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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so excited to talk today with a good friend and colleague Dr. Mary-Ellen Taplin, who is a Professor of Medicine at Harvard Medical School, as well as being a GU Medical Oncologist at the Dana Farber Cancer Institute. This year, she discussed the VISION trial at ASCO 2021. We are so pleased to talk with you about your considerations for the VISION trial. Thank you so much, Dr. Taplin.

Mary-Ellen Taplin: Thank you, Alicia. It's a pleasure to be here today.

Alicia Morgans: Wonderful. So Mary-Ellen, let's start by just having you set the stage. Can you talk a little bit about the prostate cancer therapeutic landscape in 2021?

Mary-Ellen Taplin: Certainly, Alicia. We're very fortunate in prostate cancer to have many therapies approved for castration resistant prostate cancer. I think up to about 10 different treatments at this point. But as you know, while they can work in sequence, usually it's the first line treatment for metastatic castration resistant prostate cancer that has the longest response rate and then sequential therapies after that, tend to benefit patients less. But we're fortunate and I'm thrilled that the VISION trial was a positive trial and gives us another treatment in our armamentarium against this life-threatening disease.

Alicia Morgans: Absolutely. I think especially important where the inclusion of patients who actually had really advanced, heavily pretreated disease, where there's been a paucity of options. What are your thoughts on the patient selection for this trial and the patient characteristics?

Mary-Ellen Taplin: That's a really important point to focus on. So the investigators in this trial had to decide on eligibility criteria based on PSMA pet imaging, and they chose to have what I would call a minimum positivity criteria. Exactly what it was, was patients had to have at least one PSMA positive metastatic lesion and no negative lesions that I would say were a moderate size. So for bone metastasis, they couldn't have negative lesions that were greater than a centimeter and for lymph nodes greater than two and a half centimeters, and for organ metastasis greater than a centimeter. So in fact, patients could have quite a fair amount of diffuse and small non PSMA positive lesions. In fact, a number of patients who screened for this trial who were positive was 87%. So it was quite a high positivity rate. They could have swung the other way and had more strict criteria such as been done with some of the Australian trials, but this is what they chose to do.

I think it's very reasonable, but the data has to be interpreted in the context of that. And I would say, for me, it brings up the question of, do we even need to have the PSMA pet imaging be part of the criteria for patients to be treated with this agent if 87% were positive and it was a very positive trial on both of their primary endpoints. Theorizing, it likely would have been a positive trial, even taking all comers. There's similar treatment in prostate cancer where we don't screen, comes to mind for me, which is androgen deprivation therapy. In breast cancer, they screen for estrogen receptor, progesterone receptor positivity, but we don't do that in prostate cancer. And the response rate is 90% and we treat everybody. So that's just a thought, but I think, when this is approved, the label will say some imaging criteria will need to be met.

Alicia Morgans: Yeah. I think that's a great point, especially in a patient population that's been so heavily pretreated with few treatment options, and also because, I would argue that what if a patient had a lymph node that was two and a half centimeters and they might've been excluded from the trial, but they had an overwhelming burden of PSMA positive disease elsewhere. Would they not benefit from that treatment? I'm not sure. I'm sure it's a continuum. And I at least am appreciative that the majority of patients were included that does help at least when we're talking with our patients.

You did see and point out though that similar to other trials, this is certainly not an issue specific to VISION. There seem to be a bit of a lack of diversity. Can you comment on that?

Mary-Ellen Taplin: Yeah. As you know, Alicia, prostate cancer disproportionately affects black Americans and men with African ancestry in general, and it's more aggressive and more lethal in this population. And despite that, the enrollment in this trial was only 6.6% black or African Americans, 2.4% Asian. So I just personally think we need to get better as a field, make a commitment, perhaps having a target level of accrual for certain populations and stick to that. At the Dana Farber, our institution in the wake George Floyd situation and all the atrocities that are happening in the country is putting a very, very significant commitment to increasing access to the Dana Farber for all the communities around us and recruiting more staff and faculty from underrepresented population. So, if not now, when? I think we really need to get serious about doing this. We've all been talking about it for a very long time.

Alicia Morgans: Well, thank you for continuing to have that conversation and bringing it up because, in light of the excitement around a positive trial, it's always important to remember that there are some people who were missing from this and some people that we need to continue to include, reach out to, and ensure have access just as you said. So thank you for bringing that up.

Let's transition a little bit to thinking about the primary outcome survival, and of course there were multiple secondary outcomes also positive. What are your thoughts on the improvement in overall survival and what did you discuss in your discussion for ASCO?

Mary-Ellen Taplin: Yep. So it was very positive trial in terms of improvement in median overall survival. The improvement was four months, from 11.3 months to 15.3 months. So that represented a 40% reduction in median time to death. Curves come nicely apart. It's a very positive trial. That was based on all randomized patients, 831 patients. I have to say, from my perspective in the clinic and like your yourself and many of your listeners, meeting with patients and talking to them about new treatments, I was disappointed. This improvement really dovetails with everything we've seen in prostate cancer for the last 15 years. First you have to look at the control group and did the control group in the trial, was it similar to other control groups? And in fact, if you look at the PROfound trial, L Simcoe, Tropic, Affirm, Cougar 301, the control groups all ranged from 11 to about 13 months. So the VISION control is right in there at 11 months.

