areas of bone turnover as in the case of blastic lesions in prostate cancer, bone metastases. And it goes to the areas where the metastases are occurring and then gives off what's known as an alpha particle, which is a very unique type of radiation, very injurious, causing a lot of damage to the cells locally. But fortunately, it only goes a few cell lengths. So kind of a smart bomb if you will, killing just the cancer cells and leaving the healthy tissue even in the bone marrow intact.

So the RAVENS trial is randomization between SABR and then either SABR alone or SABR plus the Xofigo®. And the reason why we decided to go with that strategy is because when we looked at the patterns of failure from ORIOLE, which is the trial of observation versus just a SABR, what we found is that many times patients would fail in areas in the bone that were not present at the original SABR treatment. Meaning there were likely micrometastatic sites that were there, but that we couldn't see and then they developed into full-blown macroscopic metastasis.

So the idea behind RAVENS is that we'll be able to potentially target these microscopic metastases at the time that we give the SABR and hopefully offer the patients more time, not only from hormones but from disease recurrence. That is a 64 patient trial, randomizing one-to-one to SABR versus SABR plus Xofigo®.

Alicia Morgans: That's great. And I think that I just really appreciate that you guys are trying to move the bar, integrating new therapies, new approaches that we really have some evidence from other studies at least may be helpful in these contexts and kind of making sure that we have the most up-to-date radiation therapy to go along with all of the updated systemic therapies that we have and certainly surgical approaches. So thank you again for pushing the needle on this, Dr. Tran, and I appreciate your time today.

Phuoc Tran: It's my pleasure.