And the overall survival of all these trials, ranged from a low of 2.4 months with cabazitaxel to a high of 4.8 months with Enzalutamide. But really the median is right around four months, same as the VISION, including radium. So I was disappointed. And the reason why I was disappointed is because the pharmacodynamics of this compounder, excellent. The PSMA target is present and it's measurable. There was a very high PSA response in the VISION trial and even a moderate resist response, which we don't usually see in advanced prostate cancer trials. But despite that, patients responded but became resistant fairly quickly. And I would theorize that the possible reason for that is under dosing of the metastasis with the radiation.

In the context of my research over the years, I've looked at a lot of metastatic prostate cancer in the bone and bone marrow. And over the years, as you'd expect I guess, since the nineties, until now, the volume and pattern of these metastases has changed greatly, probably because of the use of biophosphonates, but no longer do we see sort of chunky metastasis. We see these little nests of prostate cancer cells in the bone and bone marrow surrounded by dense stroma in most cases. And that's exactly the type of spread of cancer that, from my reading, it's difficult to get the radiation to penetrate, imprint in.

I imagine that it would be like dosing a prostate with half the radiation that we give today. You get an effect, but it's transient because you're not killing enough cells. So, I think there's a lot to learn from this work and I don't have all the details, obviously, about dose rate and uniformity of delivery and nuclear concentration and all the important radio biological characteristics. But I think, and I would hope, that there's a lot to learn from this trial. It's just going to be a start and that, over time, the experts will be able to improve the response rate, with either different types of dosing or combinations with this agent or development of new agents.

I believe there's about 30 other radiopharmaceuticals in some stage of early development at this point in time, not all for prostate cancer, but the field. One of the very positive aspects of this trial and this team is that the enthusiasm around this compound and the positive readouts, both from this trial and some work done in Australia, has really opened the door for the blossoming really of a radiopharmaceutical treatment in cancer. And I think that's only going to benefit our patients.

Alicia Morgans: I would definitely agree. And talking about patients, I wanted to make sure you had the opportunity to comment on end points that you think are probably really important to them. I know you spoke about progression-free survival. Can you tell us your thoughts on that?

Mary-Ellen Taplin: Yeah, I can, Alicia. I think all of us that actively treat patients, we know how important it is for a patient. They walk in the door, they're nervous, they're scared, they meet with us. And if we can tell them, "Your PSA's going down, your scans are stable or better," that patient and their family leaves the office with a new spring in their step. They feel like they have horizon. So I personally believe the radiographic progression-free survival endpoint is a very relevant and important clinical endpoint. The RPFS in this trial was improved by 5.3 months, which represented a 60% improvement compared to non-chemotherapy standard of care. So it was a very positive point and I don't think it can be under appreciated that this means a lot to patients.

Alicia Morgans: Absolutely. And one of the things I'd love to wrap up with is that this, as you mentioned, positive trial and a really opening up the door for future work. Where do you think the field goes next? Where does lutetium go after VISION?

Mary-Ellen Taplin: Well, any treatment in cancer, any cancer, not just prostate cancer, works better if you give it earlier in the context of less resistant disease and less volume of disease. It's a standard tenant of oncology. So, it just makes sense to look at this compound earlier in prostate cancer, either in less advanced MCRPC or non castration resistant disease, or even non metastatic disease. And I think those trials will be done. I think, it would make sense to believe that this treatment will work better in earlier, but it is a DNA damaging treatment, like all radiation, and we'll need to make sure that patients who have longer life expectancies are safe, that they don't develop second malignancies. There was not a signal of second malignancies in the VISION trial related to treatment. But if you use it in patients who have a five-year life expectancy instead of a one-year life expectancy, we're going to just need to do this work very carefully.

Same for combination therapy. I think there's a lot of promise for combining lutetium PSMA 617 with other treatments. It could be standard radiation. It could be immunotherapy. It could be PARP inhibitors. A lot of those trials are planned or launching. And I think they will be very important. I think this particular treatment is here to stay. I think we need to learn how to use it optimally in terms of patient selection and stage state of disease, but that's the fun of what we do and what keeps us all excited about new discoveries in prostate cancer, in clinical research and prostate cancer.

Alicia Morgans: I agree. And of course the promise that these combinations or earlier use may have for patients inspires us too. Well, thank you so much for sharing your thoughts and for really reminding us of all the things that we have to look forward to in our clinical practice, as we hopefully will have access to lutetium at some point in the near future, based on the results of this trial. Of course, also for reminding us that not everything is perfect and one trial of course cannot answer every question. So there is so much more for us to look into, so many more patients that we need to reach and investigate. And then of course, combinations that hopefully will continue to make a difference for our patients. Thank you so much for your time and your expertise today, Mary-Ellen.